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Dean Pomerleau

Cold Exposure & Other Mild Stressors for Increased Health & Longevity

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Link to full text from Nature:

 

http://www.nature.com/ncomms/2016/160427/ncomms11420/full/ncomms11420.html

 

Exosomal microRNA miR-92a concentration in serum reflects human brown fat activity Nature Communications 7, Article number: 11420 doi:10.1038/ncomms11420 Received 14 October 2015 Accepted 24 March 2016 Published 27 April 2016  

ABSTRACT

Brown adipose tissue (BAT) dissipates energy and its activity correlates with leanness in human adults. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography coupled with computer tomography (PET/CT) is still the standard for measuring BAT activity, but exposes subjects to ionizing radiation. To study BAT function in large human cohorts, novel diagnostic tools are needed. Here we show that brown adipocytes release exosomes and that BAT activation increases exosome release. Profiling miRNAs in exosomes released from brown adipocytes, and in exosomes isolated from mouse serum, we show that levels of miRNAs change after BAT activation in vitro and in vivo. One of these exosomal miRNAs, miR-92a, is also present in human serum exosomes. Importantly, serum concentrations of exosomal miR-92a inversely correlate with human BAT activity measured by 18F-FDG PET/CT in two unique and independent cohorts comprising 41 healthy individuals. Thus, exosomal miR-92a represents a potential serum biomarker for BAT activity in mice and humans.

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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

My FitBit was less expensive but limited (e.g., no skin temp sensor).  The MS Band 2 is loaded with 10+ sensors, extremely versatile, software updataple, 3rd party APP compatible, desktop client enabled, and runs on all three OS platforms.  An overview on just the new release improvements is at https://www.youtube.com/watch?v=lEy6k9j8BP4.  I keep mine on airplane mode and charge it every 4+ days.

Edited by Kenton

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Thanks Kenton,

 

That video was a great review of the MS Band 2. It looks cool and has a lot more functionality than the Fitbit Charge HR. But with the way the band and clasp work, I don't see how I could mount it on my leg like I do with my Fitbit to count revolutions when on my stationary bike, or to count steps while pushing a grocery cart or walking the dog. My legs are skinny, but not that skinny. A quick search didn't turn up any band extenders for the MS Band 2, and the solution I use for my Fitbit (see video above) won't work for the Band 2 because of its different clasp design. Any solution you are aware of for that (admittedly rather idiosyncratic) issue?

 

Thanks!

 

--Dean

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Nicotinamide Riboside (NR) Increases BAT Activity and (May) Extend Lifespan

 

In this post over on the the NAD Supplement thread, I discuss a brand new study [2] in the journal Science which found the NAD+ precursor Nicotinamide Riboside (NR) apparently extends lifespan when fed to mice starting fairly late in life (24 months). I happened to see on the bottle of the LEF-brand NR supplement that NR "stimulates thermogenesis". This hint, coupled the repeated observation in this thread that just about every health- and/or lifespan-promoting intervention also increases BAT activity, I figured what the heck, I might as well check it out. 

 

Sure enough, it appears NR stimulates BAT activity too. Study [1], an earlier study by the same group of researchers as [2], found that at the same (admittedly very high1) dosage as [1], NR increases NAD+ level in a variety of tissues, including BAT, as can be seen in this graph from the full text:

 

a08mquT.png

 

Additionally, NR-treated mice were better able to maintain their body temperature when exposed to cold (4 °C), as seen in this graph (filled circles = NR-treated; open circles = controls):

 

AjO0Ina.png

 

How'd they do it? You guessed it, more BAT activity, at least in part. The researchers found that the BAT of NR-treated tended to have larger mitochondrial, and their BAT mitochondria had a lot more cristae - which are the folds in the mitochondrial inner membrane that facilitate proton pumping that generates energy & heat. Here are electron micrographs of the BAT of control mice (top) and NR-treated mice (bottom), along with bar graphs for their mitochondria size and cristae content (white bars = controls, black bars = NR-treated mice):

 

fHnQyyp.png

 

If you look closely at the micrographs, you can see the circular mitochondria of the NR-treated mice are indeed larger on average, and have a ton more squiggly lines (cristae) inside them than the mitochondria of the control (Veh) mice.

 

Now I won't pretend that BAT activity is the only thing NR influences. NR is a precursor to NAD+, which is involved in many important metabolic processes, and which also serves as an important signalling molecule throughout the body. But it's long been known that administering NAD+ precursors improves serum cholesterol levels and type 2 diabetes, which are also well-known benefits of increased BAT activity. This is probably not a coincidence. Perhaps it's also not a coincidence that NR boosts BAT activity and also appears to extend lifespan [2]. It's worth noting, based on the supplemental material (pdf) from [1], that the long-lived, NR-treated mice in [2] were fed ad lib and housed at an unspecified temperature, which was almost certainly the standard (chilly-for-mice) lab temperature of 20-23 °C...

 

In summary, we once again see an example of what I'm going to call the "BAT Rule" - most interventions known to promote health and/or longevity also seem to boost BAT activity / thermogenesis. I've added Nicotinamide Riboside (NR) to the master list of BAT-promoters below, although at ~$500/month for the equivalent dose1 as used in [1] and [2], cold exposure seems a much better alternative than NR supplements...

 

--Dean

 

-----------

Here is the latest full list of modifiable and [non-modifiable] factors associated with increased BAT quantity and/or activity:
  • Cold exposure - by far the best BAT inducer/activator
  • Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions
  • Arginine-rich foods - Good vegan sources include seeds (esp. sesame, sunflower & pumpkin), nuts (esp. almonds and walnuts) and legumes (esp. soy, lupin & fava beans and peas)
  • Other foods - green tea, roasted coffee, cacao beans / chocolate
  • Olive Oil / MUFA-rich diet
  • DHA / fish-oil
  • Low protein diet
  • Methionine restriction - Reduce animal protein. Soy is low in methionine and high in arginine (see below).
  • Drugs/supplements - metformin, caffeine, Nicotinamide Riboside (NR)
  • Avoiding gluten
  • Fasting
  • Exercise
  • Avoid obesity/overweight
  • [being naturally thin - high metabolic rate]
  • [being younger]
  • [being female]
  • [Ethnicity - having cold-climate ancestors]

 

---------

1The dosage in both [1] and [2] was 400mg/kg-BW/day, which is the human equivalent of ~3000 mg/day, or about ~$500/month.

 

---------

[1] Cell Metab. 2012 Jun 6;15(6):838-47. doi: 10.1016/j.cmet.2012.04.022.

 
The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and
protects against high-fat diet-induced obesity.
 
Cantó C(1), Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y,
Fernandez-Marcos PJ, Yamamoto H, Andreux PA, Cettour-Rose P, Gademann K, Rinsch
C, Schoonjans K, Sauve AA, Auwerx J.
 
 
As NAD(+) is a rate-limiting cosubstrate for the sirtuin enzymes, its modulation 
is emerging as a valuable tool to regulate sirtuin function and, consequently,
oxidative metabolism. In line with this premise, decreased activity of PARP-1 or 
CD38-both NAD(+) consumers-increases NAD(+) bioavailability, resulting in SIRT1
activation and protection against metabolic disease. Here we evaluated whether
similar effects could be achieved by increasing the supply of nicotinamide
riboside (NR), a recently described natural NAD(+) precursor with the ability to 
increase NAD(+) levels, Sir2-dependent gene silencing, and replicative life span 
in yeast. We show that NR supplementation in mammalian cells and mouse tissues
increases NAD(+) levels and activates SIRT1 and SIRT3, culminating in enhanced
oxidative metabolism and protection against high-fat diet-induced metabolic
abnormalities. Consequently, our results indicate that the natural vitamin NR
could be used as a nutritional supplement to ameliorate metabolic and age-related
disorders characterized by defective mitochondrial function.
 
Copyright © 2012 Elsevier Inc. All rights reserved.
 
PMCID: PMC3616313
PMID: 22682224
 

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

[2] Science. 2016 Apr 28. pii: aaf2693. [Epub ahead of print]

NAD+ repletion improves mitochondrial and stem cell function and enhances life
span in mice.
 
Zhang H(1), Ryu D(1), Wu Y(2), Gariani K(1), Wang X(1), Luan P(1), D'Amico D(1),
Ropelle ER(3), Lutolf MP(4), Aebersold R(5), Schoonjans K(6), Menzies KJ(7),
Auwerx J(8).
 
 
Adult stem cells (SCs) are essential for tissue maintenance and regeneration yet
are susceptible to senescence during aging. We demonstrate the importance of the
amount of the oxidized form of cellular nicotinamide adenine dinucleotide
(NAD(+)) and its impact on mitochondrial activity as a pivotal switch to modulate
muscle SC (MuSC) senescence. Treatment with the NAD(+) precursor nicotinamide
riboside (NR) induced the mitochondrial unfolded protein response (UPR(mt)) and
synthesis of prohibitin proteins, and this rejuvenated MuSCs in aged mice. NR
also prevented MuSC senescence in the Mdx mouse model of muscular dystrophy. We
furthermore demonstrate that NR delays senescence of neural SCs (NSCs) and
melanocyte SCs (McSCs), and increased mouse lifespan. Strategies that conserve
cellular NAD(+) may reprogram dysfunctional SCs and improve lifespan in mammals.
 
Copyright © 2016, American Association for the Advancement of Science.
 
PMID: 27127236

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That video was a great review of the MS Band 2 ... But with the way the band and clasp work, I don't see how I could mount it on my leg like I do with my Fitbit to count revolutions when on my stationary bike, or to count steps while pushing a grocery cart or walking the dog. My legs are skinny, but not that skinny....

Hi Dean -  The MS Band 2 comes in three sizes.  The small size band is almost too BIG for my wrist.  Since you and I seem to have similar frame sizes, I'll bet the medium may be your fit and if not that the large.  BTW, I'm buying a Hesvit S3 (http://tinyurl.com/j56vz59 and http://tinyurl.com/z3zlbh5) for additional temperature sensors/functions/options.  It's more of a stand-alone device with a ~7 day battery--not necc better but poss more suitable for a temp tracker. Cheers, Kenton

Edited by Kenton

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Thanks Kenton,

 

Since you and I seem to have similar frame sizes, I'll bet the medium may be your fit and if not that the large.

 

I'm obviously not concerned about getting an MS Band 2 to fit my wrist. My problem is fitting it around my leg, just above my knee, so it will count steps while I'm pedalling. My legs are skinny, but not that skinny. In particular, my leg is 35cm in circumference where I wear my FitBit and the largest MS Band 2 size accommodates up to 20cm, so that wouldn't work. And even if it did - I'd have to buy one for my wrist and one for my leg, since no single size would fit both. It looks like I'll have to stick with my FitBit if I want to keep track of pedal rotations on my stationary bike & my bike desk.

 

That Hesvit S3 looks pretty cool with a variety of interesting sensors. It has a normal clasp, so I could mount it on my leg. It's especially appealing if you were able to get that $46 "panic buy" price - which is no longer valid. In fact, it looks like that site you pointed to is out of stock, and the Hesvit is $100 on Amazon. The Amazon reviews are generally positive, but with a few troubling issues - like someone unable to install the Android App, and the Hesvit conching out after a few days. I'll be curious what you think of it when it arrives. 

 

I'm considering opening a thread devoted to fitness trackers, and move all the posts about them from this thread to that one. Would anyone involved (i.e. Michael & Kenton) object?

 

--Dean

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Dean, duh, I was saying since the small size is so large the medium size or the large size would likely be huge enough to fit around your tiny CR'd CE'd leg ! ! !  You have enough m$n$y to buy both dear Dean!  I bought my Hesvit for less than 50 via ebay.  Re various temp tracking features, it looks really awesome (and I'm sure the Android App installation will be fine.)

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...I'm considering opening a thread devoted to fitness trackers, and move all the posts ...

You and MR seem to be speaking on wearable trackers for fitness (i.e., heartrate, activity, etc.).  My posts have spoke to skin temperature sensors which seems highly germane to CE.

Edited by Kenton

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Kenton,

 

Dean, duh, I was saying since the small size is so large the medium size or the large size would likely be huge enough to fit around your tiny CR'd CE'd leg ! ! !  You have enough m$n$y to buy both dear Dean!  I bought my Hesvit for less than 50 via ebay.  Re various temp tracking features, it looks really awesome (and I'm sure the Android App installation will be fine.)

 

Duh - I know that is what you were suggesting. As I clearly pointed out in my last post, I checked and even the largest MS Band 2 is too small to fit around my leg. Let us know when you get the Hesvit.

 

You and MR seem to be speaking on wearable trackers for fitness (i.e., heartrate, activity, etc.).  My posts have been on skin temperature sensors which seems quite germane for this thread.

 

Good point. Can you share what you've learned, and even better, some data, from monitoring your skin temperature with the MS Band 2?

 

As I pointed out to Gordo, I'm skeptical of how useful a single channel of skin surface temperature will be, given how it's influenced in a very modest way by thermogenesis, and in a big way by ambient temperature. And I was expressing skepticism about a single measurement from the neck area. The wrist is even less likely to provide useful data about thermogenesis, since it is so far from BAT, or even beige fat deposits.

 

--Dean

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As mentioned above, I'm tossing the MS Band 2 (MB2) and getting a Hesvit S3 because the S3 seems dramatically more suitable for the types of temp tracking I want; hence, I won't be sharing MB2 data in favor of awaiting acquiring S3 data.  (Per the link I gave above, the S3 measures wrist skin temp, temp b/w wrist and ambient, galvanic, etc., or some things like that.)  As I mentioned multiple pages up, I want an average and/or mean temp reading in any of the measured temp categories, for each day, to approx daily thermal energy intake like I approx daily food energy intake.  One might liken this restricting of thermal energy intake via skin to restricting of food energy intake via mouth.  On your thermogenesis (TH) remark, my wrist skin temp does not appear to be affected much by TH (except 1x/day before eating) possibly due in part to my CR/CE practice particulars--I'm hoping the readings will be meaningful even in consideration of TH effects and, who knows, if TH becomes stronger the readings may be meaningful in flushing out that transitioning, too.

