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Cold Exposure & Other Mild Stressors for Increased Health & Longevity

Cold Exposure Exercise Fasting UCPs UCP1 UCP3 FGF21

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#221 Dean Pomerleau

Dean Pomerleau
  • Lifetime Member
  • 2,458 posts

Posted 18 April 2016 - 11:28 AM

Cold Exposure Shrinks and Browns Visceral Fat Deposits

 

All,

 

Recall in the Beige is the New Brown post above, we learned that virtually all of what we understand to be brown adipose tissue (BAT) in humans is actually beige (otherwise known as brite) adipose tissue which is composed of cells that were formerly white fat (WAT) which has been "browned" through the catecholamine-mediated addition of mitochondria, UPC-1 receptors and other cellular machinery to enable them to burn calorie for heat rather than store calories for later.

 

With that background, I call your attention to [1], in which researchers subjected two groups of ad lib-fed, singly-housed male mice to 3 weeks of either thermoneutral temperature (30°C = 86°F) or to cold exposure (4°C = 39°F), a temperature which I would characterize as 'bone-crushingly' cold, even for a human, to say nothing of mice.

 

What they found can be summarized in the graphic below. It shows different fat deposits dissected from (unfortunate ☹) mice exposed to the two housing temperatures:

 

VM2YsG5.png

Ignore the green box around rpWAT fat deposit for now - that will become important in my next post, which focuses on a study even cooler than this one...

 

For now simply observe just how dramatically cold exposure changes the size and color of both BAT and visceral WAT deposits.  As can be seen from the tissue samples in the upper right corner, the various deposits of "native" or "real" BAT are generally bigger and browner in the 4 °C group (right) than the 30 °C group (left). This is especially evident in the classic interscapular BAT (iBAT) deposit from the mice's neck region - much bigger and browner at 4°C than 30°C. Of course this is to be expected after this sort of chronic, extreme cold exposure.

 

All the rest of the inserts are various visceral white adipose tissue (WAT) deposits. Remarkably, you can see is that virtually all of them are smaller and browner after 4°C housing compared to 30°C, representing increased mitochondrial content and therefore thermogenic potential. In short, as a result of (albeit pretty "bone-crushing") cold exposure, all these (unhealthy) visceral WAT deposits are shrunk and exhibit the type of browning characteristic of "beige" fat cells, which is the only type of thermogenic fat that adult humans possess - as discussed in the Beige is the New Brown post above.

 

Recall I speculated in that post about how the fact that adult humans don't have much if any true BAT, but only thermogenic beige fat, might explain (at least in part) the mystery of the missing calories - namely what's burning all the calories, and generating all the heat in humans if our total BAT deposits are only at most a few ounces? The solution - If lots of different white fat deposits get a little bit browner, they could all be engaged in thermogenesis, burning calories and generating heat.

 

While this study [1] was in mice and so can't definitively determine what's happening in humans, it supports this speculation - since it shows dramatic browning of lots of different, large visceral white fat deposits as a result of cold exposure.

 

Perhaps as importantly, I'm sure everyone knows that visceral fat (otherwise known as abdominal fat) is toxic to human health and longevity. Excess subcutaneous fat (the kind that forms "love handles") isn't that bad for you. But excess visceral fat is associated with systemic inflammation, insulin resistance, high cholesterol and triglycerides, cardiovascular disease and diabetes.

 

This browning of white visceral fat might explain another curious side effect of cold exposure - improved insulin sensitivity and glucose clearance, as observed by me (here and here), Gordo (here and here) and in controlled studies of rodents (hereherehere, here, and here) and people (here and here).

 

Again, while this was a study only in mice, it suggests a very direct way cold exposure in humans could both be burning extra calories and promoting health/longevity, independent of BAT, and independent of muscle thermogenesis or shivering (i.e. Michael's jiggling pecs), by shrinking and browning visceral fat deposits.

 
--Dean

 

-----------
[1] Am J Physiol Endocrinol Metab. 2015 Jun 15;308(12):E1085-105. doi:
10.1152/ajpendo.00023.2015. Epub 2015 Apr 21.
 
A stringent validation of mouse adipose tissue identity markers.
 
de Jong JM(1), Larsson O(2), Cannon B(1), Nedergaard J(3).
 
 
The nature of brown adipose tissue in humans is presently debated: whether it is 
classical brown or of brite/beige nature. The dissimilar developmental origins
and proposed distinct functions of the brown and brite/beige tissues make it
essential to ascertain the identity of human depots with the perspective of
recruiting and activating them for the treatment of obesity and type 2 diabetes. 
For identification of the tissues, a number of marker genes have been proposed,
but the validity of the markers has not been well documented. We used established
brown (interscapular), brite (inguinal), and white (epididymal) mouse adipose
tissues and corresponding primary cell cultures as validators and examined the
informative value of a series of suggested markers earlier used in the discussion
considering the nature of human brown adipose tissue. Most of these markers
unexpectedly turned out to be noninformative concerning tissue classification
(Car4, Cited1, Ebf3, Eva1, Fbxo31, Fgf21, Lhx8, Hoxc8, and Hoxc9). Only Zic1
(brown), Cd137, Epsti1, Tbx1, Tmem26 (brite), and Tcf21 (white) proved to be
informative in these three tissues. However, the expression of the brite markers 
was not maintained in cell culture. In a more extensive set of adipose depots,
these validated markers provide new information about depot identity. Principal
component analysis supported our single-gene conclusions. Furthermore, Zic1,
Hoxc8, Hoxc9, and Tcf21 displayed anteroposterior expression patterns, indicating
a relationship between anatomic localization and adipose tissue identity (and
possibly function). Together, the observed expression patterns of these validated
marker genes necessitates reconsideration of adipose depot identity in mice and
humans.
 
Copyright © 2015 the American Physiological Society.
 
PMID: 25898951

There will never be peace in the world while there are animals in our bellies.

#222 Dean Pomerleau

Dean Pomerleau
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Posted 19 April 2016 - 05:37 PM

Cold Exposure Shrinks and Browns "Love Handles" (Subcutaneous Fat) Too!

 

OK, I lied in my last post when I said my next post would be about the visceral fat deposit called rpWAT. That will have to wait until my next post - since this study [1] is a natural follow-up.

 

Recall in this post we saw that adult humans have only thermogenic "beige" fat, rather than true "brown" fat, and in the last post we saw that chronic cold exposure can convert visceral white fat cells to beige, at least in mice.

 

But in that post, no mention was made of subcutaneous (SC) fat (the kind associated with "love handles") being influenced by cold exposure. This post remedies that omissions. The research in [1] has a ton of moving parts, with a bunch of mice with different mutations - all to nail down a pretty simple idea and solve a mystery. The simple idea is to prove that cold exposure does indeed turn subcutaneous white fat to thermogenic beige fat. The mystery is how it does it.

 

The reason the mechanism is a bit mysterious is summarized by the authors as follows:

 

In the textbook view of thermogenesis, the sensing of cold
by the neuronal system triggers the sympathetic efferents that
promote the biogenesis and activation of brown fat (Cannon
and Nedergaard, 2011; Lowell and Spiegelman, 2000). Although
this model works well for tissues that are densely innervated by
the sympathetic nerves (Morrison and Nakamura, 2011), such as
the interscapular BAT, it does not explain how cold exposure
results in the rapid remodeling of the poorly innervated scWAT
(Daniel and Derry, 1969; Slavin and Ballard, 1978; Trayhurn
and Ashwell, 1987). In these classic studies, adrenergic nerves
only innervated 2%–3% of all adipocytes in WAT, leading these
authors to conclude that the sympathetic nerves primarily innervate
blood vessels of the WAT (Daniel and Derry, 1969; Slavin
and Ballard, 1978). These older observations thus suggest that
the adrenergic tone of WAT must somehow be amplified during
cold stress to stimulate biogenesis of beige fat.

 

In short, regions where BAT (or the human equivalent, beige fat) is concentrated (e.g. around the neck and shoulders) have lots of "sympathetic efferents" - i.e. nerve fibers coming from temperature-regulating parts of the brain (i.e. hypothalamus [4]) that directly stimulate white fat cells with the neurotransmitter norepinephrine (NE), and this NE stimulation causes them to morph into thermogenic beige cells. The NE also causes the differentiation of adipose stem cells into 'native' BAT cells in rodents (but probably not humans).

 

But "love handle" fat (subcutaneous fat = SC fat = scWAT) doesn't have the advantage of many direct connections from the sympathetic nervous system, so where does the NE come from to turn SC fat to beige? It will turn out to be quite an interesting story, with tantalizing implications for humans. But I get ahead of myself.

 

First, it may not be too much of a big deal for us skinny folks, but burning off love handles is something that pudgy people care a lot about - to put it mildly. So is there really evidence that cold exposure can turn white SC fat to brown? Yes - in spades!

 

In the first of the experiments in [1], experimenters subjected mice to three different housing temperatures for only 48 hours - thermoneutral (30°C), standard lab temperature (22°C), and very cold (5°C). Then they looked at cells from subcutaneous fat deposits for sign of browning. And boy did they find it! Take a look at the first three bars of this graph from [1], which shows the expression of uncoupling protein 1 (UCP1) in SC fat of mice from the three different housing temperatures:

 

gMYLW57.png

 

The first bar is the UCP1 expression in the thermoneutral mice, and is defined to be height=1 - it is the baseline. At a housing temperature of 22°C, the UCP1 expression in SC fat is 19x higher than at thermoneutrality. But look at the 5°C bar - it shows the cold mice had 550x higher expression of UCP1 in the SC fat cells than mice housed at thermoneutrality!

 

The bars with the three other colors are for a mutant mice strain we need not concern ourselves with. The other sets of bars represent the expression of different "thermogenic" genes responsible for either converting white fat to beige or generating heat in beige cells once created. For example "Ppargc1a" (peroxisome-proliferator-activated receptor γ co-activator-1α) is involved with mitochondrial biogenesis [2] crucial for white fat browning. What you can see is that they are all elevated by relatively brief cold exposure.

 

But seeing is believing - so here are pictures of subcutaneous fat deposits from mice at the three housing temperatures, as seen under a microscope:

 

xlGSR8C.png

 

The cells were stained to show the level of UCP1 expression. You can clearly see that as for UPC-1 expression, 5 °C > 22 °C > 30 °C.

 

And the new beige SC fat cells can be seen to be burning a ton of calories, as illustrated in this graph showing the oxygen consumption of isolated SC fat cells from mice housed at 22 °C and 5 °C (data for 30 °C not shown):

 

NZiUqWW.png

 

As you can see, the SC fat of the cold-housed WT mice consumed 4.5x as much oxygen as the SC fat from mice housed at standard lab temperature, as a result of all those extra mitochondria and UPC1 receptors burning calories to produce heat. But note both sets of cells were incubated at the same temperature for this test - so it wasn't simply an acute effect of the 5°C cells being colder during the test. Instead, the mice subcutaneous fat cells became ​intrinsically capable of generating more heat, and burning more calories, as a result of cold exposure and fat cell browning.

 

We could leave it there, with the nice tidy conclusion from this study that cold exposure turns subcutaneous white fat to calorie-burning beige fat. But the story gets even more interesting when we look at the "mystery" mechanism. The authors go through a litany of experiments with different mutant mice strains that overexpress or are knockouts for one gene or another.

 

What they found after a lot of hoop-jumping is summarized in this diagram:

 

M6HYxry.png

 

Basically, it works as follows: Cold exposure causes eosinophils (EOS), a type of white blood cell (WBC) circulating in the bloodstream, to congregate in the neighborhood of subcutaneous fat cells. The EOS cells release Interleukin-4 (IL4), which attracts macrophage cells (M2), another type of WBC, to the same neighborhood and causes them to synthesize and release norepinephrine (NE) which in turn signals the WAT cells to turn beige and start burning calories.

 

Skipping all the mutant mice tests in-between, here is a really interesting test of this pathway the authors did to support their model's validity. They figured that if the above model is correct, then treating normal C57BL/6J mice with Interleukin-4 (IL-4) should stimulate the browning of white fat and alter mice metabolism. Boy did it ever! Here is a description of the experiment and results in the author's own words:

 

Because administration of IL-4 selectively increased beige fat mass in thermoneutral mice, we investigated whether this newly recruited beige fat can ameliorate metabolic dysfunction in the setting of pre-established obesity. For these studies, thermoneutral C57BL/6J mice were fed normal chow (NC) or high-fat diet (HFD) for 10 weeks (Figure 7A). After matching for adiposity (Figure S7A), mice on HFD were treated with vehicle or IL-4 complexes over a period of 14 days (Figure 7A). Remarkably, dual-energy X-ray absorptiometry (DXA) revealed that, compared to vehicle-treated animals, treatment with IL-4 decreased total body mass (∼5.7 g) and fat mass (∼13.5%) without significantly affecting lean body mass (Figures 7B, 7C, and S7B). This decrease in adiposity was also reflected in the smaller mass of scWAT and eWAT (Figures S7C and S7D). Immunoblotting analysis of adipose tissues revealed that HFD feeding decreased expression of TH (∼70%) and UCP1 (∼85%) proteins in the scWAT, which were restored after IL-4 therapy (Figure 7D). This was not limited to UCP1 because expression of the entire set of core thermogenic genes was restored by IL-4 therapy in the scWAT (Figure S7E). Similar increases in expression of TH and UCP1 proteins were observed in eWAT, but not in BAT, of mice treated with IL-4 (Figures 7D and S7F), findings that were confirmed by the histologic examination of scWAT and eWAT of treated animals.

