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Cold Exposure & Other Mild Stressors for Increased Health & Longevity

Cold Exposure Exercise Fasting UCPs UCP1 UCP3 FGF21

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#281 drewab

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Posted 14 May 2016 - 01:30 PM

Paul is aware of Gordo's CE experiments.  See these two threads over at his website:

 

http://www.livingthe...h-cold-exposure

 

http://www.livingthe...-just-two-meals

 

 

And BTW, I am not Drew Lawton over there.  It's a bizarre occurrence that their is another Drew active their.  My tag is Drew_ab there. 

Gordo,

 

That is another amazingly good glucose result - thanks for sharing it! But I must say, your previous test meal looked a lot more appetizing to me . But the well-known insulin boosting effects of dairy (ice cream) makes this a much better, though less appealing, test of postprandial glucose control. I wonder if Paul McGlothin is following any of this... I'm sure even he would be impressed.

 

For anyone who has forgotten, here are Gordo's tips for implementing cold exposure effectively and cheaply - including his cold shower protocol. They certainly seem to be working like a charm for your Gordo!

 

--Dean


Edited by Dean Pomerleau, 14 May 2016 - 01:53 PM.


#282 Dean Pomerleau

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Posted 14 May 2016 - 02:02 PM

Hey - that's wonderful!

 

Thanks for those pointers Drew, and thanks to you Gordo for carrying the torch over on the LivingTheCRWay™ forums! Glad to see Paul is aware of what we've been doing/researching, and seems to be interested in it. It seems like it would be right up his alley.

 

--Dean


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

#283 Kenton

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Posted 14 May 2016 - 02:30 PM

When I was in grade school a classmate "taught" me how to not feel pain in my injured left leg by kicking my right leg (thus getting my mind off the left one).  Funny how I never seem to feel or mind being weak or hungry any more, being preoccupied with feeling cold ! ! 



#284 Dean Pomerleau

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Posted 14 May 2016 - 04:28 PM

Ray Cronise and the "Metabolic Winter" Hypothesis

 

All,

 

I just finished watching this video (embedded below) of an interview of Ray Cronise by Rhonda Patrick of FoundMyFitness.com

 

Ray was on day 23 of a 24-day supervised water fast at the time of this interview.  Ray looks good, and says he feels great. He acknowledges though that clear thinking isn't always easy at that point in a fast, and I have to admit he is a bit rambly at times in the interview. 

 

But the reason Ray and his interview is relevant for this thread is that Ray is a pioneer in human application of mild cold exposure. He has a paper [1] in which he co-author David Sinclair (of SIRT1 fame) outline their "Metabolic Winter" Hypothesis. 

 

In short, they think modern society coddles us too much; we aren't exposure to cold temperatures or significant time away from food, and as a result our health suffers. In other words, we're killing ourselves by being unnaturally warm and well-fed. Interestingly, Ray goes so far as to suggest that intentional exercise is simply leveraging the health-promoting response the body developed originally to cope with cold exposure via shivering at first, and then non-shivering thermogenesis once cold-adapted. Exercise triggers a similar response to increase thermogenic capacity by upregulating irisin (as discussed here and here). From [1]:

 

Thus, it might be reasonable to consider that many of the health benefits of physical activity are actually adaptive responses related to times of cold stress and shivering. In nature, animals do not intentionally participate in high levels of activity to mitigate excess calorie ingestion—available calories are limited and animals conserve activity. In fact, the main factors influencing energy expenditure are body mass and ambient temperature, not activity.

 

This idea sort of turns Michael's "jiggling pecs" observation on it's head - i.e. exercise is piggybacking on the adaptive cold response rather than the cold exposure piggybacking on the beneficial response to exercise.

 

Ray also suggests that CR and CE share many of the same beneficial metabolic responses. The spend the first hour or so of the video talking about fasting. Interesting stuff, but not as relevant for this thread.

 

He starts talking about CE at 1:10:00 in the video. Here are some highlights:

 

1:11:00 - The link between CR and CE via the "Metabolic Winter" hypothesis

1:13:00 - CE and improved sleep

1:15:15 - His (and Wim Hof's) cold shower protocol - (10-sec warm → 20-sec cold) repeated 10 times, end on cold.

1:21:00 - CE for treating depression via elevated epinephrine 

1:28:50 - More on the relationship between CE and exercise

1:34:15 - "We've engineered winter out of our lives in the last century"

1:37:30 - Ray's "trichotomy" of cold stress, dietary restriction and sleep

1:46:00 - Sleeping in cold bedroom. No need for blanket or sheet once you're adapted (I can confirm!)