Edited by Kenton

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Futile Creatine Cycling - Another Thermogenic Pathway

 

Given how important it is from the perspective of natural selection to avoid freezing to death, it is perhaps not surprising that mammals have developed a number of different behavioral and metabolic methods of maintaining body temperature in response to cold. We've discussed metabolic pathways for thermogenesis previously in this thread, including UCP1-mediated futile cycling of protons across the mitochondrial membrane in brown adipose tissue as well as beige adipose tissue in both subcutaneous and visceral fat deposits, and my personal favorite, sarcolipin-induced futile cycling of calcium ions in the sarcoplasmic reticulum of skeletal muscle cells. 

 

It looks like there is another game in town when it comes to thermogenesis pathways in beige fat. It involves creatine, and it looks relevant to humans. But first a little background. 

 

Creatine has long been known to be important for "explosive" power in skeletal muscles. Here is what seems to happen, as far as I understand it. During times of relative rest, ATP (the body's short-term energy 'currency') donates a phosphate group to creatine, and in the process the ATP gets converted into lower-energy ADP. The resulting phosphate-boosted creatine molecule is, not surprisingly, called phosphocreatine or PCr. PCr can be thought of as an "ATP battery" - storing up energy donated by ATP in the reaction just described for later use when needed. In particular, when a muscle needs to quickly contract, the reaction is reversed. That is, PCr is converted back to creatine, and in the process donates a phosphate group to back to ADP, in order to rapidly synthesize ATP, which the muscle needs to contract. Here is a schematic of the process - showing the "explosive" phase when the PCr battery gets rapidly drained, or in other words, when PCr is converted to creatine to generate ATP from ADP to support muscle contraction:

 

geU5GEs.png

 

The important thing to realize for our purposes is that this reaction is entirely reversible; you can go from ATP → ADP and "charge" the PCr battery, or go from ADP → ATP by "draining" the PCr battery. But obviously, you need sufficient creatine in muscles to serve as the substrate for the PCr battery. That's why weightlifters and other strength-athletes supplement with it; to facilitate creation of the PCr energy-storage 'battery' for explosive power in skeletal muscles when lots of ATP is required on short notice to facilitate rapid muscle contraction.

 

But it has been known for 40 years that creatine isn't just found in skeletal muscles; it is also found in brown adipose tissue [2]. The authors observed that:

 

The results strongly suggest that the energy metabolism of [brown] adipose tissue is closely 
dependent on the presence of creatine.

 

But it wasn't clear in 1976 how creatine was involved in energy metabolism in BAT. Fast forward twenty years, when it was discovered that rats depleted of creatine has more BAT tissue and elevated expression of UCP1, but were nevertheless unable to generate as much heat as control rats that were replete with creatine [3]. So creatine was again seen as important for BAT thermogenesis, but it still remained a mystery exactly how creatine was involved in heat production.

 

Now, fast forward another two decades to last year, when [1] was published and seems to have solved the mystery, with potentially important implications for those of us interested in boosting thermogenesis. 

 

Study [1] is another one of these long-and-involved studies with lots of different experiments with lots of different compounds administered to lots of different strains of gene-knockout mice, was well as to isolated human beige adipocytes. What they found can be summarized in this rather intimidating diagram\ to which I've added a few annotations (in blue) for explanatory purposes:

 

xZ1fEwf.png

What we're looking at is part of a mitochondria in brown (or beige) adipose tissue. What you can see at the bottom is the standard respiratory chain, culminating in the generation of ATP from ADP, which you should be familiar with by now. What I've labelled "PCr Battery Circuit" is the same reversible reaction illustrated in the diagram at the top of this post involving Creatine ⇄ PCr and ATP ⇄ ADP. What's going on in the interplay between these two circuits in BAT is the following. The standard respiratory chain burns energy and generates heat in the process of converting ADP into ATP. That ATP is then reduced back to ADP in order to charge up the PCr "battery", generating more heat in the process. Finally, through the process I've labelled "PCr Battery Leakage" the PCr gets converted back to creatine so that the whole energy-dissipating, heat-generating cycle can be repeated. 

 

In short, this is yet another pathway by which BAT and beige fat can engage in thermogenesis. The authors of [1] show that it is complementary with the well-known UPC1-mediated thermogenic pathway. Specifically, in UCP1-knockout mice, this creatine pathway for thermogenesis is upregulated to compensate, and keep the mice warm when housed at cold temperatures.

 

But an important thing to note is that to take advantage of this alternative thermogenic pathway requires a sufficient amount of creatine be present in BAT and beige fat cells. Without enough creatine, UPC1-knockout mice can't keep warm in cold conditions.  In the words of the authors of [1]:

 

If creatine metabolism plays a substantial role in thermogenesis in humans,
as suggested by the work here with isolated cells, it could open up possibilities
to manipulate energy expenditure in patients with metabolic diseases by new
drugs or even with dietary supplementation.

 

This has important implications, particularly for veg(etari)ans, whose creatine level tends be low. Michael discusses the importance of adequate creatine in his post about "conditionally essential" nutrients for vegetarians in order to maintain muscle strength and potentially brain health as well. He suggests that veg(itari)ans may be especially in need of creatine supplements, providing multiple references for lower levels of creatine in the tissues of vegetarians relative to omnivores. 

 

What study [1] shows is that creatine also appears to be important for beige-fat thermogenesis, which from my perspective makes it all the more important to ensure an adequate creatine level. In fact, it seems important enough to add creatine to the list of BAT thermogenesis inducers (see updated list below). I'm going to purchase some Creapure creatine and add it to my supplement regime, to the tune of a couple grams per day on an empty stomach, as Michael suggests. I (obviously) don't recommend the alternative, dietary sources of creatine, which are all animal products ☹. It's also interesting to note that creatine is synthesized from three amino acids, glycine, methionine and arginine - the latter of which is on the list already as a BAT activator.

 

I'll report back if I notice creatine supplements making any observable difference in my subjective impression of thermogenesis.

 

--Dean

 

Here is the latest full list of modifiable and [non-modifiable] factors associated with increased BAT quantity and/or activity:
  • Cold exposure - by far the best BAT inducer/activator
  • Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions
  • Arginine-rich foods - Good vegan sources include seeds (esp. sesame, sunflower & pumpkin), nuts (esp. almonds and walnuts) and legumes (esp. soy, lupin & fava beans and peas)
  • Creatine supplements or creatine-rich foods - lean red meat, chicken breast, salmon and tuna.
  • Other foods - green tea, roasted coffee, cacao beans / chocolate
  • Drugs - metformin, caffeine
  • Avoiding gluten
  • Olive Oil / MUFA-rich diet
  • DHA / fish-oil
  • Methionine restriction - Reduce animal protein. Soy is low in methionine and high in arginine (see below).
  • Low protein diet
  • Fasting
  • Exercise
  • Avoid obesity/overweight
  • [being naturally thin - high metabolic rate]
  • [being younger]
  • [being female]
  • [Ethnicity - having cold-climate ancestors]

 

----------

[1] Cell. 2015 Oct 22;163(3):643-55. doi: 10.1016/j.cell.2015.09.035. Epub 2015 Oct

22.
 
A creatine-driven substrate cycle enhances energy expenditure and thermogenesis
in beige fat.
 
Kazak L(1), Chouchani ET(1), Jedrychowski MP(2), Erickson BK(2), Shinoda K(3),
Cohen P(1), Vetrivelan R(4), Lu GZ(5), Laznik-Bogoslavski D(5), Hasenfuss SC(1), 
Kajimura S(3), Gygi SP(2), Spiegelman BM(6).
 
 
Thermogenic brown and beige adipose tissues dissipate chemical energy as heat,
and their thermogenic activities can combat obesity and diabetes. Herein the
functional adaptations to cold of brown and beige adipose depots are examined
using quantitative mitochondrial proteomics. We identify arginine/creatine
metabolism as a beige adipose signature and demonstrate that creatine enhances
respiration in beige-fat mitochondria when ADP is limiting. In murine beige fat, 
cold exposure stimulates mitochondrial creatine kinase activity and induces
coordinated expression of genes associated with creatine metabolism.
Pharmacological reduction of creatine levels decreases whole-body energy
expenditure after administration of a β3-agonist and reduces beige and brown
adipose metabolic rate. Genes of creatine metabolism are compensatorily induced
when UCP1-dependent thermogenesis is ablated, and creatine reduction in
Ucp1-deficient mice reduces core body temperature. These findings link a futile
cycle of creatine metabolism to adipose tissue energy expenditure and thermal
homeostasis. PAPERCLIP.
 
Copyright © 2015 Elsevier Inc. All rights reserved.
 
PMCID: PMC4656041 [Available on 2016-10-22]
PMID: 26496606
 
------------
[2] Biochim Biophys Acta. 1976 Jun 23;437(1):166-74.
 
Occurrence of free creatine, phosphocreatine and creatine phosphokinase in
adipose tissue.
 
Berlet HH, Bonsmann I, Birringer H.
 
We evaluated brown and white adipose tissues for the presence of creatine,
phosphocreatine and creatine phosphokinase activity. In rats 3.6 and 0.4 mumol of
total creatine were found per g wet weight of brown and white adipose tissues,
respectively. We were able to identify creatine by thin-layer chromatography
after a pulse label of [14C]creatine had been given in vivo. Free creatine and
phosphocreatine were shown to occur by column chromatography. Of the total
creatine of brown adipose tissue, approximately one third to one half were
attributable to phosphocreatine. The activity of creatine phosphokinase was
demonstrated in both white and brown adipose tissue, the values of the latter
prevailing over those of the former by a factor of 200, if based on wet weight,
or 50, if expressed as specific enzyme activity. The labeling of total creatine
in vivo proceeded much faster in adipose tissue than in skeletal muscle. The
results strongly suggest that the energy metabolism of adipose tissue is closely 
dependent on the presence of creatine. The specific activities of free creatine
and phosphocreatine of brown adipose tissue differed strikingly as long as 24 h
after radioactive creatine was injected; this difference points to a metabolic or
structural compartmentation of creatine.
 
PMID: 949504
 
----------
[3] Biochim Biophys Acta. 1995 Jun 1;1230(1-2):69-73.
 
Increased growth of brown adipose tissue but its reduced thermogenic activity in 
creatine-depleted rats fed beta-guanidinopropionic acid.
 
Yamashita H(1), Ohira Y, Wakatsuki T, Yamamoto M, Kizaki T, Oh-ishi S, Ohno H.
 
Author information: 
(1)Department of Hygiene, National Defense Medical College, Tokorozawa, Japan.
 
To study the responses of thermogenic activity in brown adipose tissue (BAT) to
creatine depletion, male Wistar rats were fed creatine analogue
beta-guanidinopropionic acid (beta-GPA) for about 10 weeks. Compared to control
rats, a marked decrease in the levels of high-energy phosphates, such as
phosphocreatine and ATP, was noted in BAT of beta-GPA rats. Conversely, upward
trends in other chemical components (DNA, glycogen, and total protein) in BAT as 
well as an increase in BAT mass were observed in beta-GPA rats, suggesting a
tendency to hyperplasia of the BAT. The thermogenic activity (which was assessed 
by guanosine 5'-diphosphate binding to BAT mitochondria) in the mitochondria
recovered from BAT of beta-GPA rats, however, was not increased in response to
such changes but rather decreased. Moreover, uncoupling protein (UCP) content in 
the mitochondrial fraction of beta-GPA rats was significantly lower than that in 
control rats (the relative amounts were 77 +/- 6 and 100 +/- 4%, respectively).
Nevertheless, surprisingly, the level of UCP mRNA was remarkably greater in
beta-GPA rats than in control rats. These observations indicate that there is a
discordance between BAT growth and activity in beta-GPA rats, thereby suggesting 
that a failure on and after UCP translation may be involved in the impairment of 
BAT thermogenic activity with creatine depletion. The impairment of BAT
thermogenic activity, that is, UCP activity may indicate that uncoupling or heat 
production was inhibited in order to increase the ATP synthesis in BAT of
beta-GPA rats in compensation for a reduction in the levels of high-energy
phosphates (including ATP), with resultant hypothermia.
 
PMID: 7612643

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Al Pater just posted a study to the list, that throws some light on the effect of CR on diet-induced thermogenesis. This may be of interest especially to those thinking of how CR might interact with CE:

 

https://www.jstage.jst.go.jp/article/jnsv/62/1/62_40/_pdf

 

The Effects of a Hypocaloric Diet on Diet-Induced Thermogenesis and Blood Hormone Response in Healthy Male Adults: A Pilot Study.

Ishii S, Osaki N, Shimotoyodome A.

J Nutr Sci Vitaminol (Tokyo). 2016;62(1):40-6. doi: 10.3177/jnsv.62.40.