 

Note - the mass of "native" BAT wasn't increased by IL-4 treatment - IL-4 seems to be involved only in the browning of white fat to form beige fat, not the synthesis of new "native" BAT cells. This is fine for humans, since we don't synthesize "native" BAT cells anyway.

 

Also notice, that 10 weeks of a high fat diet at thermoneutral temperatures resulted in obesity and 85% suppression of UCP1 expression in subcutaneous fat of the HFD mice relative to mice fed normal (low-fat) chow, which was reversed by treating the HFD mice with IL-4. In other words, a high fat diet without cold exposure (or injections of interleukin-4) makes mice fat and turns their subcutaneous fat even whiter than normal.

 

Take a look at these graphs showing body mass (left), fat mass (middle left), subcutaneous fat mass (middle right) and eWAT mass (right) in mice housed at 30 °F and fed normal chow (NC), a high fat diet (HFD) or a high fat diet with IL-4 treatment (HFD-IL4):

 

IqjzsNG.pngaesoOTw.png

 

In short, the IL4-treated mice fed an ad lib, high-fat diet for only 14 days lost weight and fat mass overall, rather than gaining weight and fat like the control HFD mice. They especially lost weight in the form of subcutaneous fat and eWAT (more on what eWAT is below) . Not only that, but they also kicked butt in the metabolic health department, as illustrated by improved postprandial glucose control (left), lower total cholesterol (middle) and lower serum triglycerides (right) relative to both high-fat and even normal-chow controls (for triglycerides):

 

RuEfbiS.pngVTja8uT.png

 

What caused all these benefits you ask? Apparently, their dramatically browner subcutaneous fat (scWAT), as well as browner eWAT, or "epididymal white adipose tissue", as can be seen visually in this micrograph of UCP1-stained cells from the subcutaneous and epididymal fat deposits of the three groups:

 

EROnYfY.png

 

You should be asking, what's this new epididymal stuff you're talking about now Dean? Epididymal fat (eWAT) is another one of those unhealthy visceral fat deposits down near the gonads, present in both rodents and humans. You can see it in the lower left of this image I posted yesterday:

 

VM2YsG5.png

Note this graphic was from a different study (PMID: 25898951  - see post immediately above) that also observed shrinking and browning of eWAT in response to cold exposure. And they aren't the only one's to observe this cold-induced shrinkage and browning of eWAT [3].

 

So cold exposure browns the visceral fat deposit called eWAT too. And like subcutaneous fat, this browning of eWAT appears to be mediated by the pathway:

 

Cold → ↑ eosinophils →  ↑ macrophages →  ↑ norepinephrine → browning of white fat cells

 

Are you thinking what I'm thinking?

 

If so, then you are thinking "Hey now, we know something about our own eosinophil and macrophage levels!"  Eosinophil level in the blood is indicated by the EOS measurements as part of the breakdown of white blood cell counts on a standard blood test. And the precursor to macrophages are the "monocytes" measured on a standard blood test as well. 

 

So I checked out my own bloodwork. The second-to-last column is from last December, about a month before starting cold exposure and the last column is from just last month, two months after starting cold exposure. Sure enough, since starting cold exposure both my EOS and monocytes have gone up by a factor of ~3x, from (0.01 → 0.03) and (0.17 → 0.49), respectively. In fact, both my latest monocyte percentage and absolute count are the highest they've ever been since I started documenting my blood tests 16 years ago. Similarly, except for a couple anomalies while suffering from anemia a few years ago, my EOS count is the highest it's ever been as well. Note - neither my monocytes nor eosinophils are elevated in an absolute sense. My monocytes count is in the middle of the reference range now, and EOS count is still quite near the lower end of the RR. But these two types of white blood cells have both gone up a lot since starting cold exposure. Very interesting, and perhaps not a coincidence...

 

Back in this post, Al criticized my latest (post-CE) bloodwork on the grounds that my WBC count went up (to the bottom of the normal range), and that elevated WBC count is associated with adverse outcomes. We know how that discussion ended... But now we have even more direct evidence that Al may be off base on this one.

 

In short, extrapolating the evidence from this study [1], my observations since starting cold exposure of an increase in resting heart rate (suggesting elevated norepinephrine levels), coupled with an increase in EOS and monocyte counts, may reflect a shift towards a white blood cell profile that promotes the browning of white fat, likely both the visceral and subcutaneous varieties.

 

Of course this is making quite a few assumptions about the translatability of these results from mice to humans. But if these results do apply to humans, the metabolic impact of subcutaneous fat thermogenesis could be quite substantial:

 

[T]he UCP1-dependent and IL-4-induced beige fat mass could account for ∼15%–20% of total thermogenic capacity in mice, findings that are in agreement with the recent report that suggested beige fat respiration can account for ∼10%–37% of interscapular BAT thermogenic capacity (Shabalina et al., 2013).

 

Since unlike mice who have a lot of true BAT, humans have negligible true BAT deposits, making it likely that browned subcutaneous and visceral white fat deposits throughout the body are contributing a significantly higher percentage of cold-induced thermogenesis in humans than in rodents.

 

In fact, the authors are pretty optimistic about the potential for using pharmacological means to turn white fat to beige in order to burn fat and treat human obesity:

 

Not only do these findings provide strong experimental support for the therapeutic potential of beige fat in the setting of obesity, but they also outline a rigorous experimental strategy to systematically evaluate the potency and activity of other browning factors, such as irisin, Fgf21, and natriuretic peptides. Together, our results demonstrate that recruitment of new beige fat can ameliorate the established metabolic dysfunction resulting from diet-induced obesity, thereby providing strong support for the therapeutic targeting of beige fat for the treatment of human obesity and obesity-associated insulin resistance.

 

But it appears that there may be no free lunch - even if white fat is turned beige by pharmacological means (IL-4 injections) you still need cold exposure to burn extra calories:

 

[T]reatment of thermoneutral WT mice with IL-4 increases beige fat mass, but not oxygen consumption. However, upon exposure to progressively colder temperatures, these IL-4-treated animals have ∼8%–12% higher energy expenditure, reflecting their higher thermogenic capacity.

 

It goes without saying that the significant involvement of browned subcutaneous (and visceral) fat in human thermogenesis could go a long way towards explaining how cold exposure burns calories and improves measures of metabolic health (cholesterol, glucose, triglycerides). In fact, we can now add "subcutaneous fat" to the growing list of loci where cold-induced, non-shivering thermogenesis may be happening in people, a list which now includes:

  • Concentrated pockets of 'BAT' (actually beige fat) in the neck and shoulder regions
  • Browned visceral fat in the abdomen
  • Browned subcutaneous fat, aka "love handles", throughout the body
  • Sarcolipin-mediated futile cycling of calcium channels in skeletal muscles.

In summary:

  • Cold exposure turns subcutaneous white fat ("love handles") to thermogenic beige fat, at least in mice.
  • As a result of this browning of white fat, the mice showed dramatic improvements in measures of metabolic health relative to controls when both were fed an ad lib high fat diet.
  • The pathway responsible for browning of subcutaneous fat requires elevated levels of two types of immune system cells in the neighborhood of white fat deposits - eosinophils (EOSs) and macrophages (mature monocytes), the latter of which releases norepinephrine to turn the white fat cells to beige.
  • Speculatively, my increased heart rate (suggesting ↑ norepinephrine), along with increased EOS and monocyte levels since starting cold exposure may reflect a shift in my immune system cell population to promote the browning of white fat deposits through the same pathway observed in this study.

--Dean

 

---------------

[1] Cell. 2014 Jun 5;157(6):1292-308. doi: 10.1016/j.cell.2014.03.066.

Eosinophils and type 2 cytokine signaling in macrophages orchestrate development
of functional beige fat.

Qiu Y(1), Nguyen KD(1), Odegaard JI(1), Cui X(1), Tian X(1), Locksley RM(2),
Palmiter RD(3), Chawla A(4).

Free full text: http://ac.els-cdn.co...3064694a3383d65

Comment in
Cell. 2014 Jun 5;157(6):1249-50.
Nat Rev Endocrinol. 2014 Aug;10(8):443.

Beige fat, which expresses the thermogenic protein UCP1, provides a defense
against cold and obesity. Although a cold environment is the physiologic stimulus
for inducing beige fat in mice and humans, the events that lead from the sensing
of cold to the development of beige fat remain poorly understood. Here, we
identify the efferent beige fat thermogenic circuit, consisting of eosinophils,
type 2 cytokines interleukin (IL)-4/13, and alternatively activated macrophages.
Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced biogenesis
of beige fat. Mechanistically, macrophages recruited to cold-stressed
subcutaneous white adipose tissue (scWAT) undergo alternative activation to
induce tyrosine hydroxylase expression and catecholamine production, factors
required for browning of scWAT. Conversely, administration of IL-4 to
thermoneutral mice increases beige fat mass and thermogenic capacity to
ameliorate pre-established obesity. Together, our findings have uncovered the
efferent circuit controlling biogenesis of beige fat and provide support for its
targeting to treat obesity.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMCID: PMC4129510
PMID: 24906148

 

------------

[2] Jornayvaz, François R., and Gerald I. Shulman. “Regulation of Mitochondrial Biogenesis.” Essays in biochemistry 47 (2010): 10.1042/bse0470069. PMC. Web. 19 Apr. 2016.

 

-----------

[3] J Ultrastruct Mol Struct Res. 1988 Nov-Dec;101(2-3):109-22.

 
Epididymal white adipose tissue after cold stress in rats. I. Nonmitochondrial changes.
 
Loncar D1, Afzelius BA, Cannon B.
 
Abstract
 
Epididymal adipose tissue in the rat is generally considered to be "pure" white adipose tissue (WAT) with a characteristic structure and function. Previous studies in cats have, however, indicated that adipose tissue with the morphological appearance of WAT could be converted into a tissue with the morphological appearance of brown adipose tissue (BAT) by intermittent cold stress. The present electron microscopic and morphometric study describes the effect of intermittent cold stress on the epididymal WAT of young rats. The tissue volume decreased markedly as did the lipid content. The mitochondrial volume increased dramatically. The extracellular matrix was vastly reduced as was the thickness of the plasma membrane, and the number of gap junctions between adipocytes increased markedly. Indications of neoinnervation and neovascularization were observed. A great abundance of preadipocytes indicated proliferative activity of the endothelium. The low amount of lipid droplets and a relative abundance of smooth and rough endoplasmic reticulum. Golgi apparatus, and lysosomes in the epididymal WAT of cold-stressed rats gave the cells the morphological appearance of young adipocytes or preadipocytes whereas the hypertrophic and hyperplastic mitochondria, the relative paucity of ribosomes on lipid droplet membranes, and the increased innervation and vascularization gave the cells the morphological characteristics of brown adipose tissue.
PMID: 3268608
 
---------------
[4] Front Syst Neurosci. 2015 Nov 3;9:150. doi: 10.3389/fnsys.2015.00150. eCollection
2015.
 
Hypothalamic control of brown adipose tissue thermogenesis.
 
Labbé SM(1), Caron A(1), Lanfray D(1), Monge-Rofarello B(1), Bartness TJ(2),
Richard D(1).
 
Author information: 
(1)Centre de Recherche de l'Institut Universitaire de Cardiologie et de
Pneumologie de Québec, Department of Medicine, Université Laval Québec, QC,
Canada. (2)Department of Biology, Center for Obesity Reversal (COR), Georgia
State University Atlanta, GA, USA.
 
It has long been known, in large part from animal studies, that the control of
brown adipose tissue (BAT) thermogenesis is insured by the central nervous system
(CNS), which integrates several stimuli in order to control BAT activation
through the sympathetic nervous system (SNS). SNS-mediated BAT activity is
governed by diverse neurons found in brain structures involved in homeostatic
regulations and whose activity is modulated by various factors including
oscillations of energy fluxes. The characterization of these neurons has always
represented a challenging issue. The available literature suggests that the
neuronal circuits controlling BAT thermogenesis are largely part of an autonomic 
circuitry involving the hypothalamus, brainstem and the SNS efferent neurons. In 
the present review, we recapitulate the latest progresses in regards to the
hypothalamic regulation of BAT metabolism. We briefly addressed the role of the
thermoregulatory pathway and its interactions with the energy balance systems in 
the control of thermogenesis. We also reviewed the involvement of the brain
melanocortin and endocannabinoid systems as well as the emerging role of
steroidogenic factor 1 (SF1) neurons in BAT thermogenesis. Finally, we examined
the link existing between these systems and the homeostatic factors that modulate
their activities.
 