1:48:00 - Melatonin and how it decreases body temperature. He does cold shower then melatonin (30mg!) before bed

1:52:45 - Synergy between melatonin, resveratrol and SIRT1

 

--Dean

 

 

-----------

[1] Metab Syndr Relat Disord. 2014 Sep;12(7):355-61. doi: 10.1089/met.2014.0027. Epub

2014 Jun 11.
 
The "metabolic winter" hypothesis: a cause of the current epidemics of obesity
and cardiometabolic disease.
 
Cronise RJ(1), Sinclair DA, Bremer AA.
 
 
The concept of the "Calorie" originated in the 1800 s in an environment with
limited food availability, primarily as a means to define economic equivalencies 
in the energy density of food substrates. Soon thereafter, the energy densities
of the major macronutrients-fat, protein, and carbohydrates-were defined.
However, within a few decades of its inception, the "Calorie" became a commercial
tool for industries to promote specific food products, regardless of health
benefit. Modern technology has altered our living conditions and has changed our 
relationship with food from one of survival to palatability. Advances in
agriculture, food manufacturing, and processing have ensured that calorie
scarcity is less prevalent than calorie excess in the modern world. Yet, many
still approach dietary macronutrients in a reductionist manner and assume that
isocalorie foodstuffs are isometabolic. Herein, we discuss a novel way to view
the major food macronutrients and human diet in this era of excessive caloric
consumption, along with a novel relationship among calorie scarcity, mild cold
stress, and sleep that may explain the increasing prevalence of nutritionally
related diseases.
 
PMCID: PMC4209489
PMID: 24918620

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

#285 Dean Pomerleau

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Posted 16 May 2016 - 03:36 PM

Cold Exposure and Cold-Shock Protein RBM3

 

I'm sure all of us have had the experience of forgetting the name of someone who we haven't seen (or thought of) in a few months or years. It's on the tip of your tongue, but you just can't recall it. Memory is one of those "use it or lose it" sort of deals. If the synaptic connections that encode long-term memories aren't refreshed occasionally via recall, they atrophy and disappear. Loss of synapses that encode memories is also the first indication of neurodegenerative diseases like Alzheimer's Disease (AD), happening well before the development of plaques & tangles, and well before the neuronal death that characterizes late-stage AD [7][8]. 

 

Animals that hibernate have this problem in spades - since their brains are pretty much shut down for several months during which time they aren't actively rehearsing their memories to maintain them. But when they wake up, they still need to remember where they hid their nuts the previous fall and where the neighborhood predators live. 

 

Fortunately, it appears nature and their own biochemistry have got them covered. In response to cold and a modest (i.e. 1 °C [1]) drop in temperature, cells all over the body, but particularly neurons in the brain, synthesize a 'cold shock' protein called "RNA binding motif protein 3" (RBM3) [2]. From [4]:

 

In hibernating animals, RBM3 is upregulated in muscle, liver, and heart tissues of black bears [ref, ref], as well as in brain, heart, and liver tissues of squirrels at late torpor [ref].

 

And it's not just hibernating mammals where RBM3 is found. RBM3 or it's analogs are prevalent across both the plant and animal kingdom, present in plants, fish, amphibians, birds and mammals, including mice, rats and importantly, humans [4]. Interestingly, this cold-induced synthesis of RBM3 is boosted by the presence of either melatonin and life-extending, cold-induced FGF-21 [1]. In addition to cold, RBM3 also induced by UV radiation and hypoxia [5].

 

What does RBM3 do, particularly in neurons? It appears to play a role in neuronal stem cell maintenance and proliferation [4]:

 

In mammals, RBM3 level peaks during the early postnatal period and then decreases to very low levels in youth and adulthood in most regions of the brain, except for areas where proliferation remains active, such as the subventricular zone (SVZ) and the hippocampal subgranular zone (SGZ) [ref, ref], indicating a pivotal role of RBM3 in the maintenance of stemness and proliferation in neural stem/progenitor cells. Regardless to this dynamic temporal expression of CIRP and RBM3 with high abundance in early developmental stages and low in mature organisms, many mature cells maintain their ability to overexpress CIRP and RBM3 in response to stressful conditions, such as cold.

 

So right off the bat we see cold-induced RBM3 plays a role in neurogenesis, particularly in the brain's memory formation hub, the hippocampus. So that's nice to see. But it gets even better. Again from [4]:

 

RBM3 expression ... correlates with good [cancer] prognosis and reduced risk of disease progression and recurrence... 