PMID: 27117850

 

 

Abstract

 

Calorie restriction is a common strategy for weight loss and management. Consumption of food and nutrients stimulates diet-induced thermogenesis (DIT), as well as pancreatic and gastrointestinal hormone secretion that may regulate energy metabolism. Yet, little is known about the impact of hypocaloric diets on energy metabolism-related parameters. In this study, we assessed the effects of hypocaloric diets on hormonal variance in relation to DIT in healthy adults. Ten healthy male adults were enrolled in a randomized crossover study comprising three meal trials. Each subject was given a meal of 200 (extremely hypocaloric), 400 (moderately hypocaloric), or 800 kcal (normocaloric). Postprandial blood variables and energy expenditure were measured for 4 h (after the 200- and 400-kcal meals) or 6 h (after the 800-kcal meal). DIT and postprandial changes in blood pancreatic peptide and ghrelin were significantly smaller after the extremely or moderately hypocaloric diet than after the normocaloric diet but were similar between the hypocaloric diets. Postprandial blood insulin, amylin, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide type-1 (GLP-1) increased in a calorie-dependent manner. Thermogenic efficiency (DIT per energy intake) was negatively correlated with the maximum blood level (Cmax) (p=0.01) and incremental area under the curve (p=0.01) of the blood GIP response. Calorie restriction thus leads to hormonal responses and lower DIT in healthy adults. Extreme calorie restriction, however, led to greater thermogenic efficiency compared with moderate calorie restriction. The postprandial GIP response may be a good predictor of postprandial thermogenic efficiency.

 

Thank you, Al!

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BAT Activators Besides Cold and Dietary Methods; Part 1 - Acupuncture!

 

For those of you want to join the party with BAT & thermogenesis, but who hate cold and are happy with your diet the way it is, this is the first of two (maybe three) posts discussing non-CE, non-diet ways of boosting BAT & thermogenesis that might be more up your alley. 

 

The first [1] seems crazy to me, but the study seems legit. Researchers (not surprisingly, from China) found that  acupuncture can apparently convert white fat to beige. I kid you not. The study was in mice, so a placebo effect is unlikely to explain the results, although there may be the possibility of other confounders (see below).

 

Here is what they did, and what they found. They divided mice up into two groups - a normal, relatively low-fat chow group (N = 20) which are labelled NF below, and a high-fat diet group (N = 80). After 8 weeks on the high-fat diet the experimental group was 20% fatter than the NF group. They then divided these pudgy mice into a control group (labelled 'control' below) and an electro-acupuncture (EA) group. Here is how the authors describe the treatment for the EA and control groups:

 

Mice in the EA group were physically restrained, then electro-acupunctured on Zusanli (ST36) and Neiting (ST44), while mice in the control group were restrained in the same way, without acupuncture. For the EA mice, two acupuncture needles (Gauge-28, 0.5 cm) were separately inserted into each acupoint and an electrical current was provided to the needles through an electrical stimulator with parameters of 2/15 Hz at an intensity level of 1 mA (Han Acuten, WQ1002F, Beijing, China) for 30 minutes, once a day, six days a week. 

 

For those of you non-experts when it comes to acupuncture (like me), I've highlighted the human-equivalents of the two points on the mice the researchers stimulated (Zusanli (ST36) and Neiting (ST44)) in the diagram below. One is on the left foot and the other just below the left knee:

 

ePzCRfc.png

 

 

How did they pick those two spots to apply acupuncture? Oddly, the authors don't say explicitly, but in this previous study [2] by an overlapping group at the same university, they found that acupuncture applied to those same two spots resulted in weight loss in obese rats relative to obese control rats, apparently as a result of reduced food intake stemming from changes in hypothalamic-induced satiety signalling.

 

In [2] they also cite a bunch of human studies showing acupuncture appears to be effective at treating obesity in humans [3-8]. Study [3] in particularly is a recent meta-analysis that concludes acupuncture is indeed reasonably effective for weight loss relative to placebo acupuncture, although "conclusions were limited by small sample size and low quality of methodologies." And I found this study [9] which found a highly significant 4.7% weight loss (p < 0.001) in obese women treated with electroacupuncture for 20 days, at six different spots, including the two spots used in this study (ST36 and ST44).

 

Back to the study at hand [1]. What they found was a bit at odds with their previous study [2] of acupuncture-induced weight loss in rats [2] and all the human studies. Instead of eating less and losing weight like the rats in [2], the electro-acupunctured (EA) mice in [1] ate slightly more and weighted the same as the control mice that didn't receive acupuncture, but were similarly restrained each day. Here are the graphs of body weight (A) and food intake (B) of EA mice (open circles) vs. controls (closed circles):

 

qWdEEhM.png

 

Interestingly, as shown in graphs C & D above, the EA mice had less white fat as a percent of body weight than the controls. Since the body weight of EA and control mice were virtually identical, this suggests that the EA mice had less total white fat mass.

 

But the result in [1] that was most interesting and relevant to this thread is what happened to the white fat of the mice. You guessed it, it turned to beige. Quoting from [1]:

 

We also found that UCP1 gene expression in WAT increased almost 14 folds in EA mice than in the control mice (Figure 2A), and the UCP1 protein expression also significantly increased in EA mice (Figure 2B). Our data strongly suggests that electro-acupuncture treatment results in browning of WAT in EA mice. 

 

Here is Figure 2 referenced above:

 

UoGcd1h.png

 

Perhaps as dramatic as the UPC1 upregulation shown in 2A and 2B is the visually striking shrinkage and browning of epididymal WAT shown in 2C and 2D in the EA group compared with high-fat fed controls as well as relative to much thinner mice fed normal chow (NF).

 

Figure 3A, 3B and 3C (below) show that levels of serum leptin, cholesterol and triglycerides were lower in the acupuncture mice relative to controls as well, clearly illustrating a metabolic benefit despite no overall weight loss in the acupuncture group:

 

IcY4Dtn.png

 

Most telling of all perhaps, figure 3D shows that the acupunctured mice were better able to defend their body temperature when subjected to cold (4°C for six hours), which is what you'd expect since the EA mice appeared to have more beige fat than controls.

 

See what I mean by legit? These folks seemed to have covered their bases and put together a pretty solid study showing acupuncture can induce the browning of white fat. Pretty surprising...

 

One potential criticism I can think of is that while the control mice were restrained the same way as the acupuncture mice were during their treatments, the control mice weren't actually poked with electrified needles.  So it's conceivable that the WAT browning could have been triggered by increased sympathetic nervous system activity, induced by the increased stress from the needles. Strangely, the authors don't mention this as a potential confounding factor.

 

The other disappointing thing the authors don't mention is the housing temperature for the mice during the main part of the study, which presumably means it was normal lab temperature, which is cool for mice. So it could be that it is the combination of acupuncture and cold exposure that helps turn white fat to brown.

 

But either way, this is an interesting finding, and merits the inclusion of acupuncture in the list of potential BAT & thermogenesis promoters (see below for updated list).

 

--Dean

 

-----------

Here is the latest full list of modifiable and [non-modifiable] factors associated with increased BAT quantity and/or activity:
  • Cold exposure - by far the best BAT inducer/activator
  • Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions
  • Arginine-rich foods - Good vegan sources include seeds (esp. sesame, sunflower & pumpkin), nuts (esp. almonds and walnuts) and legumes (esp. soy, lupin & fava beans and peas)
  • Creatine supplements or creatine-rich foods - lean red meat, chicken breast, salmon and tuna
  • Other foods - green tea, roasted coffee, cacao beans / chocolate
  • Drugs - metformin, caffeine
  • Avoiding gluten
  • Olive Oil / MUFA-rich diet
  • DHA / fish-oil
  • Methionine restriction - Reduce animal protein. Soy is low in methionine and high in arginine (see below).
  • Low protein diet
  • Fasting
  • Exercise
  • Acupuncture - locations Zusanli (foot - ST36) and Neiting (lower leg - ST44) 
  • Avoid obesity/overweight
  • [being naturally thin - high metabolic rate]
  • [being younger]
  • [being female]
  • [Ethnicity - having cold-climate ancestors]

 

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

[1] BMC Complement Altern Med. 2014 Dec 16;14:501. doi: 10.1186/1472-6882-14-501.

 
Acupuncture promotes white adipose tissue browning by inducing UCP1 expression on
DIO mice.
 
Shen W, Wang Y, Lu SF, Hong H, Fu S, He S, Li Q, Yue J, Xu B(1), Zhu BM.
 
Author information: 
(1)Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, 
Nanjing University of Chinese Medicine, 210023 Nanjing, China. xuuuux@sina.com.
 
BACKGROUND: To study the influence of acupuncture and its possible mechanism on
white adipose tissue of high fat diet-induced obese.
METHODS: Four-week-old C57BL/6 J mice were randomly divided into a normal diet
group and a high-fat diet (HFD) group. After 8 weeks, the HFD mice were randomly 
divided into Electro-acupuncture (EA) group and control group. Mice in the EA
group were electro-acupunctured, under physical restraint, on Zusanli (ST36) and 
Neiting (ST44) acupoints, while the mice in the control group were under physical
restraint only. Body weight and food intake were monitored, and serum leptin,
cholesterol and triglyceride levels were measured by using biochemistrical
methods. The effect of EA on white adipose tissues (WAT) was assessed by qPCR,
immunoblotting, immunohistochemistry (IHC), immunoprecipitation and cold
endurance experiment.
RESULTS: The WAT/body weight ratio decreased (P < 0.05) in the EA group, albeit
no significant difference on food consumption between EA and control groups. The 
difference in the darkness of Epi-WAT between EA and control groups could be
distinguished visually. HE staining indicated that the EA mice had an increased
number of UCP1-immunoreactive paucilocular adipocytes in their WAT. The
expressions of brown adipose tissue (BAT) markers, including UCP1, COX4il and
Nrtf1 were increased in the WAT of EA mice, acetylation of Pparγ was decreased by
electro-acupuncture.
CONCLUSION: EA can remodel WAT to BAT through inducing UCP1 expression, and this 
may be one of the mechanisms by which acupuncture affects weight loss.
 
PMCID: PMC4301852
PMID: 25514854
 
-------------------
[2] Neural Regen Res. 2013 Mar 25;8(9):809-16. doi:
10.3969/j.issn.1673-5374.2013.09.005.
 
Electroacupuncture regulates glucose-inhibited neurons in treatment of simple
obesity.
 
Yu Z(1), Xia Y(1), Ju C(1), Shao Q(1), Mao Z(1), Gu Y(1), Xu B(1).
 
Author information: 
(1)Key Laboratory of Integrated Acupuncture and Drugs Affiliated to the Ministry 
of Education of China, Nanjing University of Chinese Medicine, Nanjing 210029,
Jiangsu Province, China.
 
The glucose-inhibited neurons present in the lateral hypothalamic area are
regarded as glucose detectors. This structure is involved in the regulation of
food intake through extracellular blood glucose concentrations, and plays a
crucial role in obesity onset. In the present study, obesity models established
with high fat feeding were treated with electroacupuncture at Zusanli
(ST36)/Inner Court (ST44) on the left side and Tianshu (ST25) bilaterally. We
found that electroacupuncture could effectively reduce body weight and the
fat-weight ratio, and decrease serum leptin, resistin, tumor necrosis factor
alpha, and neuropeptide Y levels, while increase serum adiponectin and
cholecystokinin-8 levels. This treatment altered the electrical activity of
glucose-inhibited neurons in the lateral hypothalamic area, with
electroacupuncture at Zusanli/Inner Court exerting an inhibitory effect, while
electroacupuncture at bilateral Tianshu exerting an excitatory effect. These data
suggest that electroacupuncture at the lower limbs and abdominal cavity is an
effective means for regulating the activity of glucose-inhibited neurons in the
lateral hypothalamic area and for improving the secretory function of adipose
tissue.
 
PMCID: PMC4146081
PMID: 25206728
 
-------------
[3] 1. Obes Rev. 2012 May;13(5):409-30. doi: 10.1111/j.1467-789X.2011.00979.x. Epub 2012
Feb 1.
 
A systematic review on use of Chinese medicine and acupuncture for treatment of
obesity.
 
Sui Y(1), Zhao HL, Wong VC, Brown N, Li XL, Kwan AK, Hui HL, Ziea ET, Chan JC.
 
Author information: 
(1)Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese
University of Hong Kong, Hong Kong SAR, China.
 
Obesity is a major health hazard and despite lifestyle modification, many
patients frequently regain any lost body weight. The use of western anti-obesity 
drugs has been limited by side effects including mood changes, suicidal thoughts,
and gastrointestinal or cardiovascular complications. The effectiveness and
safety of traditional Chinese medicine including Chinese herbal medicine (CHM)
and acupuncture provide an alternative established therapy for this medical
challenge. In this systematic review, we used standard methodologies to search,
review, analyse and synthesize published data on the efficacy, safety and relapse
of weight regain associated with use of CHM and acupuncture. We also examined the
rationale, mechanisms and potential utility of these therapies. A total of 12
electronic databases, including Chinese, English, Korean and Japanese, were
searched up to 28 February 2010. Randomized controlled trials (RCTs) for CHM
and/or acupuncture with comparative controls were considered. We used the Jadad
scale to assess methodological qualities, the random effect model in the pooled
analysis of therapeutic efficacy to adjust for heterogeneity and funnel plots to 
explore publication bias. After screening 2,545 potential articles from the
electronic databases, we identified 96 RCTs; comprising of 49 trials on CHM
treatment, 44 trials on acupuncture treatment and 3 trials on combined therapy
for appraisal. There were 4,861 subjects in the treatment groups and 3,821 in the
control groups, with treatment duration ranging from 2 weeks to 4 months. Of the 
77 publications written in Chinese, 75 had a Jadad score <3, while 16 of the 19
English publications had a Jadad score of >3. Efficacy was defined as body weight
reduction ≥ 2 kg or body mass index (BMI) reduction ≥ 0.5 kg/m(2) . Compared with
placebo or lifestyle modification, CHM and acupuncture exhibited respective 'risk
ratio' (RR) of 1.84 (95% CI: 1.37-2.46) and 2.14 (95% CI: 1.58-2.90) in favour of
body weight reduction, with a mean difference in body weight reduction of 4.03 kg
(95% CI: 2.22-5.85) and 2.76 kg (95% CI: 1.61-3.83) and a mean difference in BMI 
reduction of 1.32 kg m(-2) (95% CI: 0.78-1.85) and 2.02 kg m(-2) (95% CI:
0.94-3.10), respectively. Compared with the pharmacological treatments of
sibutramine, fenfluramine or orlistat, CHM and acupuncture exhibited an RR of
1.11 (95% CI: 0.96-1.28) and 1.14 (95% CI: 1.03-1.25) in body weight reduction,
mean difference in body weight reduction of 0.08 kg (95% CI: -0.58 to 0.74) and
0.65 kg (95% CI: -0.61 to 1.91), and mean difference in BMI reduction of 0.18 kg 
m(-2) (95% CI: -0.39 to 0.75) and 0.83 kg m(-2) (95% CI: 0.29-1.37),
respectively. There were fewer reports of adverse effects and relapses of weight 
regain in CHM intervention studies conducted in China than studies conducted
outside China. CHM and acupuncture were more effective than placebo or lifestyle 
modification in reducing body weight. They had a similar efficacy as the Western 
anti-obesity drugs but with fewer reported adverse effects. However, these
conclusions were limited by small sample size and low quality of methodologies.
 