PMCID: PMC4630288
PMID: 26578907

There will never be peace in the world while there are animals in our bellies.

#223 Dean Pomerleau

Dean Pomerleau
  • Lifetime Member
  • 2,458 posts

Posted 20 April 2016 - 10:41 AM

Interleukin-33, Alzheimer's Disease, Cardiovascular Disease and Cold Exposure

 

Here is a brief post before I finally get to the bigger discussion rpWAT I've been promising.

Yesterday we saw that eosinophil (EOS) cells are critical for the browning of white fat especially subcutaneous WAT, and that they release the cytokine Interleukin 4 (IL-4) to orchestrate the browning process. 

 

It turns out that IL-4 isn't the only member of the interleukin family that is critical for browning of white fat. Two recent studies in the journals Cell [1] and Nature [2] found that another interleukin, IL-33, is important for the process. In fact, IL-33 may kick off the whole process, as illustrated in this graphical abstract from [1]:

 

7UgKYnA.png

 

IL-33 is a so-called "Alarmin" (alarm signal) released from cells when they get damaged or stressed [5]. Note how IL-33 is upstream of the eosinophils and IL-4 I discussed in yesterday's post, so it doesn't contradict the insight from yesterday that IL-4 can induce the browning of white fat.

 

Why do I single out IL-33 as of special interest, rather than IL-5 or IL-13 which are also part of the causal chain outlined above? Because yesterday while researching IL-4 and after reading [1] about how IL-33 is involved in WAT browning too, I happened to come across this article, talking about this study [3] on the beneficial effects of IL-33 for Alzheimer's disease.

 

The authors of [3] found that 2 days of injecting IP-33 into the bloodstream (not the brain as the popular press article claims) of mice resulted in a dramatic reduction of Amyloid-Beta plaque (Aβ) burden and reducing brain inflammation in a mouse model of Alzheimer's Disease (AD). As a result, the mice exhibited better memories in a fear-conditioning test (sorry Sthira...).  Like its role in the browning of white fat, the "alarm signal" from IL-33 reprograms the behavior of immune system cells, in this case the microglia in the brain, to more effectively degrade and "mop up" the Aβ.

 

In support of this IL-33 signalling mechanism being important in human AD, the researchers cite evidence that IL-33 expression is reduced in the brains of human AD patients, and they cite several studies showing people with a particular genetic polymorphism linked to IL-33 are more susceptible to AD. Also, like the mice in this study, AD patients have a blood-blood brain barrier which is permeable to IL-33, although I get the impression that normal blood-brain barriers (i.e. from non-AD people or mice) are not permeable to IL-33, but that it is synthesized endogenously by cells in the brain.

 

Furthermore, AD is not the only pathology it appears IL-33 may be able to mitigate. This review article [3] cites studies (e.g. [4]) showing IL-33 "has shown various protective effects in cardiovascular diseases such as atherosclerosis, obesity, type 2 diabetes and cardiac remodeling." These CVD benefits would be consistent with its triggering the conversion of pro-inflammatory white adipose tissue to beige adipose tissue.

 

But it's not all just rainbows and puppy dogs for IL-33 and it's effects: [3] also notes that IL-33 appears to be promote some diseases associated with an overactive immune system: 

 

"IL-33 strongly induces Th2 cytokine production from these cells and can promote the pathogenesis of Th2-related disease such as asthma, atopic dermatitis and anaphylaxis."

 

That's not too surprising - if IL-33 is an alarm signal, overexpressing it or overreacting to its presence, might be expected to cause the immune system to become too active, as it is in that set of diseases/conditions.

 

But in general, it appears that improved IL-33 signalling both in the peripheral bloodstream and in the brain may be beneficial. To that end, study [2] provides this intriguing positive (or negative, depending on how you look at it) feedback loop involving IL-33 and cold exposure:

 

xMLmDOj.png

 

 

As suggested above, obesity seems to block the signalling action of IL-33, which prevents it from recruiting EOS cells to white fat, which eventually prevents those white fat cells from turning brown, which results in greater obesity, in a viscous circle of ever increasing obesity, metabolic dysfunction, and less IL-33 signalling. 

 

Conversely, cold exposure has the potential to break this vicious cycle, and turn it virtuous. By browning white fat, cold exposure reduces obesity, unblocking IL-33 signalling, which facilitates further white fat browning, further reducing obesity, further unblocking IL-33 signalling, etc. - with an ultimate end result of white fat loss, improved metabolic function, reduced cardiovascular disease and very speculatively (due to blood-brain barrier issues), potentially reducing risk or progression of Alzheimer's disease.

 

--Dean

 

---------

[1] Cell. 2015 Jan 15;160(1-2):74-87. doi: 10.1016/j.cell.2014.12.011. Epub 2014 Dec 

24.
 
Activated type 2 innate lymphoid cells regulate beige fat biogenesis.
 
Lee MW(1), Odegaard JI(1), Mukundan L(1), Qiu Y(1), Molofsky AB(2), Nussbaum
JC(3), Yun K(1), Locksley RM(4), Chawla A(5).
 
Free full text:
 
Type 2 innate lymphoid cells (ILC2s), an innate source of the type 2 cytokines
interleukin (IL)-5 and -13, participate in the maintenance of tissue homeostasis.
Although type 2 immunity is critically important for mediating metabolic
adaptations to environmental cold, the functions of ILC2s in beige or brown fat
development are poorly defined. We report here that activation of ILC2s by IL-33 
is sufficient to promote the growth of functional beige fat in thermoneutral
mice. Mechanistically, ILC2 activation results in the proliferation of
bipotential adipocyte precursors (APs) and their subsequent commitment to the
beige fat lineage. Loss- and gain-of-function studies reveal that ILC2- and
eosinophil-derived type 2 cytokines stimulate signaling via the IL-4Rα in
PDGFRα(+) APs to promote beige fat biogenesis. Together, our results highlight a 
critical role for ILC2s and type 2 cytokines in the regulation of adipocyte
precursor numbers and fate, and as a consequence, adipose tissue homeostasis.
PAPERCLIP:
 
Copyright © 2015 Elsevier Inc. All rights reserved.
 
PMCID: PMC4297518
PMID: 25543153
 
-----------
[2] Nature. 2015 Mar 12;519(7542):242-6. doi: 10.1038/nature14115. Epub 2014 Dec 22.
 
Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit
obesity.
 
Brestoff JR(1), Kim BS(2), Saenz SA(2), Stine RR(3), Monticelli LA(1), Sonnenberg
GF(4), Thome JJ(5), Farber DL(6), Lutfy K(7), Seale P(3), Artis D(1).
 
Obesity is an increasingly prevalent disease regulated by genetic and
environmental factors. Emerging studies indicate that immune cells, including
monocytes, granulocytes and lymphocytes, regulate metabolic homeostasis and are
dysregulated in obesity. Group 2 innate lymphoid cells (ILC2s) can regulate
adaptive immunity and eosinophil and alternatively activated macrophage
responses, and were recently identified in murine white adipose tissue (WAT)
where they may act to limit the development of obesity. However, ILC2s have not
been identified in human adipose tissue, and the mechanisms by which ILC2s
regulate metabolic homeostasis remain unknown. Here we identify ILC2s in human
WAT and demonstrate that decreased ILC2 responses in WAT are a conserved
characteristic of obesity in humans and mice. Interleukin (IL)-33 was found to be
critical for the maintenance of ILC2s in WAT and in limiting adiposity in mice by
increasing caloric expenditure. This was associated with recruitment of
uncoupling protein 1 (UCP1)(+) beige adipocytes in WAT, a process known as
beiging or browning that regulates caloric expenditure. IL-33-induced beiging was
dependent on ILC2s, and IL-33 treatment or transfer of IL-33-elicited ILC2s was
sufficient to drive beiging independently of the adaptive immune system,
eosinophils or IL-4 receptor signalling. We found that ILC2s produce
methionine-enkephalin peptides that can act directly on adipocytes to upregulate 
Ucp1 expression in vitro and that promote beiging in vivo. Collectively, these
studies indicate that, in addition to responding to infection or tissue damage,
ILC2s can regulate adipose function and metabolic homeostasis in part via
production of enkephalin peptides that elicit beiging.
 
PMCID: PMC4447235
PMID: 25533952
 
--------
[3] Proc Natl Acad Sci U S A. 2016 Apr 18. pii: 201604032. [Epub ahead of print]
 
IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline.
 
Fu AK(1), Hung KW(1), Yuen MY(1), Zhou X(1), Mak DS(1), Chan IC(1), Cheung TH(1),
Zhang B(2), Fu WY(1), Liew FY(3), Ip NY(4).
 
 
Alzheimer's disease (AD) is a devastating condition with no known effective
treatment. AD is characterized by memory loss as well as impaired locomotor
ability, reasoning, and judgment. Emerging evidence suggests that the innate
immune response plays a major role in the pathogenesis of AD. In AD, the
accumulation of β-amyloid (Aβ) in the brain perturbs physiological functions of
the brain, including synaptic and neuronal dysfunction, microglial activation,
and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for
interleukin (IL)-33, increase in patients with mild cognitive impairment,
suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis
of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, 
using transgenic mouse models. Here we report that IL-33 administration reverses 
synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33
administration reduces soluble Aβ levels and amyloid plaque deposition by
promoting the recruitment and Aβ phagocytic activity of microglia; this is
mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates 
the innate immune response by polarizing microglia/macrophages toward an
antiinflammatory phenotype and reducing the expression of proinflammatory genes, 
including IL-1β, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, 
our results demonstrate a potential therapeutic role for IL-33 in AD.
 
PMID: 27091974
 
------------
[3] J Inflamm (Lond). 2011 Aug 26;8(1):22. doi: 10.1186/1476-9255-8-22.
 
Role of IL-33 in inflammation and disease.
 
Miller AM(1).
 
Author information: 
(1)Institute of Infection, Immunity and Inflammation, College of Medical,
Veterinary and Life Sciences, GBRC, University of Glasgow, Glasgow G12 8TA, UK.
Ashley.Miller@glasgow.ac.uk.
 
Interleukin (IL)-33 is a new member of the IL-1 superfamily of cytokines that is 
expressed by mainly stromal cells, such as epithelial and endothelial cells, and 
its expression is upregulated following pro-inflammatory stimulation. IL-33 can
function both as a traditional cytokine and as a nuclear factor regulating gene
transcription. It is thought to function as an 'alarmin' released following cell 
necrosis to alerting the immune system to tissue damage or stress. It mediates
its biological effects via interaction with the receptors ST2 (IL-1RL1) and IL-1 
receptor accessory protein (IL-1RAcP), both of which are widely expressed,
particularly by innate immune cells and T helper 2 (Th2) cells. IL-33 strongly
induces Th2 cytokine production from these cells and can promote the pathogenesis
of Th2-related disease such as asthma, atopic dermatitis and anaphylaxis.
However, IL-33 has shown various protective effects in cardiovascular diseases
such as atherosclerosis, obesity, type 2 diabetes and cardiac remodeling. Thus,
the effects of IL-33 are either pro- or anti-inflammatory depending on the
disease and the model. In this review the role of IL-33 in the inflammation of
several disease pathologies will be discussed, with particular emphasis on recent
advances.
 
PMCID: PMC3175149
PMID: 21871091 
 
--------
[4] BMC Immunol. 2014 May 10;15:19. doi: 10.1186/1471-2172-15-19.
 
IL-33 is negatively associated with the BMI and confers a protective
lipid/metabolic profile in non-diabetic but not diabetic subjects.
 
Hasan A, Al-Ghimlas F, Warsame S, Al-Hubail A, Ahmad R, Bennakhi A, Al-Arouj M,
Behbehani K, Dehbi M, Dermime S(1).
 
Author information: 
(1)Immunology and Innovative Cell Therapy Unit, Dasman Diabetes Institute, Kuwait
City, Kuwait. sdermime@hotmail.com.
 
OBJECTIVE: Recent studies have demonstrated a protective role for IL-33 against
obesity-associated inflammation, atherosclerosis and metabolic abnormalities.
IL-33 promotes the production of T helper type 2 (Th2) cytokines, polarizes
macrophages towards a protective alternatively activated phenotype, reduces lipid
storage and decreases the expression of genes associated with lipid metabolism
and adipogenesis. Our objective was to determine the level of serum IL-33 in
non-diabetic and diabetic subjects, and to correlate these levels with clinical
(BMI and body weight) and metabolic (serum lipids and HbA1c) parameters.
METHODS: The level of IL-33 was measured in the serum of lean, overweight and
obese non-diabetic and diabetic subjects, and then correlated with clinical and
metabolic parameters.
RESULTS: Non-lean subjects had significantly (P = 0.01) lower levels of IL-33
compared to lean controls. IL-33 was negatively correlated with the BMI and body 
weight in lean and overweight, but not obese (non-diabetic and diabetic),
subjects. IL-33 is associated with protective lipid profiles, and is negatively
correlated with HbA1c, in non-diabetic (lean, overweight and obese) but not
diabetic subjects.
CONCLUSIONS: Our data support previous findings showing a protective role for
IL-33 against adiposity and atherosclerosis, and further suggest that reduced
levels of IL-33 may put certain individuals at increased risk of developing
atherosclerosis and insulin resistance. Therefore, IL-33 may serve as a novel
marker to predict those who may be at increased risk of developing
atherosclerosis.
 