© 2012 The Authors. obesity reviews © 2012 International Association for the
Study of Obesity.
 
PMID: 22292480  [PubMed - indexed for MEDLINE]
 
 
-------------
[4] Cho SH, Lee JS, Thabane L, et al. Acupuncture for obesity: a systematic review and meta-analysis. Int J Obes (Lond). 2009;33(2):183-196.
 
-------------
[5] Wang F, Tian DR, Han JS. Electroacupuncture in the treatment of obesity. Neurochem Res. 2008;33(10): 2023-2027.
    
-------------
[6] Tong J, Chen JX, Zhang ZQ, et al. Clinical observation on simple obesity treated by acupuncture. Zhongguo Zhen Jiu. 2011;31(8):697-701.
    
-------------
[7] Abdi H, Zhao B, Darbandi M, et al. The effects of body acupuncture on obesity: anthropometric parameters, lipid profile, and inflammatory and immunologic markers. ScientificWorldJournal. 2012;2012:603539.
    
-------------
[8]. Yang JJ, Xing HJ, Wang SJ, et al. Effects of acupuncture combined with dietary adjustments and aerobic exercise on body weight, body mass index and serum leptin level in simple obesity patients. Zhen Ci Yan Jiu. 2010;35(6): 453-457.

 

---------

[9] Am J Chin Med. 2008;36(6):1029-39.

 
The efficacy of electroacupuncture therapy for weight loss changes plasma
lipoprotein A, apolipoprotein A and apolipoprotein B levels in obese women.
 
Cabioglu MT(1), Gündogan N, Ergene N.
 
Author information: 
(1)Department of Physiology, Medical Faculty, Başkent University, Ankara, Turkey.
tugcab@yahoo.com
 
In the present study, we aimed to investigate the effects of electroacupuncture
treatment on lipoprotein A, apolipoprotein A and apolipoprotein B levels in obese
subjects. Fifty-eight women were studied in 3 groups as follows: 1) Placebo
acupuncture (n = 15; mean age = 41.47 +/- 4.61, and mean body mass index {BMI} = 
33.43 +/- 3.10); 2) Electroacupuncture (EA) (n = 20; mean age = 40.55 +/- 5.30,
and BMI = 35.65 +/- 3.84) and 3) Diet restriction groups (n = 23; mean age =
42.91 +/- 4.02, and BMI = 34.78 +/- 3.29). EA was performed using the ear points,
Hungry, Shen Men and Stomach the body points, Hegu (LI 4), Quchi (LI 11), Tianshu
(St 25), Zusanli (St 36), Neiting (St 44) and Taichong (Liv 3) for 20 days.
Intragroup comparisons were made by using paired samples t-test whereas
intergroup differences were investigated by the two-way variation analysis and
LSD test. There was a 4.7% (p < 0.001) weight reduction in patients with
electroacupuncture application, whereas patients in diet restriction had a 2.9%
(p < 0.001) weight reduction. There were significant decreases in lipoprotein A
(p < 0.05) and apolipoprotein B (p < 0.05) levels in the EA compared to the
control group and no changes in apolipoprotein A levels was observed in EA, diet 
and placebo acupuncture groups. EA therapy may be a useful approach for the
treatment of obesity for both losing weight and lowing the risk factors for
cardiovascular disease associated with obesity, since this application may
decrease the plasma lipoprotein A and apolipoprotein B levels.
 
PMID: 19051333  [PubMed - indexed for MEDLINE]

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Tom wrote:

Al Pater just posted a study to the list, that throws some light on the effect of CR on diet-induced thermogenesis. This may be of interest especially to those thinking of how CR might interact with CE:

https://www.jstage.j...62/1/62_40/_pdf
 

The Effects of a Hypocaloric Diet on Diet-Induced Thermogenesis and Blood Hormone Response in Healthy Male Adults: A Pilot Study.

Ishii S, Osaki N, Shimotoyodome A.

J Nutr Sci Vitaminol (Tokyo). 2016;62(1):40-6. doi: 10.3177/jnsv.62.40.

PMID: 27117850

 

Thanks Tom (and Al!). Interesting stuff. Here is the most relevant graph from PMID: 27117850 relating to diet-induced thermogenesis (DIT). It shows the change in energy expenditure per minute for a few hours after the three different test meals: 200kcal (open circles), 400kcal (closed triangles) or 800kcal (open squares):

kdUxru7.png

 

As you can see, the difference in DIT between the 800kcal meal and the other two was quite modest - about +0.1 kcal/min for a few hours. Eyeballing the insert bar graph, it looks like the bigger meal resulted in a total of about 30-35 extra kcal burned via thermogenesis in the period after the big meal. The increase in DIT induced by the bigger meal was significant, but obviously not huge. One other piece of information from the full text was that the subjects were kept seated in a room at 24 °C for the entire post-meal measurement period - which is about thermal neutrality for humans.

 

--Dean

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BAT Activators Besides Cold and Dietary Methods; Part 2 - Vibration Therapy


 


If acupuncture isn't your cup of tea, perhaps vibration therapy is more your style?!


 


If so, you're in luck, since another group of Chinese researchers found that whole body vibration (WBV) therapy helps to burn calories and promote weight loss in obese rats [1], mice [2], and people [3].  But the mechanism by which WBV appears to induce weight loss is what makes it most interesting for this thread.


 


To explore this mechanism, the researchers in [1] divided rats up into two groups - low-fat chow controls (referenced below was 'CHOW') and high-fat diet group (HFD). After a eight weeks of acclimation to the diets, half of the rats in each group were "trained for 15 min twice a day and intermittent for 5 min in the frequency 25 Hz in LD-P vertical vibration machine..." and the other half of the rats in each diet group served as untreated controls. After 8 weeks of this WBV training, the researchers compared the four sets of rats along a range of measurements. Here is what they found.


 


The rats on both diets that received the WBV training weighed somewhat less than the corresponding control groups, and the difference in body weight was significant in the WBV-HFD group relative to CON-HFD group. The WBV-HFD group also showed improved metabolic health - reduced serum glucose, total cholesterol and triglycerides relative to controls. The CHOW (low-fat) WBV group saw a tiny improvement in these parameters as well, but it wasn't close to significant, as can be seen in these graphs:


 


YkSIAmY.png


 


 


Importantly, UPC1 expression in both BAT and visceral WAT increased in the WBV-HFD group relative to HFD controls. But interestingly, WBV didn't (significantly) increase UPC1 in the slimmer rats fed normal chow. The visceral WAT UPC1 result can be seen in the graph below - basically WBV prevented the drop in UCP1 expression in visceral fat induced by the high-fat diet:


pG6zSSj.png


 


Finally, a result whose importance will become evident in my next post, WBV increased expression of Interleukin-6 (IL-6) in both groups, but most dramatically in the HFD group:


 


9Ryily1.png


 


In short, whole body vibration appears to increase the browning of white fat, especially unhealthy visceral fat and especially in obese individuals, at least in rats, translating into weight loss in both obese rodents [1-2] and people [3]. I've therefore added whole body vibration training to the list of thermogenesis inducers (see below). But it should be kept in mind that once again, these rats were housed at what for them was a cold temperature (22 °C), so it could be the combination of vibration and cold exposure that results in increased adipose tissue browning.


 


But what is perhaps most interesting about this result is that vibration therapy has also been shown to build bones in older folks, as we discussed on the old CR email list. In fact, back in the day, I and several others CR practitioners uses to use one of those vibrating car-seat covers for just this bone-building purpose - although now I'm not sure the sort of mild vibration produced by such a device would accomplish the same thing as whole body vibration therapy, which is apparently much more vigorous.


 


Encouragingly, these two recent meta-analyses [4-5] improved bone density. In fact, [4] found WBV even increases bone mineral density in the femoral neck in older folks more than conventional exercise. It also appears to improve balance, knee strength & muscle power.


 


Given all these benefits, I'm giving serious consideration to the idea of adding whole body vibration treatment to my regime. While I do run several miles a day, and walk a couple more, keeping my bones healthy is a particular concern for me, and many other CR folks. If it also has the potential to build beige fat, and improve strength and balance, it seems like a win all around.


 


A quick Amazon search turned up this model as the most affordable ($260) and highly-rated (avg 4.5 stars with 1350 ratings) WBV machine. Here is an image of it:


 


fgLuKcA.png


 


What do people think? Anyone interested in giving whole body vibration therapy a try?


 


Update: I'm not sure if he's going to chime in, but Kenton told he via private message that he's been using this $179 vibration plate (also available as an auction w/ free shipping from ebay) for about a year and really likes it. Given his endorsement, I'm leaning towards this one now...


 


--Dean


 


--------


Here is the latest full list of modifiable and [nonmodifiable] factors associated with increased brown/beige adipose tissue and/or thermogenesis:

  • Cold exposure - by far the best BAT inducer/activator
  • Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions
  • Arginine-rich foods - Good vegan sources include seeds (esp. sesame, sunflower & pumpkin), nuts (esp. almonds and walnuts) and legumes (esp. soy, lupin & fava beans and peas)

  • Creatine supplements or creatine-rich foods - lean red meat, chicken breast, salmon and tuna


  • Other foods - green tea, roasted coffee, cacao beans / chocolate
  • Drugs - metformin, caffeine
  • Avoiding gluten
  • Olive Oil / MUFA-rich diet
  • DHA / fish-oil
  • Methionine restriction - Reduce animal protein. Soy is low in methionine and high in arginine.
  • Low protein diet
  • Fasting
  • Exercise

  • Acupuncture - locations Zusanli (foot - ST36) and Neiting (lower leg - ST44) 


  • Whole body vibration therapy
  • Avoid obesity/overweight
  • [being naturally thin - high metabolic rate]
  • [being younger]
  • [being female]
  • [Ethnicity - having cold-climate ancestors]

 


----------


[1] Biomed Res Int. 2015;2015:919401. doi: 10.1155/2015/919401. Epub 2015 Jun 1.


 

Vibration Training Triggers Brown Adipocyte Relative Protein Expression in Rat

White Adipose Tissue.

 

Sun C(1), Zeng R(2), Cao G(1), Song Z(1), Zhang Y(3), Liu C(1).

 


 

Recently, vibration training is considered as a novel strategy of weight loss;

however, its mechanisms are still unclear. In this study, normal or high-fat

diet-induced rats were trained by whole body vibration for 8 weeks. We observed

that the body weight and fat metabolism index, blood glucose, triglyceride,

cholesterol, and free fatty acid in obesity rats decreased significantly compared

with nonvibration group (n = 6). Although intrascapular BAT weight did not change

significantly, vibration enhanced ATP reduction and increased protein level of

the key molecule of brown adipose tissue (BAT), PGC-1α, and UCP1 in BAT.

Interestingly, the adipocytes in retroperitoneal white adipose tissue (WAT)

became smaller due to vibration exercise and had higher protein level of the key 

molecule of brown adipose tissue (BAT), PGC-1α, and UCP1 and inflammatory

relative proteins, IL-6 and TNFα. Simultaneously, ATP content and PPARγ protein

level in WAT became less in rats compared with nonvibration group. The results

indicated that vibration training changed lipid metabolism in rats and promoted

brown fat-like change in white adipose tissues through triggering BAT associated 

gene expression, inflammatory reflect, and reducing energy reserve.

 

PMCID: PMC4466483

PMID: 26125027

-------


[2] Int J Med Sci. 2014 Sep 18;11(12):1218-27. doi: 10.7150/ijms.9975. eCollection


2014.

 

Whole-body vibration training effect on physical performance and obesity in mice.

 

Huang CC(1), Tseng TL(1), Huang WC(2), Chung YH(3), Chuang HL(4), Wu JH(5).

 


 

The purpose of this study was to verify the beneficial effects of whole-body

vibration (WBV) training on exercise performance, physical fatigue and obesity in

mice with obesity induced by a high-fat diet (HFD). Male C57BL/6 mice were

randomly divided into two groups: normal group (n=6), fed standard diet

(control), and experimental group (n=18), fed a HFD. After 4-week induction,

followed by 6-week WBV of 5 days per week, the 18 obese mice were divided into 3 

groups (n=6 per group): HFD with sedentary control (HFD), HFD with WBV at

relatively low-intensity (5.6 Hz, 0.13 g) (HFD+VL) or high-intensity (13 Hz, 0.68

g) (HFD+VH). A trend analysis revealed that WBV increased the grip strength in

mice. WBV also dose-dependently decreased serum lactate, ammonia and CK levels

and increased glucose level after the swimming test. WBV slightly decreased final

body weight and dose-dependently decreased weights of epididymal, retroperitoneal

and perirenal fat pads and fasting serum levels of alanine aminotransferase, CK, 

glucose, total cholesterol and triacylglycerol. Therefore, WBV could improve

exercise performance and fatigue and prevent fat accumulation and

obesity-associated biochemical alterations in obese mice. It may be an effective 

intervention for health promotion and prevention of HFD-induced obesity.