PMCID: PMC4053278
PMID: 24886535
 
---------------
[5] Curr Opin Immunol. 2014 Dec;31:31-7. doi: 10.1016/j.coi.2014.09.004. Epub 2014

Sep 29.

IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation
and allergy.

Cayrol C(1), Girard JP(2).

Author information:
(1)CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route
de Narbonne, F-31077 Toulouse, France; Université de Toulouse, UPS, IPBS, F-31077
Toulouse, France. (2)CNRS, IPBS (Institut de Pharmacologie et de Biologie
Structurale), 205 route de Narbonne, F-31077 Toulouse, France; Université de
Toulouse, UPS, IPBS, F-31077 Toulouse, France. Electronic address:
Jean-Philippe.Girard@ipbs.fr.

IL-33 is a nuclear cytokine from the IL-1 family constitutively expressed in
epithelial barrier tissues and lymphoid organs, which plays important roles in
type-2 innate immunity and human asthma. Recent studies indicate that IL-33
induces production of large amounts of IL-5 and IL-13 by group 2 innate lymphoid
cells (ILC2s), for initiation of allergic inflammation shortly after exposure to
allergens or infection with parasites or viruses. IL-33 appears to function as an
alarmin (alarm signal) rapidly released from producing cells upon cellular damage
or cellular stress. In this review, we discuss the cellular sources, mode of
action and regulation of IL-33, and we highlight its crucial roles in vivo with
particular emphasis on results obtained using IL33-deficient mice.

Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

PMID: 25278425

 

-----------

[5] Curr Opin Immunol. 2014 Dec;31:31-7. doi: 10.1016/j.coi.2014.09.004. Epub 2014

Sep 29.
 
IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation
and allergy.
 
Cayrol C(1), Girard JP(2).
 
IL-33 is a nuclear cytokine from the IL-1 family constitutively expressed in
epithelial barrier tissues and lymphoid organs, which plays important roles in
type-2 innate immunity and human asthma. Recent studies indicate that IL-33
induces production of large amounts of IL-5 and IL-13 by group 2 innate lymphoid 
cells (ILC2s), for initiation of allergic inflammation shortly after exposure to 
allergens or infection with parasites or viruses. IL-33 appears to function as an
alarmin (alarm signal) rapidly released from producing cells upon cellular damage
or cellular stress. In this review, we discuss the cellular sources, mode of
action and regulation of IL-33, and we highlight its crucial roles in vivo with
particular emphasis on results obtained using IL33-deficient mice.
 
Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.
 
PMID: 25278425  

There will never be peace in the world while there are animals in our bellies.

#224 TomBAvoider

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Posted 20 April 2016 - 05:04 PM

In support of this IL-33 signalling mechanism being important in human AD, the researchers cite evidence that IL-33 expression is reduced in the brains of human AD patients, and they cite several studies showing people with a particular genetic polymorphism linked to IL-33 are more susceptible to AD.

 

This study seems interesting: 

 

http://www.ncbi.nlm....les/PMC2860783/

 

Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer’s disease

 
 
Abstract

 

The only recognised genetic determinant of the common forms of Alzheimer’s disease (AD) is the ε4 allele of the apolipoprotein E gene (APOE). To identify new candidate genes, we recently performed transcriptomic analysis of 2,741 genes in chromosomal regions of interest using brain tissue of AD cases and controls.

From 82 differentially expressed genes, 1,156 polymorphisms were genotyped in two independent discovery sub-samples (n=945). Seventeen genes exhibited at least one polymorphism associated with AD risk and following correction for multiple testing, we retained the IL-33 gene.

We first confirmed that the IL-33 expression was decreased in the brain of AD cases compared with that of controls. Further genetic analysis led us to select 3 polymorphisms within this gene, which we analysed in three independent case-control studies. These polymorphisms and a resulting protective haplotype were systematically associated with AD risk in non-APOE ε4 carriers. Using a large prospective study, these associations were also detected when analyzing the prevalent and incident AD cases together or the incident AD cases alone. These polymorphisms were also associated with less cerebral amyloid angiopathy (CAA) in the brain of non-APOE ε4 AD cases. Immunohistochemistry experiments finally indicated that the IL-33 expression was consistently restricted to vascular capillaries in the brain. Moreover, IL-33 overexpression in cellular models led to a specific decrease in secretion of the Aβ40 peptides, the main CAA component.

In conclusion, our data suggest that genetic variants in IL-33 gene may be associated with a decrease in AD risk potentially in modulating CAA formation.

 
As more and more such studies come out, it will be more and more interesting to see where one stands with one's own promethease analysis. In principle, it should be possible to see if you are a candidate for IL-33 over/under expression and what that might mean for all sorts of things including beige fat mobilization.


#225 TomBAvoider

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Posted 20 April 2016 - 06:58 PM

I haven't seen this study referenced (at least in the last 6 pages of this thread) - PMC3335871 which allows for exploring your own 23andme data after some backtracking in the following sequence:

 

From PMC3335871:

 

http://www.ncbi.nlm....les/PMC3335871/

 

Essential Role for miR-196a in Brown Adipogenesis of White Fat Progenitor Cells

 

Abstract

The recent discovery of functional brown adipocytes in adult humans illuminates the potential of these cells in the treatment of obesity and its associated diseases. In rodents, brown adipocyte-like cells are known to be recruited in white adipose tissue (WAT) by cold exposure or β-adrenergic stimulation, but the molecular machinery underlying this phenomenon is not fully understood. Here, we show that inducible brown adipogenesis is mediated by the microRNA miR-196a. We found that miR-196a suppresses the expression of the white-fat gene Hoxc8 post-transcriptionally during the brown adipogenesis of white fat progenitor cells. In mice, miR-196a is induced in the WAT-progenitor cells after cold exposure or β-adrenergic stimulation. The fat-specific forced expression of miR-196a in mice induces the recruitment of brown adipocyte-like cells in WAT. The miR-196a transgenic mice exhibit enhanced energy expenditure and resistance to obesity, indicating the induced brown adipocyte-like cells are metabolically functional. Mechanistically, Hoxc8 targets and represses C/EBPβ, a master switch of brown-fat gene program, in cooperation with histone deacetylase 3 (HDAC3) through the C/EBPβ 3′ regulatory sequence. Thus, miR-196a induces functional brown adipocytes in WAT through the suppression of Hoxc8, which functions as a gatekeeper of the inducible brown adipogenesis. The miR-196a-Hoxc8-C/EBPβ signaling pathway may be a therapeutic target for inducing brown adipogenesis to combat obesity and type 2 diabetes.

 

Back through PMID: 25557604 (full text available):

 

http://onlinelibrary.../oby.20975/full

 

[my bold TomBAvoider]

 

The rs11614913 is a common functional variant located in pre-miR-196a2 that has linked to several disorders and phenotypes. This variant contributes to the increased risk of breast cancer, lung cancer, and cancers of digestive system [28, 29]. A meta-analysis of GWAS on bone mineral density (BMD) demonstrates that the risk allele of rs11614913 is inversely associated with lumbar spine and femoral neck BMD [30]. Furthermore, rs11614913 has been reported to be associated with the risk of CVD in type 2 diabetes patients [31] and congenital heart disease [32]. However, despite using a large sample size (22,233 cases and 64,762 controls) from the CARDIOGRAM consortium, we did not find a significant association between rs11614913 and risk of CAD [19]. Our findings showed a significant association between the rs11614913 mutant allele and higher WHR. We found that there is a difference between MFE of the thermodynamic ensemble of pre-miR-196a2 with the mutant versus wild-type alleles which may affect the structure and processing of the pre-miRNA. In agreement with our conjecture, it has experimentally shown that rs11614913 affects the processing of pre-miR-196a2 and results in altered expression levels of the mature miRNA [27, 33]. For example, Hoffman et al. by delivering expression vectors containing either wild-type or mutant precursors of miR-196a2 have shown that mature miRNA levels in cells transfected with pre-miR-196a2 hosting the mutant allele (T) is significantly lower than cells transfected with the wild-type allele construct [27]. In addition, Hu et al. have demonstrated that rs11614913 wild-type allele © is associated with a significant increase in mature miR-196a2 expression [33]. Therefore, an altered expression level of mature miR-196a2 due to rs11614913 could serve as a functional mechanism underlying the observed association between the variant and WHR. MiRNAs regulate phenotypes through regulation of their target genes expression. Therefore, we sought to identify target genes that may mediate the effect miR-196a2 on WHR and found SFMBT1 and HOXC8. We showed these genes are bona fide targets of miR-196a2. Previous studies have provided evidence for co-expression of miR-196a2 and its two highlighted targets in adipose tissue which is a prerequisite for miRNA-mRNA interaction. MiR-196a2 has been identified as a regulator in brown adipogenesis of white fat progenitor cells [22]. Accordingly, HOXC8 is known to increase white fat cells and the risk of obesity [34]. SFMBT1 has reported to be associated with circulating adiponectin levels [35]. In addition, it has experimentally shown that decreasing HOXC8 expression by overexpression of miR-196a2 lead to an increased brown adipocyte [34]. Taken together, these findings suggest that depletion of miR-196a2 by rs11614913 mutant allele T elevate HOXC8 and SFMBT1 expression and subsequently contribute to higher WHR, potentially through an increase in white fat cells.

 

And of course, rs11614913 in snpedia:

 

https://www.snpedia.....php/Rs11614913 

 

is available from your 23andme raw data. I'm a CC FWIW. 



#226 Dean Pomerleau

Dean Pomerleau
  • Lifetime Member
  • 2,458 posts

Posted 21 April 2016 - 02:28 AM

TomB,

Thanks for the digging on miR-196a2, and SNP rs11614913. I'm CT for that SNP according to 23andMe. Not as favorable as your CC, at least for converting white fat to brown.

 

On the other hand, being CC (or event CT like me) for that allele appears to have its downsides as well according to SNPedia - in the form of elevated risk of various forms of cancer, for example colorectal cancer (CRC) [1].

 

Expression analysis revealed that rs11614913 CC or carrying at least one C allele was associated with a significantly increased level of mature miR-196a (p = 0.010 or = 0.022).
 
Frequency of the CC genotype was higher in CRC patients than controls, implying that the subjects with the CC genotype or C allele containing genotypes (CT and CC) have a higher risk of CRC.
 

So you win some, you lose some I guess. But now that clever scientists have figured out a way to use CRISPR to edit single base pairs [2], all that may one day change... 

--Dean

--------
[1] Arch Med Res. 2011 Feb;42(2):144-8. doi: 10.1016/j.arcmed.2011.04.001.

A functional variant in microRNA-196a2 is associated with susceptibility of
colorectal cancer in a Chinese population.

Zhan JF(1), Chen LH, Chen ZX, Yuan YW, Xie GZ, Sun AM, Liu Y.

Author information:
(1)Department of Health Management Centre, Guangzhou First Municipal People's
Hospital Affiliated to Guangzhou Medical College, Guangzhou, Guangdong Province,
China. zhanjunfang@sina.cn

BACKGROUND AND AIMS: MicroRNAs (miRNA) can act as oncogenes or tumor suppressors.
Polymorphisms present in pri-, pre- and mature miRNAs can potentially modulate
the expression of hundreds of genes, broadly affecting miRNA function. Notably,
the rs11614913 SNP in miR-196a2 has been implicated in carcinogenesis, but its
association with colorectal cancer (CRC) remains unexplored. We performed a
case-control study to investigate the genetic association between this functional
SNP and CRC susceptibility and progression.
METHODS: We genotyped the rs11614913 SNP in 252 CRC patients and 543 healthy
controls by polymerase chain reaction-restriction fragment length polymorphism
(PCR-RFLP). In addition, we examined miR-196a expression level in colorectal
cancer tissues (n = 50) obtained from the studied CRC patients.
RESULTS: Frequency of the CC genotype was higher in CRC patients than controls,
implying that the subjects with the CC genotype or C allele containing genotypes
(CT and CC) have a higher risk of CRC.
However, no significant association
between this polymorphism and CRC progression was observed. Expression analysis
revealed that rs11614913 CC or carrying at least one C allele was associated with
a significantly increased level of mature miR-196a (p = 0.010 or = 0.022).

CONCLUSIONS: The present study provides the first evidence that miR-196a2
polymorphism may contribute to CRC susceptibility in a Chinese population through
modulating mature miR-196a expression.

Copyright © 2011 IMSS. All rights reserved.

PMID: 21565628

 

----------

[2] 1. Nature. 2016 Apr 20. doi: 10.1038/nature17946. [Epub ahead of print]

 
Programmable editing of a target base in genomic DNA without double-stranded DNA 
cleavage.
 