 

PMCID: PMC4196122

PMID: 25317067

 

----------


[3] Int J Med Sci. 2013;10(3):307-11. doi: 10.7150/ijms.5161. Epub 2013 Feb 2.


 

Ten-week whole-body vibration training improves body composition and muscle

strength in obese women.

 

Milanese C(1), Piscitelli F, Zenti MG, Moghetti P, Sandri M, Zancanaro C.

 


 

This work explored the short-term effect of whole body vibration (WBV) training

on anthropometry, body composition and muscular strength in obese women. Fifty

obese women (age = 46.8 ± 7.81[sD]y; BMI = 35.1 ± 3.55 kg/m(2)) were assigned to 

a ten-week WBV training period, two times a week (in each session, 14 min

vibration training, 5 min rest; vibration amplitude 2.0-5.0mm, frequency 40-60

Hz), with (n = 18) or without (n = 17) radiofrequency, or to a non-exercise

control group (n = 15). Subjects were instructed not to change their habitual

lifestyle. Before and after the ten-week experimental period, anthropometric

measurements, dual-energy X-ray absorptiometry (DXA), and the leg press, leg curl

and leg extension strength tests were carried out. All changes in the two groups 

of WBV training, with or without radiofrequency, were similar and these groups

were combined in a single WBV intervention group. As compared to controls,

subjects submitted to WBV training had significantly lower BMI, total body and

trunk fat, sum of skinfolds and body circumferences. On the other hand, lower

limb strength tests were increased in the WBV group. These preliminary results

suggest that WBV training may improve body composition and muscular strength in

obese women and may be a useful adjuvant to lifestyle prescriptions.

 

PMCID: PMC3575626

PMID: 23423629

 

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

[4] Disabil Rehabil. 2012;34(11):883-93. doi: 10.3109/09638288.2011.626486. Epub 2012

Jan 6.

 

Efficacy of whole body vibration exercise in older people: a systematic review.

 

Sitjà-Rabert M(1), Rigau D, Fort Vanmeerghaeghe A, Romero-Rodríguez D, Bonastre

Subirana M, Bonfill X.

 

Author information: 

(1)Blanquerna School of Health Science, Universitat Ramon Llull, Barcelona,

Spain. mercesr@blanquerna.url.edu

 

PURPOSE: The aim of this study was to perform a systematic review of the

literature on whole body vibration programs in older population and a

meta-analysis of randomized controlled clinical trials.

METHOD: A search was conducted in MEDLINE, EMBASE, CENTRAL, CINAHL and PsychINFO 

databases. We included randomized controlled trials evaluating the efficacy and

safety of whole body vibration training in older populations compared to

conventional exercise or control groups that assessed balance, muscle strength,

falls, bone mineral density and adverse events.

RESULTS: Sixteen trials met the inclusion criteria. Comparing the vibration and

the control group, we found that vibration significantly improved knee muscle

isometric strength (18.30 Nm, 95% CI 7.95-28.65), muscle power (10.44 W, 95% CI

2.85-18.03) and balance control (Tinetti test: 4.5 points, 95% CI 0.95-8.11).

Comparison with a conventional exercise showed that the only significant

difference was bone mineral density in the femoral neck (0.04 g/cm(-2), 95% CI

0.02-0.07). There were no serious complications in most of studies.

CONCLUSION: Whole body vibration training may improve strength, power and balance

in comparison with a control group, although these effects are not apparent when 

compared with a group that does conventional exercise.

 

PMID: 22225483

 

-------

[5] Sportverletz Sportschaden. 2014 Sep;28(3):125-31. doi: 10.1055/s-0034-1366545.

Epub 2014 May 14.

 

[Does muscle activation during whole-body vibration induce bone density

improvement in postmenopausal women?--A systematic review].

 

[Article in German]

 

Calendo LR(1), Taeymans J(2), Rogan S(2).

 

Author information: 

(1)Fachhochschule Südschweiz, Departement Graubünden, Landquart, Schweiz.

(2)Berner Fachhochschule, Fachbereich Gesundheit, Disziplin Physiotherapie.

 

BACKGROUND: Whole body vibration training (WBV) stimulates muscles by mechanical 

vibrations. The resulting muscle activity and bone deformation may provoke an

increase in bone density. The aim of this systematic review was to evaluate

whether muscle activation and muscle strengthening caused by vibration training

has an effect on bone density in postmenopausal women.

METHODS: This systematic review was conducted according to the guidelines of the 

PRISMA statement for meta-analyses and systematic reviews. The literature search 

was conducted in several electronic databases (PubMed und CINAHL) and Google

Scholar. The literature search was conducted between June 2012 and August 2013.

The methodological quality of the included studies was assessed using the

Cochrane risk of bias tool by two independent persons.

RESULTS: A total of 246 studies was found. In this present analysis three studies

with vertical and two studies with side-alternating WBV were included, totalling 

368 participants with an age range between 60.7 and 79.6 years. From those 132

participants trained on vertically while 67 participants trained on

side-alternating WBV engines. The included study shows a moderate to high risk of

bias. The selected frequencies ranged from 12.0 Hz to 40.0 Hz for vertical WBV

and 12.5 Hz for side-alternating WBV. The amplitude ranged between 1.7 and

12.0 mm with an acceleration from 0.1 to 10.0 g.

CONCLUSION: This systematic review showed significant influences on the isometric

maximal voluntary contraction (IMVC) between 15.1 and 16.5 % and on dynamic

maximal strength (DMS) between 7.9 to 16.5 % after vertically WBV (frequencies:

30.0 to 40.0 Hz; 3 sessions per week; 15 minutes per session) and on IMV with

26.6 % (frequency: 12.5 Hz; 3 sessions per week; 15 minutes per session). This

increased muscle activity resulted in an improved bone density in the lumbar

spine between 0.5 % to 0.7 % and the hip between 0.8 % to 0.9 % in postmenopausal

women. These clinically significant findings should be confirmed by a large

high-quality randomised controlled trial and reported following the CONSORT

Statement guidelines.

 

© Georg Thieme Verlag KG Stuttgart · New York.

 

PMID: 24828509

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Exercise, IL-6 and the Browning of WAT

 

This is the third (and maybe final - for now...) post in my mini-series on non-CE ways to boost brown/beige fat and/or thermogenesis, following the first two on acupuncture and whole body vibration therapy

 

In this study [1], researchers looked at UPC-1 expression in mice in a particular subcutaneous white adipose deposit called inguinal WAT (iWAT) - which is located in the groin area of rodents and humans. They subjected both wild-type and Interleukin-6 (IL-6) knockout mice to 3 days of cold exposure (4 °C) or 5 weeks of exercise training, and then measure the mice's iWAT UCP-1 expression.

 

Why IL-6 knockout mice you ask? Because according to the introduction:

 

The cytokine interleukin 6 (IL-6) is released from contracting skeletal muscle to the circulation [ref] and previous observations suggest that IL-6 elicits metabolic effects in adipose tissue [ref], [ref]. ...The decreased oxygen consumption and increased respiratory exchange ratio at room temperature observed in IL-6 KO mice relative to WT mice [ref], indicating reduced whole body energy expenditure and fat oxidation in IL-6 KO mice, support that mice lacking IL-6 have dysfunctional regulation of metabolism. Interestingly, IL-6 KO mice have also been shown to have lower core body temperature than WT mice when housed at 4°C without a decrease in UCP1 expression in interscapular BAT (iBAT) [ref]. This may suggest that cold-induced UCP1 expression and thermogenesis in WAT are lower in IL-6 KO than in WT mice.

 

In short, they wanted to see if exercise triggered the browning of iWAT via a pathway involving IL-6.

 

All the animals were fed standard rodent chow ad lib, and were housed at 22 °C for most of the study. The exercise mice were exercised trained on a treadmill for 1h/day, 5d/week for 5 weeks. Unlike other cruel rodent exercise studies we've looked at, which used an electric shock to discourage the rodents from dropping off the back of the treadmill, I was happy to see this study used a puff of air instead - "the mice were encouraged by air blown gently from behind with an air gun."

 

First, the easy part. Not surprisingly, mice exposed to cold for three days showed a massive (9 to 19x) increase in UPC1 mRNA content in iWAT, and it didn't matter whether there were wild-type or IL-6 knockout mice (top graph below). Clearly cold induced WAT browning by a pathway that doesn't require IL-6.

 

Exercise also induced a large (5x) increase in UPC1 mRNA content in iWAT, but only in WT mice. The exercised IL-6 knockout mice exhibited no increase in UPC1 mRNA content in iWAT relative to sedentary controls (bottom graph below). Clearly, IL-6 is indeed required for the browning of subcutaneous white fat as the researchers postulated. 

 

TTC2pvX.png

 

But notice all of the results above are for UCP1 mRNA content, and not UCP1 protein expression itself. In other words, both exercise (in WT mice) and cold got the mice ready to produce UCP1 by boosting UCP1 mRNA, and hence prepared them crank up thermogenesis. But the bigger question is how much UPC1 protein did they actually generate in iWAT? In other words, just how brown did their iWAT get? The two graphs below tell the story. Ignore the grey bars (IL-6 knockout mice) and focus on the black bars:

 

cdQNMmu.png

 

From the graph on the right, you can see that the UCP1 protein content of iWAT of cold-exposed mice came in at around 4 (arbitrary) units - much higher than mice kept at standard lab temperature. From the graph on the left, you can see that exercise training doubled UCP1 protein content in iWAT of WT mice compared with untrained mice, and brought the exercised mice up to about 1.75 (arbitrary) units - i.e. just under half as much as the cold-exposed mice.

 

Of course, with a housing temperature of 22 °C, the exercised mice were actually exercised and (modestly) cold exposed. 

 

So in short, what this study shows is that consistent exercise training coupled with mild cold exposure can turn subcutaneous white fat to thermogenic beige fat, although not quite as effectively as more severe cold exposure without exercise.

 

Finally, recall from yesterday's post that whole body vibration therapy results in an increase in IL-6 expression as well, mimicking exercise and turning white (visceral) fat to beige. Nice how it all fits together...

 

So while exercise was already on the list of brown/beige adipose tissue inducers, I've highlighted it again in the list below for emphasis.

 

--Dean

 

P.S. I'm working this afternoon with my PC tethered to my (Verizon) Android phone, since our internet service is out. It was actually trivially easy to do, although it eats up your data pretty fast. Here is a description of how to do it. 

 

--------

Here is the latest full list of modifiable and [nonmodifiable] factors associated with increased brown/beige adipose tissue and/or thermogenesis:
  • Cold exposure - by far the best BAT inducer/activator
  • Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions
  • Arginine-rich foods - Good vegan sources include seeds (esp. sesame, sunflower & pumpkin), nuts (esp. almonds and walnuts) and legumes (esp. soy, lupin & fava beans and peas)
  • Creatine supplements or creatine-rich foods - lean red meat, chicken breast, salmon and tuna
  • Other foods - green tea, roasted coffee, cacao beans / chocolate
  • Drugs - metformin, caffeine
  • Avoiding gluten
  • Olive Oil / MUFA-rich diet
  • DHA / fish-oil
  • Methionine restriction - Reduce animal protein. Soy is low in methionine and high in arginine.
  • Low protein diet
  • Fasting
  • Exercise
  • Acupuncture - locations Zusanli (foot - ST36) and Neiting (lower leg - ST44) 
  • Whole body vibration therapy
  • Avoid obesity/overweight
  • [being naturally thin - high metabolic rate]
  • [being younger]
  • [being female]
  • [Ethnicity - having cold-climate ancestors]

-----------

[1] PLoS One. 2014 Jan 8;9(1):e84910. doi: 10.1371/journal.pone.0084910. eCollection 

2014.
 
Role of IL-6 in exercise training- and cold-induced UCP1 expression in
subcutaneous white adipose tissue.
 
Knudsen JG(1), Murholm M(2), Carey AL(3), Biensø RS(1), Basse AL(2), Allen TL(4),
Hidalgo J(5), Kingwell BA(3), Febbraio MA(4), Hansen JB(6), Pilegaard H(1).
 
 
Expression of brown adipose tissue (BAT) associated proteins like uncoupling
protein 1 (UCP1) in inguinal WAT (iWAT) has been suggested to alter iWAT
metabolism. The aim of this study was to investigate the role of interleukin-6
(IL-6) in exercise training and cold exposure-induced iWAT UCP1 expression. The
effect of daily intraperitoneal injections of IL-6 (3 ng/g) in C57BL/6 mice for 7
days on iWAT UCP1 expression was examined. In addition, the expression of UCP1 in
iWAT was determined in response to 3 days of cold exposure (4°C) and 5 weeks of
exercise training in wild type (WT) and whole body IL-6 knockout (KO) mice.
Repeated injections of IL-6 in C57BL/6 mice increased UCP1 mRNA but not UCP1
protein content in iWAT. Cold exposure increased iWAT UCP1 mRNA content similarly
in IL-6 KO and WT mice, while exercise training increased iWAT UCP1 mRNA in WT
mice but not in IL-6 KO mice. Additionally, a cold exposure-induced increase in
iWAT UCP1 protein content was blunted in IL-6 KO mice, while UCP1 protein content
in iWAT was lower in both untrained and exercise trained IL-6 KO mice than in WT 
mice. In conclusion, repeated daily increases in plasma IL-6 can increase iWAT
UCP1 mRNA content and IL-6 is required for an exercise training-induced increase 
in iWAT UCP1 mRNA content. In addition IL-6 is required for a full induction of
UCP1 protein expression in response to cold exposure and influences the UCP1
protein content iWAT of both untrained and exercise trained animals.
 
PMCID: PMC3885654
PMID: 24416310
 

bgaj978

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Btw., about "naturally thin" - how do you know if you are or not, given that BMI is so influenced by diet and eating habits. If you have your genome sequenced, there are several markers that correlate with "thinner" or "heavier"; in 23andme, it's under "traits", and f.ex you'll see: rs6548238, rs925946, rs7138803, rs9939609, rs13130484, rs4788102, rs10838738, rs10871777, and for waist circumference rs12970134, and the effect of exercise on BMI rs9939609.

Edited by TomBAvoider

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Hi Kenton - Nice to hear from you!

 

You wrote:

Holy cow Kenton! ... if you're feeling good (physically & psychologically), more power to you!

P.S. Do you plan to be at the CR Conference? I'd love to finally meet you in person!

--Dean

 

Did you ever find any better tape-on sensors than the one you posted on in this thread?  All the bands I keep getting don't provide just a simple average temp reading--just want a tape on sensor that will take a reading every half hour and then give me an average temperature at the end of the day.  (BTW, we met at the November 2004: Third Scientific Calorie Restriction Conference -- Charleston, SC.)

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A Potpourri of Dietary BAT, Beige Fat and Thermogenesis Inducers

 

In my research I've been collecting additional studies with evidence that specific foods and supplements may increase BAT, beige fat, and/or thermogenesis. Rather than covering them each in detail and in separate posts, I decided to create a single posts that lists them all, with references. Some of them represent additional evidence for the thermogenic effects of foods or compounds I've discussed previously in this thread. I've bolded the new ones in the list below:

  • Turmeric / Curcumin [1]
  • Nitrate-rich foods - beets, celery, arugula, and spinach [2] [5]
  • Resveratrol  [3]
  • Cacao [6]
  • Hot peppers / chilli peppers / capsaicin [7]
  • Ginseng [8]
  • (Aged) Garlic [9][11] 
  • Apples / Apple Peals / Ursolic Acic [10]

 

To me the finding about nitrates and nitrate-rich foods triggering the browning of white adipose tissue [2][5] is particularly interesting and exciting, because of all the recent evidence that nitrate-rich beets and beet juice can boost cardiovascular health  [12-15] and athletic performance. I'm running in a 5K this coming weekend (a memorial race for Kyle...) and I'm considering boosting my nitrate intake over the next few days with whole fresh beets...

 

With the addition of nitrate-rich foods like beets, along with apples, ginseng, and reaffirmation of other healthy foods/supplements as inducers of thermogenesis, we see more evidence for what I call the "BAT Rule" - most interventions known to promote health and/or longevity also seem to boost BAT activity white fat browning, and/or thermogenesis. 

 

--Dean

 

--------

Here is the latest full list of modifiable and [nonmodifiable] factors associated with increased brown/beige adipose tissue and/or thermogenesis:
  • Cold exposure - by far the best BAT inducer/activator
  • Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions
  • Arginine-rich foods - Good vegan sources include seeds (esp. sesame, sunflower & pumpkin), nuts (esp. almonds and walnuts) and legumes (esp. soy, lupin & fava beans and peas)
  • Healthy Fats - Olive Oil / MUFA-rich diet, DHA / EPA / fish-oil
  • Nitrate-rich foods - beets, celery, arugula, and spinach
  • Other foods - Apples / Apple Peals / Ursolic Acic
  • Beverages - green tea, roasted coffee, red winecacao beans / chocolate
  • Drugs / Supplements - metformin, caffeine, creatine, nicotinamide riboside (NAD), resveratrol, ginseng
  • Low gluten diet
  • Methionine restriction - Reduce animal protein. Soy is low in methionine and high in arginine.
  • Low protein diet
  • Fasting
  • Exercise
  • Acupuncture - locations Zusanli (foot - ST36) and Neiting (lower leg - ST44) 
  • Whole body vibration therapy
  • Avoid obesity/overweight
  • [being naturally thin - high metabolic rate]
  • [being younger]
  • [being female]
  • [Ethnicity - having cold-climate ancestors]

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

1. J Nutr Biochem. 2016 Jan;27:193-202. doi: 10.1016/j.jnutbio.2015.09.006. Epub
2015 Sep 21.

Curcumin induces brown fat-like phenotype in 3T3-L1 and primary white adipocytes.

Lone J(1), Choi JH(1), Kim SW(1), Yun JW(2).

Author information:
(1)Department of Biotechnology, Daegu University, Kyungsan, Kyungbuk 712-714,
Republic of Korea. (2)Department of Biotechnology, Daegu University, Kyungsan,
Kyungbuk 712-714, Republic of Korea. Electronic address: jwyun@daegu.ac.kr.

Recent advances have been made in the understanding of pharmacological and
dietary agents that contribute to browning of white adipose tissue in order to
combat obesity by promoting energy expenditure. Here, we show that curcumin
induces browning of 3T3-L1 and primary white adipocytes via enhanced expression
of brown fat-specific genes. Curcumin-induced browning in white adipocytes was
investigated by determining expression levels of brown adipocyte-specific
genes/proteins by real-time reverse transcriptase polymerase chain reaction,
immunoblot analysis and immunocytochemical staining. Curcumin increased
mitochondrial biogenesis, as evidenced by transmission electronic microscopic
detection and enhanced expression of proteins involved in fat oxidation. Cucurmin
also increased protein levels of hormone-sensitive lipase and p-acyl-CoA
carboxylase, suggesting its possible role in augmentation of lipolysis and
suppression of lipogenesis. Increased expression of UCP1 and other brown
adipocyte-specific markers was possibly mediated by curcumin-induced activation
of AMP-activated protein kinase (AMPK) based on the fact that inhibition of AMPK
by dorsomorphin abolished expression of PRDM16, UCP1 and peroxisome
proliferator-activated receptor gamma co-activator 1-alpha while the activator
5-Aminoimidazole-4-carboxamide ribonucleotide elevated expression of these brown
marker proteins. Our findings suggest that curcumin plays a dual modulatory role
in inhibition of adipogenesis as well as induction of the brown fat-like
phenotype and thus may have potential therapeutic implications for treatment of
obesity.

Copyright © 2015 Elsevier Inc. All rights reserved.

PMID: 26456563 [PubMed - in process]
 

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

2. Adipocyte. 2015 Jan 14;4(4):311-4. doi: 10.1080/21623945.2015.1005525.

Does inorganic nitrate say NO to obesity by browning white adipose tissue?

Roberts LD(1).

Author information:
(1)Medical Research Council - Human Nutrition Research; Elsie Widdowson
Laboratory ; Cambridge, UK ; Department of Biochemistry and Cambridge Systems
Biology Center; University of Cambridge ; Cambridge, UK.

The dietary constituent inorganic nitrate, found in large concentrations in green
leafy vegetables, has beneficial effects on cardiometabolic health. Contemporary
studies employing nitrate have demonstrated that the anion has anti-obesity and
anti-diabetic properties; however the nitrate-mediated mechanisms for improving
metabolic health remain unclear. Recently, we employed a combined histological,
metabolomics, and transcriptional and protein analysis approach to establish that
nitrate promoted the "browning" of white adipose tissue via the xanthine
oxidoreductase catalyzed reductive nitrate-nitrite-nitric oxide pathway.
Interestingly, it was observed that nitrate-stimulated brown adipose-associated
gene expression in white adipose tissue was augmented in hypoxia. These findings
not only suggest that protection from metabolic disease offered by vegetable
consumption may, in part, be mediated through the effects of nitrate on white
adipose tissue, but also, since hypoxia is a serious co-morbidity affecting
adipose tissue in obese individuals, that nitrate may be effective in promoting
the browning of adipose tissue to improve metabolic fitness.

PMCID: PMC4573180
PMID: 26451288 [PubMed]

--------------
3. Int J Obes (Lond). 2015 Jun;39(6):967-76. doi: 10.1038/ijo.2015.23. Epub 2015 Mar
12.

Resveratrol induces brown-like adipocyte formation in white fat through
activation of AMP-activated protein kinase (AMPK) α1.

Wang S(1), Liang X(2), Yang Q(2), Fu X(2), Rogers CJ(2), Zhu M(3), Rodgers BD(2),
Jiang Q(4), Dodson MV(2), Du M(2).

Author information:
(1)1] College of Animal Science, ALLTECH-SCAU Animal Nutrition Control Research
Alliance, South China Agricultural University, Guangzhou, China [2] Department of
Animal Sciences, Washington Center for Muscle Biology, Washington State
University, Pullman, WA, USA. (2)Department of Animal Sciences, Washington Center
for Muscle Biology, Washington State University, Pullman, WA, USA. (3)School of
Food Sciences, Washington State University, Pullman, WA, USA. (4)College of
Animal Science, ALLTECH-SCAU Animal Nutrition Control Research Alliance, South
China Agricultural University, Guangzhou, China.

OBJECTIVE: Development of brown-like/beige adipocytes in white adipose tissue
(WAT) helps to reduce obesity. Thus we investigated the effects of resveratrol, a
dietary polyphenol capable of preventing obesity and related complications in
humans and animal models, on brown-like adipocyte formation in inguinal WAT
(iWAT).
METHODS: CD1 female mice (5-month old) were fed a high-fat diet with/without 0.1%
resveratrol. In addition, primary stromal vascular cells separated from iWAT were
subjected to resveratrol treatment. Markers of brown-like (beige) adipogenesis
were measured and the involvement of AMP-activated protein kinase (AMPK) α1 was
assessed using conditional knockout.
RESULTS: Resveratrol significantly increased mRNA and/or protein expression of
brown adipocyte markers, including uncoupling protein 1 (UCP1), PR
domain-containing 16, cell death-inducing DFFA-like effector A, elongation of
very long-chain fatty acids protein 3, peroxisome proliferator-activated
receptor-γ coactivator 1α, cytochrome c and pyruvate dehydrogenase, in
differentiated iWAT stromal vascular cells (SVCs), suggesting that resveratrol
induced brown-like adipocyte formation in vitro. Concomitantly, resveratrol
markedly enhanced AMPKα1 phosphorylation and differentiated SVC oxygen
consumption. Such changes were absent in cells lacking AMPKα1, showing that
AMPKα1 is a critical mediator of resveratrol action. Resveratrol also induced
beige adipogenesis in vivo along with the appearance of multiocular adipocytes,
increased UCP1 expression and enhanced fatty acid oxidation.
CONCLUSIONS: Resveratrol induces brown-like adipocyte formation in iWAT via
AMPKα1 activation and suggest that its beneficial antiobesity effects may be
partly due to the browning of WAT and, as a consequence, increased oxygen
consumption.

PMCID: PMC4575949
PMID: 25761413 [PubMed - in process]

--------------
4. Mol Metab. 2014 Dec 18;4(2):118-31. doi: 10.1016/j.molmet.2014.12.008.
eCollection 2015.

SIRT1 enhances glucose tolerance by potentiating brown adipose tissue function.

Boutant M(1), Joffraud M(1), Kulkarni SS(1), García-Casarrubios E(2),
García-Roves PM(3), Ratajczak J(4), Fernández-Marcos PJ(5), Valverde AM(2),
Serrano M(5), Cantó C(1).

Author information:
(1)Nestlé Institute of Health Sciences (NIHS) SA, EPFL Campus, Quartier de
l'Innovation, Bâtiment G, Lausanne CH-1015, Switzerland. (2)Instituto de
Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain ; Spanish
Biomedical Research Centre in Diabetes and Associated Metabolic Disorders
(CIBERDEM), 28029 Madrid, Spain. (3)Spanish Biomedical Research Centre in
Diabetes and Associated Metabolic Disorders (CIBERDEM), 28029 Madrid, Spain ;
Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomediques
August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain. (4)Nestlé Institute of
Health Sciences (NIHS) SA, EPFL Campus, Quartier de l'Innovation, Bâtiment G,
Lausanne CH-1015, Switzerland ; Ecole Polytechnique Fédérale de Lausanne (EPFL),
CH-1015 Lausanne, Switzerland. (5)Spanish National Cancer Research Center (CNIO),
Madrid E28029, Spain.

OBJECTIVE: SIRT1 has been proposed to be a key signaling node linking changes in
energy metabolism to transcriptional adaptations. Although SIRT1 overexpression
is protective against diverse metabolic complications, especially in response to
high-fat diets, studies aiming to understand the etiology of such benefits are
scarce. Here, we aimed to identify the key tissues and mechanisms implicated in
the beneficial effects of SIRT1 on glucose homeostasis.
METHODS: We have used a mouse model of moderate SIRT1 overexpression, under the
control of its natural promoter, to evaluate glucose homeostasis and thoroughly
characterize how different tissues could influence insulin sensitivity.
RESULTS: Mice with moderate overexpression of SIRT1 exhibit better glucose
tolerance and insulin sensitivity even on a low fat diet.
Euglycemic-hyperinsulinemic clamps and in-depth tissue analyses revealed that
enhanced insulin sensitivity was achieved through a higher brown adipose tissue
activity and was fully reversed by housing the mice at thermoneutrality. SIRT1
did not influence brown adipocyte differentiation, but dramatically enhanced the
metabolic transcriptional responses to β3-adrenergic stimuli in differentiated
adipocytes.
CONCLUSIONS: Our work demonstrates that SIRT1 improves glucose homeostasis by
enhancing BAT function. This is not consequent to an alteration in the brown
adipocyte differentiation process, but as a result of potentiating the response
to β3-adrenergic stimuli.