Komor AC(1,)(2), Kim YB(1,)(2), Packer MS(1,)(2), Zuris JA(1,)(2), Liu DR(1,)(2).
 
Author information: 
(1)Department of Chemistry and Chemical Biology, Harvard University, Cambridge,
Massachusetts 02138, USA. (2)Howard Hughes Medical Institute, Harvard University,
Cambridge, Massachusetts 02138, USA.
 
Current genome-editing technologies introduce double-stranded (ds) DNA breaks at 
a target locus as the first step to gene correction. Although most genetic
diseases arise from point mutations, current approaches to point mutation
correction are inefficient and typically induce an abundance of random insertions
and deletions (indels) at the target locus resulting from the cellular response
to dsDNA breaks. Here we report the development of 'base editing', a new approach
to genome editing that enables the direct, irreversible conversion of one target 
DNA base into another in a programmable manner, without requiring dsDNA backbone 
cleavage or a donor template. We engineered fusions of CRISPR/Cas9 and a cytidine
deaminase enzyme that retain the ability to be programmed with a guide RNA, do
not induce dsDNA breaks, and mediate the direct conversion of cytidine to
uridine, thereby effecting a C→T (or G→A) substitution. The resulting 'base
editors' convert cytidines within a window of approximately five nucleotides, and
can efficiently correct a variety of point mutations relevant to human disease.
In four transformed human and murine cell lines, second- and third-generation
base editors that fuse uracil glycosylase inhibitor, and that use a Cas9 nickase 
targeting the non-edited strand, manipulate the cellular DNA repair response to
favour desired base-editing outcomes, resulting in permanent correction of
~15-75% of total cellular DNA with minimal (typically ≤1%) indel formation. Base 
editing expands the scope and efficiency of genome editing of point mutations.
 
PMID: 27096365  [PubMed - as supplied by publisher]
 

There will never be peace in the world while there are animals in our bellies.

#227 Dean Pomerleau

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Posted 21 April 2016 - 12:59 PM

Cold Exposure Turns Subcutaneous White Fat to Beige in Humans Too!

 

Strap on your cooling vests everyone, things are about to get interesting... I know you're waiting with bated (not baited) breath, but my promised rpWAT post is getting bumped once again...

 

Recall over the last few days I've built up a case that virtually all thermogenic fat in humans is not true BAT, but former white adipose tissue that has been turned to brown (beige) as a result of cold exposure, or in some experimental cases, via drugs. And we've seen that browning of white fat appears to occur in both visceral and subcutaneous fat.

 

But all that evidence was in mice. What about humans? Is there really evidence for conversion of WAT into thermogenic beige fat in parts of the human body away from the well-known 'BAT' pockets around the neck, upper chest, back and ribcage?

 

Yup!

 

After reading my recent posts, my friend Eric from CoolFatBurner.com sent me a heads up about this paper [1]. It's actually two studies for the price of (reading) one.

 

In the first part, the researchers examined the abdominal (Group 1) and thigh (Group 2) subcutaneous (SC) fat from 71 people who were biopsied in either the summer or winter in Kentucky or Arkansas to see if the season influenced the degree of browning of their SC fat.

 

The average outdoor temperatures were ~6°C (43°F) in winter and ~22°C (72 °F) in summer.  None of the subjects had jobs that would subject them to extended outdoor exposure. All the subjects were "generally healthy", and were about evenly split between "obese" (BMI > 30, avg ~35) and simply "overweight" (BMI <30, avg ~27) - which the authors will refer to as the "obese" and "lean" <sic> groups.

 

What they found in this first part was pretty dramatic. UCP1 expression was about 3x higher, and mitochondria-proliferator PGC1α was almost 2x higher in abdominal fat from Group 1 subjects in winter compared with summer, as illustrated in the graph on the left. In the thigh fat biopsy folks (Group 2), the seasonal difference was even greater (right graph), with UPC1 about a factor of 7x higher (eyeballing the graph) in winter vs. summer biopsies.

 

  8gmS6Yw.pngCB5JJkD.png

 

Notice in the right graph the spike in TMEM26 expression in the winter? TMEM26 is a genetic marker of beige (rather than true brown) adipose tissue. In contrast, none of the known genetic markers of true BAT were elevated (data not shown). So it was definitely conversion of subcutaneous white fat cells to beige fat cells that was happening in these folks in wintertime, rather than de novo lipogenesis of true BAT cells.

 

Next they compared abdominal SC fat from "lean" (avg BMI ~27) vs "obese" (avg BMI ~35) to see how their respective browness compared, in summer and winter. Here is the graph:

 

LiA1kQg.png

 

As you can see, the "lean" subjects had browner abdominal SC fat than the obese subjects did at both times of year - an effect we've discussed previously, i.e. intermediate BMI folks like this "lean" <sic> group have the most BAT. And as you can see, it was only the "lean" subjects who saw a dramatic (and significant p < 0.05) increase in UCP-1 content in winter relative to summer. In other words, the browning of SC fat in general, and the browning induced by cooler winter temperatures, was blunted in the obese folks. 

 

So that's Part 1 of the study - representing pretty strong evidence that a cooler environment results in browning of subcutaneous fat, at least in non-obese folks.

 

But it only showed correlation of increased browning of SC fat with season/temperature, and not causation, and the biopsy data for winter and summer were from different groups of people, so the evidence wasn't definitive that cold causes browning of subcutaneous fat.

 

Moreover, their observation that "lean" (i.e. just overweight) subjects exhibited browner subcutaneous fat both in summer and winter, and gained more brown fat in association with the change in season, doesn't prove that having more BAT helps keep them leaner. It may be the result of better insulation that the obese people have need, and therefore develop, less BAT for thermogenic purposes.

 

That's where Part 2 of this study comes in, and where things get really cool.

 

They took the thigh biopsy folks from Part 1, did a further test to investigate the browning effects of acute and localized cold exposure. The tested 16 of the relatively "lean" folks (avg BMI ~26) from the thigh group who had their biopsy performed in the summer. In addition to a biopsy done on the "warm" thigh for the tests described in Part 1, the researchers also applied a 2 kg ice pack to the other thigh of these subjects for 30 minutes, waited 4 hours, and then took a biopsy of this "cold-exposed" thigh. So the subjects served as their own controls. During the cold stimulus, "subjects reported that the site felt numb, and there was a rewarming sensation, but no unpleasant side effects or shivering were observed." See it's not that bad.

 

They then did the obvious - they compared the degree of "browning" in the SC fat from the two thigh tissue samples - a control, warm "summer thigh" vs a summer thigh exposed to acute, localized cooling.

 

Since I'm telling you this, I bet you can guess what they found - increased browning in the SC thigh fat exposed to acute localized cooling. Here are the two graphs. Focus for now on the bars I've highlighted:

 

p4FqP6P.png

 

The top graph shows expression of PGC1α, a protein known to be involved in mitochondrial biogenesis, and the lack of which in adipose tissue is associated with insulin resistance [2]. The bottom graph shows expression of mitochondrial uncoupling protein 1, UCP1. The white bars are cells taken from the control thigh, and the black bars are from cells taken from the cold-exposed thigh. As you can see, the cold-exposed fat cells expressed twice as much PGC1α and 3.5 times more UCP1 relative to fat cells from the control thigh. After just half an hour of direct cold simulation. Pretty impressive!

 

The other bars in the two graphs represent tests to see if a pro-inflammatory environment (known to occur in the fat tissue of obese people) blunted the browning of SC fat tissue in response to cold.  They bathed the fat cells in a medium containing chemicals given off by macrophages of several types sometimes associated with an inflammatory response (named M1, M2a and M2c), or infused with the well-known marker of inflammation, TNFα at various concentrations. What you can see is that these inflammatory signals did indeed blunt the browning of SC fat.

 

This suggests that "better insulation" is not the only (or main) reason obese people have whiter (less thermogenic) subcutaneous fat than leaner people (as seen in Part 1). Instead or in addition, the systemic inflammation the obese exhibit likely suppresses the browning of SC fat, even when exposed to cold. This is another way of explaining part of the Ո-shaped relationship between BMI and BAT (beige fat) mass in humans. Really heavy people have increased systemic inflammation, suppression the conversion of white fat to beige.

 

Notice that this results in a vicious circle not unlike the one I described yesterday involving IL-33. In this one, obese people have increased inflammation, which suppresses SC fat browning, which results in their fat tissue burning fewer calories, which leads to weight gain, which leads to additional inflammation. Here again it would seem cold exposure has the potential to break the vicious cycle of weight gain begatting more weight gain in the obese, at least if done rigorously and consistently to overcome the initial "browning handicap" that obese people are saddled with.

 

Here are some other interesting tidbits from the discussion section of the paper (my emphasis):

 

In the abdominal SC WAT, other genes involved with lipolysis
and energy utilization (adiponectin, AMPK, HSL, and
ACC) were also elevated in the winter, as was the adipose
protein level of UCP1.

 

Recall from this post about CE and AMPK, and from this post about the synergy between the biochemical pathways of CR and CE, that adiponectin and AMPK are two of the enzymes the model points out as elevated by CE - so it makes sense they'd be observed to be elevated in winter relative to summer.

 

What they didn't observe was changes in gene expression in the thigh muscle tissue cells, despite the muscle receiving a similar degree of acute cooling as the thigh SC fat (the thigh fat on these folks wasn't very thick, according to the authors).  Although they didn't say explicitly which genes they tested, it was presumably the same UCP1 and Pgc1α they tested in the fat samples, which might not be involved in muscle non-shivering thermogenesis, as pointed out in this post about sarcolipin-induced thermogenesis in skeletal muscles. 

 

They also saw that signals of inflammation, in the form of either the presence of certain types of macrophages or the inflammatory cytokine TNFα, suppressed the browning of SC fat .

 

I can hear you saying, "But Dean, didn't you say two days ago in this post that macrophages were an important part of the SC fat browning pathway? Remember you said EOS → ↑ IL-4 → ↑ macrophages → ↑ norepinephrine → SC fat browning? Now you're saying macrophages suppress browning? What gives?"

 

It turns out that (not surprisingly), all macrophages are not created equal. There are all kinds of different macrophages that respond to different activators and that do different jobs. Notice in the above graph they tested three different macrophage types, M1, M2a and M2c, and it was M1 and M2c macrophages that really put the whammy on SC fat browning, while M2a macrophages had a relatively modest (although still negative) effect on browning. 

 

The M1 macrophages are the classic ones that get recruited to "seek and destroy" bacteria or viruses during acute infections - and are definitely pro-inflammatory. The M2c macrophages are activated by IL-10 and glucocorticoids, the latter of which we saw in this post suppressed brown fat and induced muscle wasting via reduced mTOR activity in people. So it's not surprising the M2c macrophages blunt the browning effect in SC fat.

 

That leaves the M2a macrophages, which recall weren't as bad for SC fat browning as the other two. Not surprisingly, it's these M2a macrophages that were the type involved in promoting SC fat browning - they are the ones recruited by IL-4 and IL-13, the two interleukins downstream of IL-33 shown to be responsible for the norepinephrine release so critical to turn white fat to beige in the diagrams in this post on IL-33 and this post on IL-4.

 

And in those two posts, we saw it wasn't just the presence of M2a macrophages that turned white fat to beige - the macrophages had to be induced to release norepinephrine by the presence of EOS cells and their release of IL-4. Since the in vitro experiment done with the thigh fat cells in this study didn't have either of these norepinephrine-inducing factors, it's not surprising that even the M2a macrophages caused a modest reduction in SC fat browning, rather than boosting the browning process as we saw previously. In other words, it takes cold to recruit EOS cells to release IL-4 to induce M2a macrophages to release the brown-inducing norepinephrine, and the SC fat cells in the petri dish in this study weren't exposed to cold, nor were there EOS cells around in the culture medium to help induce browning.

 

In short, inflammation is bad for SC fat browning, or as the authors put it:

 

When cold exposed adipocytes were exposed to inflammatory products,
either macrophage conditioned medium or TNF,
the cold response was considerably blunted. This effect
was especially pronounced with M1 macrophage conditioned
medium, indicating that a proinflammatory environment
blunts the beiging effect of WAT in response to cold.

 

The authors cite Michael' jiggling pecs study (PMID 26993316), saying:

 

[C]old-induced thermogenesis in BAT [around the neck region - DP]
could only explain a small fraction of the
total increase in overall energy expenditure, leaving open
the possible contribution of other tissues, such as WAT.

 

Here is a cool statistic for you from the final paragraph of the paper (my emphasis):

 

In contrast to BAT mass, which in humans is small (ref),
SC WAT mass is at least 1000-fold greater than that of BAT,
and therefore even a small increase in UCP1-mediated
mitochondrial uncoupling in WAT could significantly increase
energy expenditure. These changes in energy expenditure
may occur naturally with seasons, and this effect could
potentially be manipulated through drug therapy [or cold exposure! - DP].

 

This statement, and the results of this study, are right in line with the hypothesis I've been developing ever since Michael's jiggling pecs challenge - namely that the tiny amount of "BAT" tissue (actually beige fat cells) observed in the neck, upper chest, back and ribcage region of people is just the "tip of the iceberg" when it comes to sources of non-shivering thermogenesis in humans. 

 

In summary, this study [1] shows that what was observed in mice holds for humans as well - namely that cold exposure turns white fat to beige in subcutaneous fat pockets (aka "love handles") all around the human body. And most excitingly of all, they go one step further than any rodent experiments I've seen, to show that acute, localized cold exposure (via application of cold packs) can very quickly kick off the process of turning white fat deposits to calorie-burning beige fat. 

 

Of course once again there is no free lunch. To maintain the cold-induced beige adipose tissue, and to get it to actually burn extra calories, you need to expose it to cold, either acutely or systemically. You can't just apply a cold pack for 30 minutes and expect to burn extra calories in warm ambient conditions and in perpetuity.

 

So if you are interested in boosting brown (= beige) fat, I suggest you buy and start wearing one of those stylish cooling vests reviewed in this post.

 

--Dean

 

----------

[1] J Clin Endocrinol Metab. 2014 Dec;99(12):E2772-9. doi: 10.1210/jc.2014-2440.

 
The effects of temperature and seasons on subcutaneous white adipose tissue in
humans: evidence for thermogenic gene induction.
 
Kern PA(1), Finlin BS, Zhu B, Rasouli N, McGehee RE Jr, Westgate PM,
Dupont-Versteegden EE.
 
 
CONTEXT: Although brown adipose tissue (BAT) activity is increased by a cold
environment, little is known of the response of human white adipose tissue (WAT) 
to the cold.
DESIGN: We examined both abdominal and thigh subcutaneous (SC) WAT from 71
subjects who were biopsied in the summer or winter, and adipose expression was
assessed after an acute cold stimulus applied to the thigh of physically active
young subjects.
RESULTS: In winter, UCP1 and PGC1α mRNA were increased 4 to 10-fold (p < 0.05)
and 1.5 to 2-fold, respectively, along with beige adipose markers, and UCP1
protein was 3-fold higher in the winter. The seasonal increase in abdominal SC
WAT UCP1 mRNA was considerably diminished in subjects with a BMI > 30 kg/m(2),
suggesting that dysfunctional WAT in obesity inhibits adipose thermogenesis.
After applying an acute cold stimulus to the thigh of subjects for 30 min, PGC1α 
and UCP1 mRNA was stimulated 2.7-fold (p < 0.05) and 1.9-fold (p = 0.07),
respectively. Acute cold also induced a 2 to 3-fold increase in PGC1α and UCP1
mRNA in human adipocytes in vitro, which was inhibited by macrophage-conditioned 
medium and by the addition of TNFα.
CONCLUSION: Human SC WAT increases thermogenic genes seasonally and acutely in
response to a cold stimulus and this response is inhibited by obesity and
inflammation.
 
PMCID: PMC4255113
PMID: 25299843 
 
-------
[2] Kleiner S, Mepani RJ, Laznik D, et al. Development of insulin resistance
in mice lacking PGC-1alpha in adipose tissues. Proc. Natl.
Acad. Sci. USA. 2012;109:9635–9640.

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#228 TomBAvoider

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Posted 21 April 2016 - 04:05 PM

Very cool (forgive the lazy pun) science, Dean, thanks for all your hard work!

 

However, being a low down pleb, grubby and uncouth, when I read one of these cool science papers I always end up with "verrry interrestink! I tink I understand the vorld a bit better! BUT how can I apply this to MY life, mwahahaha!". Which is why I am much more excited to read about studies in humans, rather than in rodents. But the low down pleb that I am, I still end up: can I apply this to my life?

 

I hope that at some point there can be more focus on how a CRONie might apply CE in their life - supported by science insofar as one can. Now, since I'm a CRONie, that right there tells you that I'm willing to take a bit of a leap of faith (that CR works in humans, even a little), but I still cling to the hope that I can find some scientific backing to a lifestyle that already raises eyebrows and gets lots of eyes rolling. 

 

I'm talking about protocol based on science. It's all well and good to put on a cooling vest, turn down the thermostat, sleep without sheets in winter etc., but isn't this as serious as a CRON diet with a thousand considerations beyond just "cut calories!". What about initiation? Is it safe in late middle age (where many on this list find themselves), do we start exposure on a slope over time - 70° 6 months, 60° 4 months, 50° 3 months, 40° maintenance; how does the therapy look: ice vest at x temp for y amount of time z times a day... what are the x, y, z values? What are the contraindications which might inadvertently obviate CE bennies - the way there are plenty such in CR. All hopefully somewhat backed by science. Aren't we all pretty obsessive about our CR protocols, constantly tweaking them? Is CE different in that regard? Is it somehow a simpler intervention?

 

Again, not to take away from the intellectual aspect of this - no question very interesting. But there is also the grubby pleb side of me - how do I harness all this coolness?  



#229 Dean Pomerleau

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Posted 21 April 2016 - 04:35 PM

Tom,

 

All good points. I think the short answer is that we simply don't know what CE protocol is best for humans - i.e. we are in pretty much the same boat as we are in for CR. We don't know the best way to get cold, how cold is too cold, should we ease into cold exposure, can one be too old or frail for cold exposure, etc.

 

It's too new and unexplored even in rodents, to say nothing of people, to have answers to these questions.

 

Heck, we certainly don't know unequivocally that it will provide health & longevity benefits beyond weight loss (for those who need that...) although I would say improvements in glucose metabolism / insulin sensitivity / diabetes prevention seem extremely likely.

 

My hypothesis that "serious CR without CE will be futile" is just that - a hypothesis. But there is what I consider to be pretty compelling support for it from the rodent data (e.g. discussed here), from epidemiological data across species and in particularly long-lived small mammals (e.g. bats, grey squirrels and naked mole rats), and circumstantial and indirect support from the failure of "warm CR" to extend lifespan in monkeys as discussed here...

 

Regarding contraindications - that is the topic of my next post (yes, before rpWAT...), so stay tuned.

 

--Dean


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#230 Kenton

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Posted 22 April 2016 - 10:23 AM

I have been  tracking my body temp (trying to keep the average low) through the day the way one might track calories (trying to keep them low) throughout the day.  I tossed my FitBit and got a new fitness tracker band (after 1.5 days research) that tracks skin temperature (along with many other fancy sensors and software features like a "smart alarm" that does not wake me if I'm in the middle of a REM stage of sleep).  It's a "Microsoft Band 2."



#231 Dean Pomerleau

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Posted 22 April 2016 - 10:25 AM

Thanks Kenton,

 

I didn't realize the Microsoft Band 2 tracks skin temperature. That's a pretty handy feature. How's it compare with your Fitbit in it's other features?

 

--Dean


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#232 Michael R

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Posted 22 April 2016 - 12:57 PM

Thanks Kenton,

 

I didn't realize the Microsoft Band 2 tracks skin temperature. That's a pretty handy feature. How's it compare with your Fitbit in it's other features?

 

--Dean

 

The Basis Peak also tracks skin temp, and its heart rate monitoring has consistently outperformed FitBit and beaten or tied all competitors in both independent and company-sponsored tests (more and less rigorous). I've been meaning to post about its many virtues in the Cool Tools thread (title in this context amusing) for some time ...



#233 Dean Pomerleau

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Posted 22 April 2016 - 03:26 PM

Michael,

 

So nice to see you're still monitoring this thread. I was beginning to wonder. Does your silence on other topics of discussion imply your agreement?

 

The Basis Peak also tracks skin temp, and its heart rate monitoring has consistently outperformed FitBit and beaten or tied all competitors in both independent and company-sponsored tests (more and less rigorous). I've been meaning to post about its many virtues in the Cool Tools thread (title in this context amusing) for some time ...

 

Thanks for the tip on the Basis Peak. I didn't realize it tracks skin temperature too. But it is one butt-ugly fitness tracker:

 

997BuOm.png

 

I initially read the word "Basic" at the bottom of the watch as "Casio" . Did you ever own one of these Casio calculator watches?

 

MQUYPHR.png

 

I loved mine, back in the '70s...

 

Looking over the reviews of the Basis Peak, it looks pretty mixed, with almost as many 1- and 2-star ratings as 4 and 5-star ratings. And the first, and longest video review in the product description is pretty mixed - which is surprising, given it's provided by the seller. I presume you own one and find it useful?

 

I came across an attribute of the Basic Peak that would pretty much makes it a non-starter for my usage pattern, if it's still the case. In this review, the Basis Peak owner says:

 

The most frustrating aspect of using the device is that data does not sync in real time and has to be uploaded to the cloud before it will show you anything on your mobile device. Syncing and uploading that data takes more than a minute.

 

But that review is from over a year ago. Has the software changed to continuously update the app? Continuous updates are one thing I really like and rely on with my Fitbit Charge HR. I have my phone on top of my bike desk and monitor at a glance how far I've gone, how many "steps" I've taken, my HR etc via the Fitbit app. Since I've got my Fitbit strapped around my lower quad for a lot of the day, which is moving and under my desk, I can't easily read it while pedaling. I guess I could manually trigger a sync sporadically to see the latest data, but it would be a bit of a hassle.

 

On the other hand, the Basis Peak's other features do look pretty cool - skin temperature, waterproof, text messages and notifications, connects to other HR monitoring software. Do you think it really can track REM sleep? I'd be curious to hear more about your experience with it. 

 

--Dean


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#234 Dean Pomerleau

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Posted 22 April 2016 - 05:28 PM

Cold Exposure Downsides?

 

All,

 

I'm surprised this news story, entitled Lab Mice Are Freezing Their Asses Off—and That’s Screwing Up Science hasn't already been posted by one of the CE detractors (I'm looking at you Al ). I've been meaning to post about it, and since Tom brought up the question of what contraindications there might be for CE, I figure now is a good time to discuss it. 

 

It basically focuses on the findings by a team of cancer researchers at the Roswell Park Cancer Institute, led by Elizabeth Repasky, that has been investigating the effects of temperature on cancer growth in mice. There body of work, which this new review paper [1] summarizes, boils down to the fact that mice at Standard Temperatures (ST = 20-24 °C) are cold-stressed relative to Thermoneutral Temperatures (TT = 30-32 °C), and must engage in much more calorie-burning thermogenesis to maintain their body temperature. As a result:

 

It is likely that with the burden of rapid tumor growth, expansion of immune cell populations would compete for energy needed for thermogenesis such that, ultimately, immunosuppression may protect the ability of the organism to maintain body temperature.

 

In other words, experiments conducted at ST require mice to burn a lot of calories to stay warm, and so they have less energy left over to mount an effective immune response to slow the rapid growth of tumors in cancer experiments.

 

So what's the deal Dean? I thought you said (and Michael even agreed! ) that one of the benefits of CE in mouse lifespan is reduced mortality from cancer relative to warmer housing conditions? E.g. in the famous Koizumi & Walford study (PMID 9032756) discussed  here and here, and in greater detail & more recently here.

 

Indeed, the authors of [1] cite Koizumi & Walford, acknowledging in that instance cancer rates were lower at ST than TT in the context of calorie restriction:

 

Interestingly, Koizumi and colleagues showed that the reported ability of dietary restriction to reduce the incidence of lymphoma in mice only occurred at ST, and that this effect was lost in mice housed at TT [ref], again demonstrating a dichotomy of experimental results at ST versus TT.

 

So overall, the authors of [1] aren't claiming "cold house is bad", but that "cold housing is different" from thermoneutral housing when it comes to cancer. They also acknowledge that TT housing is different, and potential worse, when it comes to inflammation and atherosclerosis:

 

Tian et al. [ref] found increased inflammation in mice at TT, which was associated with promoting atherosclerosis...

 

But focusing on their main point about cancer, the difference appears to be similar to what we see with CR and immunity, as we've recently discussed here, here and here. In fact, the CR & immunity story may be almost synonymous with the CE & immunity story, since CR rodent studies are almost invariably "CR + CE" rodent studies...

 

Both the CR science and our CR Society Poll on immunity suggest that CR increases one's ability to prevent infections and cancer. But once a foreign invader gains a foothold in the body, CR makes it more difficult to mount an effective immune response in order to fight it off. There just aren't enough calories available to "feed a fever". In fact, according to the latest science, the old saying should actually be "feed a cold, feed a fever":

 

Fever is part of the immune system’s attempt to beat the bugs. It raises body temperature, which increases metabolism and results in more calories burned; for each degree of temperature rise, the energy demand increases further. So taking in calories becomes important.

 

CR alone, or CR with CE to create a net calorie deficit (as I recommend), results in relatively less energy available to devote to an immune response. This is bad news if you've got an established illness or cancer, either naturally acquired, or in the case of rodents used in cancer research, as a result of being injected with a bolus of cancer cells.

 

The bottom line seems to be that both CR & CE, and especially the combination, are beneficial for preventing infections and cancer, but are contraindicated when/if you've already got an infection or cancer.

 

Tomorrow I hope to finally get to my post about CE and rpWAT.