PMCID: PMC4314542
PMID: 25685699 [PubMed]

--------------
5. Diabetes. 2015 Feb;64(2):471-84. doi: 10.2337/db14-0496. Epub 2014 Sep 23.

Inorganic nitrate promotes the browning of white adipose tissue through the
nitrate-nitrite-nitric oxide pathway.

Roberts LD(1), Ashmore T(2), Kotwica AO(3), Murfitt SA(4), Fernandez BO(5),
Feelisch M(5), Murray AJ(3), Griffin JL(1).

Author information:
(1)Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory,
Cambridge, U.K. Department of Biochemistry and Cambridge Systems Biology Centre,
University of Cambridge, Cambridge, U.K. lee.roberts@mrc-hnr.cam.ac.uk
jules.griffin@mrc-hnr.cam.ac.uk. (2)Department of Biochemistry and Cambridge
Systems Biology Centre, University of Cambridge, Cambridge, U.K. Department of
Physiology, Development and Neuroscience, University of Cambridge, Cambridge,
U.K. (3)Department of Physiology, Development and Neuroscience, University of
Cambridge, Cambridge, U.K. (4)Department of Biochemistry and Cambridge Systems
Biology Centre, University of Cambridge, Cambridge, U.K. (5)Faculty of Medicine,
Clinical and Experimental Sciences, University of Southampton, Southampton
General Hospital, Southampton, U.K.

Inorganic nitrate was once considered an oxidation end product of nitric oxide
metabolism with little biological activity. However, recent studies have
demonstrated that dietary nitrate can modulate mitochondrial function in man and
is effective in reversing features of the metabolic syndrome in mice. Using a
combined histological, metabolomics, and transcriptional and protein analysis
approach, we mechanistically defined that nitrate not only increases the
expression of thermogenic genes in brown adipose tissue but also induces the
expression of brown adipocyte-specific genes and proteins in white adipose
tissue, substantially increasing oxygen consumption and fatty acid β-oxidation in
adipocytes. Nitrate induces these phenotypic changes through a mechanism distinct
from known physiological small molecule activators of browning, the recently
identified nitrate-nitrite-nitric oxide pathway. The nitrate-induced browning
effect was enhanced in hypoxia, a serious comorbidity affecting white adipose
tissue in obese individuals, and corrected impaired brown adipocyte-specific gene
expression in white adipose tissue in a murine model of obesity. Because
resulting beige/brite cells exhibit antiobesity and antidiabetic effects, nitrate
may be an effective means of inducing the browning response in adipose tissue to
treat the metabolic syndrome.

© 2015 by the American Diabetes Association. Readers may use this article as long
as the work is properly cited, the use is educational and not for profit, and the
work is not altered.

PMCID: PMC4351918
PMID: 25249574 [PubMed - indexed for MEDLINE]

--------------
6. Life Sci. 2014 Sep 26;114(1):51-6. doi: 10.1016/j.lfs.2014.07.041. Epub 2014 Aug
14.

The flavan-3-ol fraction of cocoa powder suppressed changes associated with
early-stage metabolic syndrome in high-fat diet-fed rats.

Osakabe N(1), Hoshi J(2), Kudo N(3), Shibata M(4).

Author information:
(1)Department of Bio-science and Engineering, Shibaura Institute of Technology
Tokyo, Japan. Electronic address: nao-osa@sic.shibaura-it.ac.jp. (2)Department of
Bio-science and Engineering, Shibaura Institute of Technology Tokyo, Japan.
Electronic address: mf12054@sic.shibaura-it.ac.jp. (3)Department of Bio-science
and Engineering, Shibaura Institute of Technology Tokyo, Japan. Electronic
address: mf13033@sic.shibaura-it.ac.jp. (4)Department of Bio-science and
Engineering, Shibaura Institute of Technology Tokyo, Japan. Electronic address:
shibatam@sic.shibaura-it.ac.jp.

AIMS: Previous epidemiological studies have suggested that ingestion of chocolate
reduces the risk of cardiovascular disease. In the present study, we examined the
effects of flavan-3-ols derived from cocoa on blood pressure, lipolysis, and
thermogenesis in rats fed a high-fat diet and that showed early signs of
metabolic syndrome.
MAIN METHODS: The rats were divided into three groups, and fed either normal diet
(normal), 60% fat high-fat diet (HFD), or HFD containing 0.2% flavan-3-ols
(HFD-flavan) for 4 weeks. At the end of the feeding period, blood pressure was
measured and animals were sacrificed under anesthesia. Lipolysis and
thermogenesis-related protein levels were measured in several tissues by Western
blotting, and mitochondrial DNA copy number was measured by RT-PCR.
KEY FINDINGS: Mean blood pressure and epididymal adipose tissue weight of
HFD-flavan were significantly lower compared with those of HFD. Uncoupling
protein (UCP)1 in brown adipose tissue and UCP3 in gastrocnemius of HFD-flavan
were significantly increased compared with those of HFD group. Carnitine
palmitoyltransferase (CPT) 2 levels in liver and medium-chain acyl-CoA
dehydrogenase (MCAD) levels in gastrocnemius and liver were significantly
increased by the supplementation of flavan-3-ols.
SIGNIFICANCE: In addition to having hypotensive effects, flavan-3-ols enhance
thermogenesis and lipolysis and consequently reduce white adipose tissue weight
gain in response to high-fat diet feeding.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID: 25132363 [PubMed - indexed for MEDLINE]

--------------
7. J Nutr Biochem. 2014 Sep;25(9):893-902. doi: 10.1016/j.jnutbio.2014.04.004. Epub
2014 May 2.

Capsaicin-induced transcriptional changes in hypothalamus and alterations in gut
microbial count in high fat diet fed mice.

Baboota RK(1), Murtaza N(1), Jagtap S(2), Singh DP(1), Karmase A(2), Kaur J(3),
Bhutani KK(2), Boparai RK(4), Premkumar LS(5), Kondepudi KK(1), Bishnoi M(6).

Author information:
(1)National Agri-Food Biotechnology Institute, SAS Nagar, Punjab, India 160071.
(2)National Institute of Pharmaceutical Education and Research, SAS Nagar,
Punjab, India 160062. (3)Department of Biotechnology, University Institute of
Engineering and Technology, Panjab University, Chandigarh, India 160025.
(4)Department of Biochemistry, Panjab University, Chandigarh, India 160014.
(5)Department of Pharmacology, Southern Illinois University School of Medicine,
Springfield, IL 62702, USA. (6)National Agri-Food Biotechnology Institute, SAS
Nagar, Punjab, India 160071. Electronic address: mbishnoi@gmail.com.

Obesity is a global health problem and recently it has been seen as a growing
concern for developing countries. Several bioactive dietary molecules have been
associated with amelioration of obesity and associated complications and
capsaicin is one among them. The present work is an attempt to understand and
provide evidence for the novel mechanisms of anti-obesity activity of capsaicin
in high fat diet (HFD)-fed mice. Swiss albino mice divided in three groups
(n=8-10) i.e. control, HFD fed and capsaicin (2mg/kg, po)+HFD fed were
administered respective treatment for 3months. After measuring phenotypic and
serum related biochemical changes, effect of capsaicin on HFD-induced
transcriptional changes in hypothalamus, white adipose tissue (WAT) (visceral and
subcutaneous), brown adipose tissue (BAT) and gut microbial alterations was
studied and quantified. Our results suggest that, in addition to its well-known
effects, oral administration of capsaicin (a) modulates hypothalamic satiety
associated genotype, (b) alters gut microbial composition, © induces "browning"
genotype (BAT associated genes) in subcutaneous WAT and (d) increases expression
of thermogenesis and mitochondrial biogenesis genes in BAT. The present study
provides evidence for novel and interesting mechanisms to explain the
anti-obesity effect of capsaicin.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID: 24917046 [PubMed - indexed for MEDLINE]

--------------
8. Biochem Biophys Res Commun. 2014 May 16;447(4):644-8. doi:
10.1016/j.bbrc.2014.04.056. Epub 2014 Apr 20.

Panax red ginseng extract regulates energy expenditures by modulating PKA
dependent lipid mobilization in adipose tissue.

Cho HM(1), Kang YH(1), Yoo H(1), Yoon SY(2), Kang SW(3), Chang EJ(3), Song Y(4).

Author information:
(1)Department of Biomedical Sciences, Cell Dysfunction Research Center (CDRC),
University of Ulsan, College of Medicine, Seoul 138-736, Republic of Korea.
(2)Department of Anatomy and Cell Biology, University of Ulsan, College of
Medicine, Seoul 138-736, Republic of Korea. (3)Department of Biomedical Sciences,
Cell Dysfunction Research Center (CDRC), University of Ulsan, College of
Medicine, Seoul 138-736, Republic of Korea; Department of Anatomy and Cell
Biology, University of Ulsan, College of Medicine, Seoul 138-736, Republic of
Korea. (4)Department of Biomedical Sciences, Cell Dysfunction Research Center
(CDRC), University of Ulsan, College of Medicine, Seoul 138-736, Republic of
Korea; Department of Anatomy and Cell Biology, University of Ulsan, College of
Medicine, Seoul 138-736, Republic of Korea. Electronic address:
ysong@amc.seoul.kr.

Regulation of balance between lipid accumulation and energy consumption is a
critical step for the maintenance of energy homeostasis. Here, we show that Panax
red ginseng extract treatments increased energy expenditures and prevented mice
from diet induced obesity. Panax red ginseng extracts strongly activated Hormone
Specific Lipase (HSL) via Protein Kinase A (PKA). Since activation of HSL induces
lipolysis in WAT and fatty acid oxidation in brown adipose tissue (BAT), these
results suggest that Panax red ginseng extracts reduce HFD induced obesity by
regulating lipid mobilization.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID: 24759232 [PubMed - indexed for MEDLINE]

--------------
9. Int J Cardiol. 2013 Oct 3;168(3):2310-4. doi: 10.1016/j.ijcard.2013.01.182. Epub
2013 Mar 1.

Aged garlic extract with supplement is associated with increase in brown adipose,
decrease in white adipose tissue and predict lack of progression in coronary
atherosclerosis.

Ahmadi N(1), Nabavi V, Hajsadeghi F, Zeb I, Flores F, Ebrahimi R, Budoff M.

Author information:
(1)Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center,
Torrance, CA, USA; Greater Los Angeles Veterans Administration Medical Center,
UCLA-School of Medicine, Los Angeles, CA, USA. Electronic address:
ahmadi@ucla.edu.

BACKGROUND: Aged garlic extract with supplement (AGE-S) significantly reduces
coronary artery calcium (CAC). We evaluated the effects of AGE-S on change in
white (wEAT) and brown (bEAT) epicardial adipose tissue, homocysteine and CAC.
METHODS: Sixty subjects, randomized to a daily capsule of placebo vs. AGE-S
inclusive of aged garlic-extract (250 mg) plus vitamin-B12 (100 μg), folic-acid
(300 μg), vitamin-B6 (12.5mg) and L-arginine (100mg) underwent CAC, wEAT and bEAT
measurements at baseline and 12 months. The postcuff deflation
temperature-rebound index of vascular function was assessed using a
reactive-hyperemia procedure. Vascular dysfunction was defined according to the
tertiles of temperature-rebound at 1 year of follow-up. CAC progression was
defined as an annual-increase in CAC>15%.
RESULTS: From baseline to 12 months, there was a strong correlation between
increase in wEAT and CAC (r(2)=0.54, p=0.0001). At 1 year, the risks of CAC
progression and increased wEAT and homocysteine were significantly lower in AGE-S
to placebo (p<0.05). Similarly, bEAT and temperature-rebound were significantly
higher in AGE-S as compared to placebo (p<0.05). Strong association between
increase in temperature-rebound and bEAT/wEAT ratio (r(2)=0.80, p=0.001) was
noted, which was more robust in AGE-S. Maximum beneficial effect of AGE-S was
noted with increase in bEAT/wEAT ratio, temperature-rebound, and lack of
progression of homocysteine and CAC.
CONCLUSIONS: AGE-S is associated with increase in bEAT/wEAT ratio, reduction of
homocysteine and lack of progression of CAC. Increases in bEAT/wEAT ratio
correlated strongly with increases in vascular function measured by
temperature-rebound and predicted a lack of CAC progression and plaque
stabilization in response to AGE-S.

Published by Elsevier Ireland Ltd.

PMID: 23453866 [PubMed - indexed for MEDLINE]

--------------
10. PLoS One. 2012;7(6):e39332. doi: 10.1371/journal.pone.0039332. Epub 2012 Jun 20.

Ursolic acid increases skeletal muscle and brown fat and decreases diet-induced
obesity, glucose intolerance and fatty liver disease.

Kunkel SD(1), Elmore CJ, Bongers KS, Ebert SM, Fox DK, Dyle MC, Bullard SA, Adams
CM.

Author information:
(1)Department of Internal Medicine, and Fraternal Order of Eagles Diabetes
Research Center, Roy J. and Lucille A. Carver College of Medicine, The University
of Iowa, Iowa City, Iowa, United States of America.