 

--Dean

 

-----------

[1] Trends In Cancer (59) http://dx.doi.org/10...can.2016.03.005 1

 

Thermoneutrality, Mice, and Cancer: A Heated Opinion

 
Bonnie L. Hylander1 and Elizabeth A. Repasky1,*
 
 
The ‘mild’ cold stress caused by standard sub-thermoneutral housing temperatures
used for laboratory mice in research institutes is sufficient to significantly
bias conclusions drawn from murine models of several human diseases. We
review the data leading to this conclusion, discuss the implications for research
and suggest ways to reduce problems in reproducibility and experimental
transparency caused by this housing variable. We have found that these cool
temperatures suppress endogenous immune responses, skewing tumor growth
data and the severity of graft versus host disease, and also increase the
therapeutic resistance of tumors. Owing to the potential for ambient temperature
to affect energy homeostasis as well as adrenergic stress, both of which
could contribute to biased outcomes in murine cancer models, housing temperature
should be reported in all publications and considered as a potential
source of variability in results between laboratories. Researchers and regulatory
agencies should work together to determine whether changes in housing
parameters would enhance the use of mouse models in cancer research, as
well as for other diseases. Finally, for many years agencies such as the National
Cancer Institute (NCI) have encouraged the development of newer and more
sophisticated mouse models for cancer research, but we believe that, without
an appreciation of how basic murine physiology is affected by ambient temperature,
even data from these models is likely to be compromised.
 

http://www.cell.com/...er/TRECAN59.pdf


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#235 Gordo

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Posted 23 April 2016 - 01:08 PM

Along the lines of practical application and contraindications...

I think if CE is a detriment to your sleep, is causing any physical problems (cold burns/frost bite, certain hypothermia symptoms: irritability, combativeness, confusion, delirium, slow reflexes, seizures, stupor, coma) you are obviously going way overboard.  Remember, if you are doing this right, your body is going to produce its own heat, and lots of it, so that your core temperature remains steady instead of dropping (requiring extra calories in the process).  If you are seeing excessively low body temperatures I would speculate that you are either not eating enough calories, possibly not eating enough fat (I get 30-40% of my calories from fat), or do not have enough adipose (and possibly muscle) tissue to begin with to support thermogenesis (may require higher BMI).

 

Some studies have noted beneficial effects from as little as 2 hours a day at just 66 degrees F exposure.  The cooling vest I use has a phase change temp of 58 degrees and I think that is just about perfect honestly.

 

More tips on "how to stay cool when it's hot out"

 

Now that the temps are rising where I live, I've been experimenting with various ways to stay cooler without blasting air conditioning all the time.  These are also low cost things you can do if you don't own a cooling vest.

 

  • Take cold showers.  I can't believe it took me so long to discover this, but cold showers are amazing.  A good way to get started is by getting in with lukewarm water, then slowly make it colder taking it as far as you can handle until you can take 100% cold water.  The first couple times I did "full cold" it was a real shock to my system causing involuntary hyperventilation, discomfort, and probably spiking blood pressure, but it only took a few times before I got acclimated to it, now I can step directly into a full cold shower with no warm up and minimal shock factor.  There is nothing quite like the feeling you get after stepping out from a cold shower - I have come to really enjoy this now, the sense of invigoration and positive alertness is a wonderful way to start your day!  If you google: cold shower norepinephrine you will get a taste for the fascinating research that has been done with this.  Note: If for some reason your tap water isn't cold, a good alternative is to fill your bath with water and add ice, no reason to go below about 55 degrees though.  Research has shown that immersion in 57 degree water results in:
    "increased metabolic rate (by 350%), heart rate and systolic and diastolic blood pressure (by 5%, 7%, and 8%, respectively). Plasma noradrenaline and dopamine concentrations were increased by 530% and by 250% respectively, while diuresis increased by 163% (more than at 32 degrees C). Plasma aldosterone concentrations increased by 23%. Plasma renin activity was reduced as during immersion in water at the highest temperature. Cortisol concentrations tended to decrease. Plasma adrenaline concentrations remained unchanged." 

     

     As a bonus, it is nearly impossible to be or become depressed when you are following a cold shower protocol due to the boost it causes in endorphins, noradrenaline, and dopamine. 

TIP: Let the cold water hit your face alone at first, this activates your dive reflex which in turn prepares your body for full cold water immersion and less shock.

 

[Amusing anecdote of the day: I was taking my cold shower this morning while listening to the radio, when they decided to play the classic hip hop song Cool Like Dat  (Digable Planets) where the chorus repeats "I'm cool like dat" and later "I'm chill like that", thought that was great... ]

 

 

  • Drink ice water with crushed ice.  It is possible to be in a 75 degree room without a cooling vest, and still have goose bumps on your arms, just from drinking crushed ice.  Note: I also tried swallowing bigger ice cubes just to see if it was viable -- I do NOT recommend this, they sometimes get stuck "on the way down" resulting in intense pain, and sometimes brain freeze as you try to line it up just right, definitely not worth it.  One doctor has even been promoting what he calls "The Ice Diet" which is an interesting read.  Eating a liter of ice per day may burn over 100 extra calories although this is disputed.

 

  • Eat frozen superfoods.  Things like frozen berries not only taste great, but promote great health.  Frozen foods can even pack more nutrients than their fresh counterparts.  When I find the best tasting, in season, fresh produce that freezes well, I stock up the deep freezer.  I was really enjoying some amazing frozen Chilean blueberries yesterday.  I'm going to go get some more right now...

Edited by Gordo, 03 June 2016 - 02:54 PM.


#236 TomBAvoider

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Posted 23 April 2016 - 02:32 PM

Aah, yes, lots of good tips on CE practice! For years now - decades - I've drunk my coffee and tea at room temperature; I hate to burn my mouth while drinking hot liquids, and some of my friends take pride in being able to drink piping hot liquids. And that was even before I read how drinking scalding hot tea results in elevated mouth/throat cancer. On the occasions that I go to some place like Starbucks, I always order my coffee with a side cup of ice which I use to rapidly lower the temp of the coffee. I have also been independently interested in cold brewed coffees and teas. And now with view to CE bennies, I wonder whether it would make sense to transition entirely to ice tea and ice coffee. However, that still leaves open the question: consuming cold coffee/tea is one thing - but what about the process of brewing? Is there a difference from the point of view of what you get in polyphenols, various substances from cold brewing tea/coffee/cacao versus hot brewing (and then chilling)?



#237 Dean Pomerleau

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Posted 23 April 2016 - 02:40 PM

I second Tom - thanks for the good tips Gordo! 

 

Regarding cold brewing (vs. cold drinking) of tea and coffee - I do both, just to cover my bases. I cold brew overnight (on the countertop) and then hot brew the mix in order to maximum extraction. See this post and this post for the best info I've been able to find on cold vs. hot brewing.

 

--Dean


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#238 Dean Pomerleau

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Posted 24 April 2016 - 06:39 PM

An "Enriched Environment" and Brain-Boosting BDNF Boosts Beige Fat Too!

 

Finally, here is my long-awaited, long-promised post about rpWAT.
 
Recall in this post we saw that adult humans have only "beige" fat, rather than true "brown" fat, and in recent posts we saw that chronic cold exposure can turn both white visceral and subcutaneous fat to beige, in both mice and people.
 
In this post, I focus on this study [1], which helps shed light on the conditions that stimulate the 'browning' of white fat, and its implications for human health and longevity. It's another one of those studies with a lot going on, but which I promise is worth the effort to understand.
 

Here is a pretty surprising (to me anyway) result. This study [1] divided standard C57Bl/6 mice into three groups, all of which were fed ad lib and housed at standard lab temperature (22 °C - chilly for mice):

  • Control Group - (CTR) standard, small, boring cages with 5 mice per cage.
  • Exercise Group - (EX) standard, small, boring cages with 5 mice per cage, augmented with a running wheel.
  • Enriched Environment Group - (EE) housed in the equivalent of a deluxe mouse resort, including:

[L]arge cages (63 cm x 49 cm x 44 cm, 5 mice per cage) supplemented with running wheels, tunnels, igloos, huts, retreats, wood toys, a maze, and nesting material in addition to standard lab chow and water. 

 

During 4 weeks of treatment, the EX and EE groups ate a bit more, and weighed a bit less than the controls. The EX and EE groups ate and weighed about the same, but the EE group had a lot less white fat than the EX group, despite running on their wheel an average of only 33% as far as the EX group. But here is where it really gets interesting...

 

They extracted different types of fat cells from the different groups and measured their oxygen consumption ex vivo. They found classic BAT cells from the EX group had a lot higher thermogenic activity than either the CTR or EE group (top graph), but the "RWAT" of the enriched mice consumed a lot more energy than either the runners or the controls (bottom graph):

 

Ti3wX1r.png

 

 

So now you should be asking - what the heck is RWAT? RWAT, also known as rpWAT stands for "retroperitoneal white adipose tissue". It is a visceral, abdominal fat next to the kidneys, as illustrated in the mouse in the following graphic we saw in a much earlier posts from last week:

 

VM2YsG5.png

I've labelled the RWAT (= rpWAT) with the green box and arrow. As you can see it is just above and behind the kidney, and is "browner" as a result of cold exposure (right insert) vs. thermoneutral housing (left insert). In fact, while the above fat deposit pictures are from a completely different study [3], the pictures showing rpWAT in the severely cold-exposed vs. thermoneutral mice from [3] are likely very similar to the rpWAT (= RWAT) of the "enriched environment" mice relative to controls in [1]. How do I know? Because the RWAT in the EE mice in [1] was 73% smaller and 62% 'browner' (more thermogenic) than the RWAT of controls, which (eyeballing it) appears to be a pretty good match to the pictures above of the rpWAT difference between 30°C and 4°C.

 

In short, between [1] and [3], we see the following results in mice:

  • Ad lib food + bone-crushing CE    → skinnier mice with increased BAT activity & 'browner' WAT
  • Ad lib food + mild CE + EX          → skinnier mice with increased BAT activity
  • Ad lib food + mild CE + EX + EE  → skinnier mice with 'browner' WAT (at least rpWAT)

where 'bone crushing' CE = 4°C, 'mild' CE = 22°C, EX = exercise, and EE = enriched environment.

 

So do humans have this same retroperitoneal fat (i.e. RWAT = rpWAT) that mice have? Yup, it's behind our kidneys, just like in mice. Take a look at this diagram:

 

xD5ueOK.png

 

As noted in the caption, retroperitoneal fat is considered a "visceral" fat - the type of fat associated with all the major SAD diet-related health problems (high cholesterol, metabolic syndrome, diabetes, CVD etc.). 

 

So far so good. The enriched environment seems to be helping to turn white fat brown, particularly rpWAT. But how much of the effect is attributable to the enriched environment per se vs. the extra exercise that the mice in the enriched environment (which recall includes a running wheel) engage in?

 

To find out, the authors tested another group of mice housed in the enriched environment, but with the running wheel removed. Remarkably, it appears that it takes the combination of the enriched environment and the running wheel to get the change in rpWAT gene expression, as illustrated by this graph:

 

 FNlkdK1.png

 

Look at the last set of bars representing UCP1 expression in rpWAT. The "enrich" environment, which included all the toys and the running wheel, had a hugely increased UPC1 expression (red bar) compared to the other conditions, including both a boring cage with a running wheel (green bars), or an enriched cage without the running wheel (blue bars).

 

They then put the EE and control mice on a high fat diet for four weeks to see if the EE would prevent obesity. It did. Here are the relevant graphics:

 

olGRX6V.png

 

As you can see, the EE mice ate more, weighed less, has smaller amounts of various white fats (but no smaller liver), had greater expression of thermogenic genes in their white fat (including UCP1), and had significantly better markers of metabolic health, including lower serum insulin, IGF-1, glucose, and cholesterol.

 

Notice however the EWAT and RWAT (= rpWAT) is smaller but doesn't look much browner in the EE mice relative to controls. But that was after only four weeks of living in the EE environment. When they extended the EE exposure to three months and fed them a normal chow diet (rather than high fat chow), things got a lot browner. Take a look at these images of the BAT, EWAT and RWAT of EE mice vs. controls:

 

qxDUYmJ.png

 

Pretty dramatic difference huh!?

 

The difference was evident in the gene expression data as well - UCP1 expression in rpWAT was boosted by 40x and the expression of the Elovl3 gene (responsible for elongating C16 fatty acids to C18 fatty acids in BAT to facilitate thermogenesis [2]) was upregulated in rpWAT by a factor of 118x (see full text for graphs).

 

Here is how the authors summarize the results up to this point:

 

EE consists of increased dynamic social interactions, frequent exposure to novel objects and enhanced physical activity. It is unlikely that a single variable accounts for all the effects of EE. Indeed several lines of evidence suggest exercise alone does not account for the EE-induced phenotype: 

  1. EE reduced adiposity more effectively than wheel running (Figure 1A, G).
  2. EE showed less physical activity than wheel running.
  3. EE with no wheel was able to decrease adiposity (Figure 1G).
  4. EE and wheel running mice displayed different behavioral adaption in CLAMS (Figure S1A).
  5. EE showed increased oxygen consumption in RWAT whereas wheel running showed an increase in BAT (Figure 1E).
  6. At the level of transcription, EE induced changes primarily in RWAT while wheel running influenced gene expression mainly in BAT (Figure 2A, B).
  7. EE and wheel running showed two qualitatively distinct gene expression profiles in PVH (Figure 1H) and whole hypothalamus (Figure S1B). However, the removal of running wheels attenuated WAT browning induced by EE suggesting that access to wheels is an important part of the complex environment provided in EE (Figure 2F).

They then did a bunch of genetic knockout experiments and determined that Brain-Derived Neurotrophic Factor (BDNF) was responsible for the EE-induced browning of WAT into beige fat. In support of BDNF's role in the browning of white fat in the enriched environment:

  1.  EE induced BDNF expression in the hypothalamus..
  2. Hypothalamic overexpression of BDNF mimicked EE-induced “browning” of WAT (Figure 5D).
  3.  Inhibition of hypothalamic BDNF function ... led to a complete reversal of the EE-associated molecular features in WAT (Figure 6B, 6D). 
  4. Inhibition of the EE-induced BDNF upregulation in hypothalamus by microRNA blocked the EE-induced brown fat molecular signature (Figure 6E). 
  5.  β-AR blockade attenuated EE- or hypothalamic BDNF overexpression-induced WAT browning (Figure S3C, S4E).

The authors summarize their results as follows:

 

In summary, our data demonstrate that EE decreases adiposity, increases energy expenditure, causes resistance to obesity, and induces a genetic, morphological and functional transformation from WAT to BAT through a central mechanism with hypothalamic BDNF as the key mediator linking environmental stimuli, sympathetic outflow and the “browning” of white fat and subsequent energy dissipation.

 

The takeaway for us humans appears to be that the combination of mild cold exposure, moderate sustained physical activity and keeping one's brain active through mental stimulation synergistically combine to turn white fat visceral fat to beige fat, and likely keep one's brain healthy, through increased expression of BDNF.

 

This is music to the ears of someone who spends a lot of his time in a cold basement pedaling continuously at his bike desk while researching health/longevity topics and reading voraciously. However I must acknowledge I come up a bit short on the "social interaction" that the EE mice enjoyed, unless engaging online discussions with friends count...

 

--Dean

 

----------

[1] Cell Metab. 2011 Sep 7;14(3):324-38. doi: 10.1016/j.cmet.2011.06.020.

 
White to brown fat phenotypic switch induced by genetic and environmental
activation of a hypothalamic-adipocyte axis.
 
Cao L(1), Choi EY, Liu X, Martin A, Wang C, Xu X, During MJ.
 
 
Comment in
    Cell Metab. 2011 Sep 7;14(3):287-8.
 
Living in an enriched environment with complex physical and social stimulation
leads to improved cognitive and metabolic health. In white fat, enrichment
induced the upregulation of the brown fat cell fate determining gene Prdm16,
brown fat-specific markers, and genes involved in thermogenesis and β-adrenergic 
signaling. Moreover, pockets of cells with prototypical brown fat morphology and 
high UCP1 levels were observed in the white fat of enriched mice associated with 
resistance to diet-induced obesity. Hypothalamic overexpression of BDNF
reproduced the enrichment-associated activation of the brown fat gene program and
lean phenotype. Inhibition of BDNF signaling by genetic knockout or
dominant-negative trkB reversed this phenotype. Our genetic and pharmacologic
data suggest a mechanism whereby induction of hypothalamic BDNF expression in
response to environmental stimuli leads to selective sympathoneural modulation of
white fat to induce "browning" and increased energy dissipation.
 
Copyright © 2011 Elsevier Inc. All rights reserved.
 
PMCID: PMC3172615
PMID: 21907139

 

-----------

[2] Cell Rep. 2015 Dec 15;13(10):2039-47. doi: 10.1016/j.celrep.2015.11.004. Epub

2015 Nov 25.
 
Brown Adipose Tissue Thermogenic Capacity Is Regulated by Elovl6.
 
Tan CY(1), Virtue S(2), Bidault G(1), Dale M(1), Hagen R(1), Griffin JL(3),
Vidal-Puig A(4).
 
Although many transcriptional pathways regulating BAT have been identified, the
role of lipid biosynthetic enzymes in thermogenesis has been less investigated.
Whereas cold exposure causes changes in the fatty acid composition of BAT, the
functional consequences of this remains relatively unexplored. In this study, we 
demonstrate that the enzyme Elongation of Very Long Chain fatty acids 6 (Elovl6) 
is necessary for the thermogenic action of BAT. Elovl6 is responsible for
converting C16 non-essential fatty acids into C18 species. Loss of Elovl6 does
not modulate traditional BAT markers; instead, it causes reduced expression of
mitochondrial electron transport chain components and lower BAT thermogenic
capacity. The reduction in BAT activity appears to be counteracted by increased
beiging of scWAT. When beige fat is disabled by thermoneutrality or aging, Elovl6
KO mice gain weight and have increased scWAT mass and impaired carbohydrate
metabolism. Overall, our study suggests fatty acid chain length is important for 
BAT function.
 
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
 
PMCID: PMC4688035
PMID: 26628376
 
---------
[3] Am J Physiol Endocrinol Metab. 2015 Jun 15;308(12):E1085-105. doi:
10.1152/ajpendo.00023.2015. Epub 2015 Apr 21.
 
A stringent validation of mouse adipose tissue identity markers.
 
de Jong JM(1), Larsson O(2), Cannon B(1), Nedergaard J(3).
 
 
The nature of brown adipose tissue in humans is presently debated: whether it is 
classical brown or of brite/beige nature. The dissimilar developmental origins
and proposed distinct functions of the brown and brite/beige tissues make it
essential to ascertain the identity of human depots with the perspective of
recruiting and activating them for the treatment of obesity and type 2 diabetes. 
For identification of the tissues, a number of marker genes have been proposed,
but the validity of the markers has not been well documented. We used established
brown (interscapular), brite (inguinal), and white (epididymal) mouse adipose
tissues and corresponding primary cell cultures as validators and examined the
informative value of a series of suggested markers earlier used in the discussion
considering the nature of human brown adipose tissue. Most of these markers
unexpectedly turned out to be noninformative concerning tissue classification
(Car4, Cited1, Ebf3, Eva1, Fbxo31, Fgf21, Lhx8, Hoxc8, and Hoxc9). Only Zic1
(brown), Cd137, Epsti1, Tbx1, Tmem26 (brite), and Tcf21 (white) proved to be
informative in these three tissues. However, the expression of the brite markers 
was not maintained in cell culture. In a more extensive set of adipose depots,
these validated markers provide new information about depot identity. Principal
component analysis supported our single-gene conclusions. Furthermore, Zic1,
Hoxc8, Hoxc9, and Tcf21 displayed anteroposterior expression patterns, indicating
a relationship between anatomic localization and adipose tissue identity (and
possibly function). Together, the observed expression patterns of these validated
marker genes necessitates reconsideration of adipose depot identity in mice and
humans.
 
Copyright © 2015 the American Physiological Society.
 
PMID: 25898951

There will never be peace in the world while there are animals in our bellies.

#239 Cloud

Cloud
  • Member
  • 74 posts

Posted 25 April 2016 - 11:24 AM

 

But focusing on their main point about cancer, the difference appears to be similar to what we see with CR and immunity, as we've recently discussed here, here and here. In fact, the CR & immunity story may be almost synonymous with the CE & immunity story, since CR rodent studies are almost invariably "CR + CE" rodent studies...

 

Both the CR science and our CR Society Poll on immunity suggest that CR increases one's ability to prevent infections and cancer. But once a foreign invader gains a foothold in the body, CR makes it more difficult to mount an effective immune response in order to fight it off. There just aren't enough calories available to "feed a fever". In fact, according to the latest science, the old saying should actually be "feed a cold, feed a fever":

 

Fever is part of the immune system’s attempt to beat the bugs. It raises body temperature, which increases metabolism and results in more calories burned; for each degree of temperature rise, the energy demand increases further. So taking in calories becomes important.

 

CR alone, or CR with CE to create a net calorie deficit (as I recommend), results in relatively less energy available to devote to an immune response. This is bad news if you've got an established illness or cancer, either naturally acquired, or in the case of rodents used in cancer research, as a result of being injected with a bolus of cancer cells.

 

The bottom line seems to be that both CR & CE, and especially the combination, are beneficial for preventing infections and cancer, but are contraindicated when/if you've already got an infection or cancer.

 

 

Hello Dean, thanks for all the reported analysis .

I have some doubts on the finals. I remember that Luigi fontana in the lecture i linked some months ago ( link at about 33:40) recalled some studies on the inibitory effects of protein restrictions on prostate cancer models on mice [1] and of protein restrictions and intermittent fasting in breast cancer [2] (open issue: relationship between CR and protein restrictions)

 

If then we consider the new view on cancer seen like a failure of the body's immune defense system, for convenience I cite the text regarding that from Josh Mitteldorf's blog here :

<< The old view was that there are random mutations in a particular cell line, a series of unfortunate accidents that cause the cells to disregard regulating signals from the body and just continue replicating and growing out of control.  Now we realize that cancer is a failure of the body’s immune defense system.  When we are young, our white blood cells search and destroy incipient cancers, but as we get older the immune early warning system is gradually shut down.>>  

the difference between prevention and inhibition becomes more smooth, could not be so? In other words if CR is effective in preventing infections and cancer and the reason is  the reinforced immunitary system (isn't it so?), then should be effective also if you have got an infection or cancer (with the inhibiting effects reported by Fontana).  What do you think?

 

Cloud

 

[1] Fontana, Oncotarget, 2013 PMID 24353195

[2] Lamming, Oncotarget, 2015  PMI 26378060



#240 Dean Pomerleau

Dean Pomerleau
  • Lifetime Member
  • 2,458 posts

Posted 25 April 2016 - 12:15 PM

Cloud,

 

CR and protein restriction like in the two paper you cite downregulates the pro-growth Insulin/IGF-1/AKT/MTOR pathway, and that should be a good thing for preventing cancer and for slowing the growth of slow-growing cancers like prostate cancer in your Fontana (PMID 24353195) reference. I've heard it said the IGF-1 is like rocket fuel for cancer cells - encouraging them to grow and divide. So elevated IGF-1 fans the flames of the cancer flame, and CR & PR avoids this.

 

But at the same time, it's becoming increasingly evident that immunotherapy, where the body's own immune system is revved up to kill cancer cells, is probably the best way to combat cancer once established - as opposed to poorly-targeted, often toxic chemotherapy and/or radiation. But to mount an effective immune response to cancer requires synthesizing new immune system cells, and that requires energy and the right anabolic hormonal milieu to turn immature progenitor cells into the various types of leukocytes. And this is seems to be dependent on MTOR activation. 

 

So CR / protein restriction may have good effects and bad effects on cancer proliferation via it's downregulation of IGF-1 & MTOR. 

 

The other good thing that CR / protein restriction (or cold exposure) seems to do is prevent the immune system from constantly being in a hyperactive state by reducing obesity and systemic inflammation. This had two salutary effects. It requires the immune system to produce fewer leukocytes, and therefore avoids depleting the reserve of stem cells, thereby preserving immunocompetence into old age. And with lower systemic inflammation, the (fewer) immune cells that are produced can focus their energy on hunting down and eliminating the real bad guys (e.g. cancer cells, viruses or bacteria), rather than wasting their time trying to clean up gunk and killing off cells that have been damaged by the toxic environment that has triggered the viscous circle of inflammation - e.g. macrophages mopping up oxidized cholesterol in the bloodstream, turning into harmful foam cells themselves and creating plaques in the arteries.

 

In short, it seems the interaction between CR, PR and CE on the one hand and the immune system, cancer and infections on the other is a complicated balance. It's not easy to say what their effects will be and it's almost certainly dependent on the type of cancer/infection and its stage. It appears from the evidence that CR, PR and CE are on beneficial on balance for preventing cancer. But once cancer has gotten a foothold, it's gets pretty confusing.

 

If I got cancer today (heaven forbid), and I wanted some kind of adjunctive therapy on top of whatever standard treatment my oncologist and I agree is best, I'd probably try to adopt a plant-based ketogenic diet (high fat, low protein, low carb) diet that was pretty replete with calories. That way my body would get the calories it needs to mount an effective immune response (and avoid sarcopenia), but at the same time avoid fanning the cancer flame with elevated Insulin, IGF-1 or glucose, the favored energy source for cancer cells. Note - I would not eschew traditional treatments in favor of diet & lifestyle cancer treatments alone, but use diet & lifestyle to boost the effectiveness of standard treatments.

 

Sorry for the lack of references...

 

--Dean


There will never be peace in the world while there are animals in our bellies.





Also tagged with one or more of these keywords: Cold Exposure, Exercise, Fasting, UCPs, UCP1, UCP3, FGF21