Skeletal muscle Akt activity stimulates muscle growth and imparts resistance to
obesity, glucose intolerance and fatty liver disease. We recently found that
ursolic acid increases skeletal muscle Akt activity and stimulates muscle growth
in non-obese mice. Here, we tested the hypothesis that ursolic acid might
increase skeletal muscle Akt activity in a mouse model of diet-induced obesity.
We studied mice that consumed a high fat diet lacking or containing ursolic acid.
In skeletal muscle, ursolic acid increased Akt activity, as well as downstream
mRNAs that promote glucose utilization (hexokinase-II), blood vessel recruitment
(Vegfa) and autocrine/paracrine IGF-I signaling (Igf1). As a result, ursolic acid
increased skeletal muscle mass, fast and slow muscle fiber size, grip strength
and exercise capacity. Interestingly, ursolic acid also increased brown fat, a
tissue that shares developmental origins with skeletal muscle. Consistent with
increased skeletal muscle and brown fat, ursolic acid increased energy
expenditure, leading to reduced obesity, improved glucose tolerance and decreased
hepatic steatosis. These data support a model in which ursolic acid reduces
obesity, glucose intolerance and fatty liver disease by increasing skeletal
muscle and brown fat, and suggest ursolic acid as a potential therapeutic
approach for obesity and obesity-related illness.

PMCID: PMC3379974
PMID: 22745735 [PubMed - indexed for MEDLINE]

--------------
11. J Nutr. 2011 Nov;141(11):1947-53. doi: 10.3945/jn.111.146050. Epub 2011 Sep 14.

Reduction of body weight by dietary garlic is associated with an increase in
uncoupling protein mRNA expression and activation of AMP-activated protein kinase
in diet-induced obese mice.

Lee MS(1), Kim IH, Kim CT, Kim Y.

Author information:
(1)Department of Nutritional Science and Food Management, Ewha Womans University,
Seoul, Korea.

This study investigated the antiobesity effect of garlic in diet-induced obese
mice. Male C57BL/6J mice were fed a high-fat diet (45% fat) for 8 wk to induce
obesity. Subsequently, they were fed a high-fat control diet, high-fat diets
supplemented with 2%, or 5% garlic (wt:wt) for another 7 wk. Dietary garlic
reduced body weight and the mass of various white adipose tissue deposits and
also ameliorated the high-fat diet-induced abnormal plasma and liver lipid
profiles. Garlic supplementation significantly decreased the mRNA levels of
adipogenic genes in white adipose tissues (WAT). However, consumption of garlic
increased the expression of mRNA for uncoupling proteins in brown adipose tissue
(BAT), liver, WAT, and skeletal muscle. Mice treated with garlic maintained a
significantly higher body temperature than untreated mice during a 6-h, 4°C cold
challenge and, notably, AMP-activated protein kinase (AMPK) activity was
stimulated in BAT, liver, WAT, and skeletal muscle. These results suggest that
the antiobesity effects of garlic were at least partially mediated via activation
of AMPK, increased thermogenesis, and decreased expression of multiple genes
involved in adipogenesis.

PMID: 21918057 [PubMed - indexed for MEDLINE]

 
------------------
12. Nutr Metab (Lond). 2015 May 16;12:16. doi: 10.1186/s12986-015-0013-6. eCollection
2015.
 
Beneficial effects of inorganic nitrate/nitrite in type 2 diabetes and its
complications.
 
Bahadoran Z(1), Ghasemi A(2), Mirmiran P(3), Azizi F(4), Hadaegh F(5).
 
 
BACKGROUND AND AIM: The ability of inorganic nitrate and nitrite to convert to
nitric oxide (NO), and some of its properties e.g. regulation of glucose
metabolism, vascular homeostasis, and insulin signaling pathway, have recently
raised the hypothesis that inorganic nitrate and nitrite could be potential
therapeutic agents in type 2 diabetes. In this review, we reviewed experimental
and clinical studies investigating the effect of nitrate/nitrite administration
on various aspects of type 2 diabetes.
FINDINGS: Studies showed that an altered metabolism of nitrate/nitrite and
impaired NO pathway occurs in diabetes which could contribute to its
complications. Some important beneficial properties, including regulation of
glucose homeostasis and insulin signaling pathway, improvement of insulin
resistance and vascular function, hypotensive, hypolipidemic as well as
anti-inflammatory and anti-oxidative effects have been observed following
administration of inorganic nitrate/nitrite.
CONCLUSION: It seems that dietary nitrate/nitrite could be a compensatory fuel
for a disrupted nitrate/nitrite/NO pathway and related disorders in diabetes.
Although some beneficial properties of nitrate/nitrite have been reported by
experimental investigations, long-term clinical studies with various doses of
inorganic nitrate/nitrite supplementation, are recommended to confirm these
effects.
 
PMCID: PMC4436104
PMID: 25991919
 
-----------
13. Nutrients. 2014 Nov 18;6(11):5224-64. doi: 10.3390/nu6115224.
 
Nitrate ingestion: a review of the health and physical performance effects.
 
Clements WT(1), Lee SR(2), Bloomer RJ(3).
 
 
 
 
This paper provides an overview of the current literature and scientific evidence
surrounding inorganic nitrate (NO3-) supplementation and its potential for
improving human health and physical performance. As indicative of the
ever-expanding organic and natural food consumer market, athletes and health
enthusiasts alike are constantly searching for ingredient-specific "super foods" 
and dietary supplements capable of eliciting health and performance benefits.
Evidence suggests that NO3- is the viable active component within beetroot juice 
(BRJ) and other vegetables, responsible for health-promoting and ergogenic
effects. Indeed, multiple studies support NO3- supplementation as an effective
method to improve exercise performance. NO3- supplementation (either as BRJ or
sodium nitrate [NaNO3-]) has also demonstrated modest benefits pertaining to
cardiovascular health, such as reducing blood pressure (BP), enhancing blood
flow, and elevating the driving pressure of O2 in the microcirculation to areas
of hypoxia or exercising tissue. These findings are important to cardiovascular
medicine/exercise physiology and suggest a possible role for NO3-
supplementation: (1) as a low-cost prevention and treatment intervention for
patients suffering from blood flow disorders; and (2) an effective, natural
ergogenic aid for athletes. Benefits have been noted following a single bolus, as
well as daily supplementation of NO3-. While results are promising, additional
research is needed to determine the impact of NO3- supplementation on anaerobic
exercise performance, to identify principle relationships between isolated
nitrate and other ingredients found in nitrate-rich vegetables (e.g., vitamin C, 
polyphenols, fatty acids, thiocyanate), to explore the specific dose-response
relationships needed to elicit health and ergogenic benefits, to prolong the
supplementation period beyond a relatively short period (i.e., >15 days), to
determine if more robust effects can be observed with longer-term treatment, and 
to fully examine the safety of chronic NO3- supplementation, as this continues to
be a concern of some.
 
PMCID: PMC4245587
PMID: 25412154 
 
-------------
14. J Appl Physiol (1985). 2014 Mar 1;116(5):463-77. doi:
10.1152/japplphysiol.01100.2013. Epub 2014 Jan 9.
 
Inorganic nitrite supplementation for healthy arterial aging.
 
Sindler AL(1), Devan AE, Fleenor BS, Seals DR.
 
 
Aging is the major risk factor for cardiovascular diseases (CVD). This is
attributable primarily to adverse changes in arteries, notably, increases in
large elastic artery stiffness and endothelial dysfunction mediated by inadequate
concentrations of the vascular-protective molecule, nitric oxide (NO), and higher
levels of oxidative stress and inflammation. Inorganic nitrite is a promising
precursor molecule for augmenting circulating and tissue NO bioavailability
because it requires only a one-step reduction to NO. Nitrite also acts as an
independent signaling molecule, exerting many of the effects previously
attributed to NO. Results of recent studies indicate that nitrite may be
effective in the treatment of vascular aging. In old mice, short-term oral sodium
nitrite supplementation reduces aortic pulse wave velocity, the gold-standard
measure of large elastic artery stiffness, and ameliorates endothelial
dysfunction, as indicated by normalization of NO-mediated endothelium-dependent
dilation. These improvements in age-related vascular dysfunction with nitrite are
mediated by reductions in oxidative stress and inflammation, and may be linked to
increases in mitochondrial biogenesis and health. Increasing nitrite levels via
dietary intake of nitrate appears to have similarly beneficial effects in many of
the same physiological and clinical settings. Several clinical trials are being
performed to determine the broad therapeutic potential of increasing nitrite
bioavailability on human health and disease, including studies related to
vascular aging. In summary, inorganic nitrite, as well as dietary nitrate
supplementation, represents a promising therapy for treatment of arterial aging
and prevention of age-associated CVD in humans.
 
PMCID: PMC3949212
PMID: 24408999
 
------------
15. Mol Nutr Food Res. 2015 Jan;59(1):106-28. doi: 10.1002/mnfr.201400286. Epub 2014 
Oct 14.
 
Nitrate and nitrite in the diet: how to assess their benefit and risk for human
health.
 
Habermeyer M(1), Roth A, Guth S, Diel P, Engel KH, Epe B, Fürst P, Heinz V, Humpf
HU, Joost HG, Knorr D, de Kok T, Kulling S, Lampen A, Marko D, Rechkemmer G,
Rietjens I, Stadler RH, Vieths S, Vogel R, Steinberg P, Eisenbrand G.
 
Author information: 
(1)Department of Food Chemistry and Toxicology, University of Kaiserslautern,
Kaiserslautern, Germany**
 
Nitrate is a natural constituent of the human diet and an approved food additive.
It can be partially converted to nitrogen monoxide, which induces vasodilation
and thereby decreases blood pressure. This effect is associated with a reduced
risk regarding cardiovascular disease, myocardial infarction, and stroke.
Moreover, dietary nitrate has been associated with beneficial effects in patients
with gastric ulcer, renal failure, or metabolic syndrome. Recent studies indicate
that such beneficial health effects due to dietary nitrate may be achievable at
intake levels resulting from the daily consumption of nitrate-rich vegetables.
N-nitroso compounds are endogenously formed in humans. However, their relevance
for human health has not been adequately explored up to now. Nitrate and nitrite 
are per se not carcinogenic, but under conditions that result in endogenous
nitrosation, it cannot be excluded that ingested nitrate and nitrite may lead to 
an increased cancer risk and may probably be carcinogenic to humans. In this
review, the known beneficial and detrimental health effects related to dietary
nitrate/nitrite intake are described and the identified gaps in knowledge as well
as the research needs required to perform a reliable benefit/risk assessment in
terms of long-term human health consequences due to dietary nitrate/nitrite
intake are presented.
 
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
 
PMID: 25164923

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Kenton,

 

Did you ever find any better tape-on sensors than the one you posted on in this thread?  All the bands I keep getting don't provide just a simple average temp reading--just want a tape on sensor that will take a reading every half hour and then give me an average temperature at the end of the day.  

 

Hesvit didn't work out like you'd hoped, I presume? That's unfortunate.

 

I'm still not quite sure what a single average temperature reading is going to tell you (except perhaps when you're ovulating ), but here are three bluetooth-enabled, stick-on thermometers, designed for infants but that work on adults too, ranging in price from $29 - $70. Each has iPhone and Android Apps for continuous temperature monitoring.

 

iRULU Temp Sitter Wireless Smart Thermometer Bluetooth Temperature Sensor Intelligent Monitor - $29

Fridababy FeverFrida the iThermonitor - $54

Infanttech Smarttemp -The Award-Winning FDA Approved Bluetooth Baby Thermometer - $70

 

Amazing what you can find on Amazon... Let us know if you give any of these a try.

 

(BTW, we met at the November 2004: Third Scientific Calorie Restriction Conference -- Charleston, SC.)

 

Wow - that was so many moon ago. I'm afraid I don't remember too much about that conference, except it was a fun time!

 

--Dean

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thx for replying to my post but i was not asking for a tape on thermometer.  i need one that will take readings (eg, one every half hour) and then give me one single average temperature for the day.  (As I have tried earlier in this thread to say, i want to count/restrict my thermal energy input (entering through my skin) for the day like I count/restrict food energy input (entering via mouth) for the day.  For example, I may eat 1700 cal in a day and have an average armpit temp for the day of 97F.  The next day, my eaten calories may be 1800 and that same avge temp may be 97.3F.  The thermometer needs to do that.  (The Hesvit takes the temps and plots them for the day but does not *average* them for the day.)  Got it?  If one or all of the links you gave me do that, then I would be a happy man!  ! 

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Kenton,

 

It would seem pretty straightforward to take the continuous readings from one of those bluetooth thermometers (or your Hesvit for that matter) and average them (even via eyeball from the graph) to serve your purpose. Given how much your skin temperature will vary day-to-day with ambient temperature, it would seem you'll be able to get all the precision available by simply eyeballing it.

 

What am I missing?

 

--Dean

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In reality, I did for years but now do not count my calories.  I get on the weight scale once a day and check a single number.  I would prefer not to count temp readings daily for similar reasons. BTW, my ambient temp does not vary much as I am mostly indoors and I have watched it on my Hesvit; it is quite consistent at a given time for any given day...hence, accuracy from day to day is crucial. BTW2, my calories don't vary much either day to day even though I do not count.  I want to check a single accurate number for average temp, like I check a single number for weight, 1x/day.

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OK Kenton,

 

I guess you've got your reasons.

 

As I said, what you want to know is when you are ovulating. Seriously. What you are looking for is TempDrop, with the OvuView ovulation tracking android application. Here is the TempDrop video and below that, a screenshot from the OvuView app:

 

 

tkDsMho.png

 

Nice and easy one averaged reading per day. 

 

Of course, TempDrop is crowdfunded and not quite ready yet. Shipping for Xmas, apparently...

 

--Dean

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It only provides the lowest ("basal") temp/day rather than the average temp/day.  Hence, in addition to not being available it will not be useful if/when ever available.  LMK if you find anything on the market, now, and I'll do the same. (Meanwhile, I'm grateful for and keeping the S3.)  Thank you!

Edited by Kenton

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