 

Conversely [4]:

 

A large variety of immunohistochemical studies, including many tumor types, have shown consistently that loss of RBM3 expression is associated with clinically more aggressive tumors and an independent factor of poor prognosis.

 

In particular, high expression of RBM3 is associated with good prognosis in breast, epithelial, ovarian, prostate, testicular, bladder, esophageal, stomach, colorectal, and skin cancer [4].

 

RBM3 even appears to be beneficial for preventing sarcopenia and bone loss [4]:

 

RBM3 is involved in the regulation of skeletal muscle size and the prevention of muscle loss, indicating a novel vital function of RBM3 in muscle disease [ref]. A subsequent study has further revealed that RBM3 inhibits both necrosis and apoptosis in muscle myoblasts, consistent with a general cytoprotective function of RBM3 [ref]. Moreover, RBM3 is suggested to mediate hypothermia-induced overexpression of bone protein alkaline phosphatase and osteocalcin [ref].

 

The above combination of effects is interesting and pretty unusual. Usually anabolic agents that help preserve muscles and bones (i.e. IGF-1) are associated with increased cancer proliferation. But here, we see the best of both worlds - muscle & bone preservation and lower cancer risk associated with expression of RBM3.

 

In summary, RBM3 appears to be a) induced by mild cold exposure / reduced body temperature, and b) have many beneficial effects all over the body, including preventing cancer proliferation, preventing muscle and bone loss, and boosting growth of new neurons, especially in the hippocampus.

 

But a closer look at the effects of RBM3 on the brain is warranted.  A certain molecular variant of RBM3 (i.e. RBM3 which is 'absent a single arginine residue in the RGG domain' - whatever that means...) is found in heavy concentrations in neural dendrites [6] - which anyone familiar with neuroanatomy will know are the post-synaptic (i.e. the receiving side) of synapses. 

 

What's it doing there? In general, from [3]:

 

[RBM3] is known to increase local protein synthesis at dendrites [ref] and global protein synthesis through ribosomal subunit binding and/or microRNA biogenesis [ref].

 

That sounds good, but what exactly does it mean in terms of brain health? That is what this study [3] from Nature last year (popular press account, another one, and a detailed review on an Alzheimer's forum), aimed to find out. Here is where things get really interesting. What prompted the researchers from [3] was the question we started with - how do mammals pull off the previously-observed [9][10] trick of preserving memories & synapses during hibernation and/or reconstruct them upon awakening? By now you won't be surprised to hear that it appears to be RBM3 that mediates this synaptic preservation/reconstruction. 

 

In particular, study [3] investigated the effects of cold exposure and RBM3 on the synapses in both normal mice, and in mice models of two neurodegenerative disease, Alzheimer's Disease (AD) via genetically-mutant 5XFAD mice1 and a mad-cow-like prion disease, which I'll abbreviate as MCD for "mad cow disease" although it isn't exactly, simply to avoid using PD as an abbreviation for "prion disease". PD would be more accurate, but it is too easily confused with another neurodegenerative disease, Parkinson's Disease. 

 

Basically what they found was that in wild-type mice (w/o the AD or MCD), a short but deep bout of hypothermia (17 °C body temperature for 45 minutes) resulted in the loss of synapses, but upon rewarming the synapses were restored, at least in number, through a process dubbed structural plasticity. I'll talk about whether memory performance was also preserved/restored shortly (preview - it was). This sort of cold-induced structural plasticity is exactly what appears to happen during and after hibernation in mammals. 

 

Mice with the AD and MCD models, in the first few weeks after exposure, i.e. before their diseases had time to take hold, showed the same structural plasticity - they lost synapse with cooling but then the synapses were restored after rewarming. And in these mice, they did test memory, via a clever object recognition task you can read about in the full text. The memories that the infected (and wild-type) mice had formed prior to cooling was preserved upon rewarming. Just like in the case of hibernation (now where did I hide those nuts?).

 

But a few weeks/months later, when the diseases had progressed more in the AD and MCD mice, if they cooled these messed up mice their synapses were not restored after rewarming, and memory performance  was impaired after cooling and then rewarming. Importantly, as time (and the diseases) progressed, the AD and MCD mice produced less and less RBM3 in response to cooling, and this drop paralleled their drop in synapse recovery and memory performance upon rewarming - suggesting RBM3 was causal in the synapse and memory preserving process (more on that below).

 

By now you should be thinking to yourself - so what Dean? So you can cool normal or (early) neurodegenerative mice and rewarm them without trashing their synapses or their memory performance and this may happen as a result of upregulation of RBM3 - what good it that? 

 

Here are three possibilities:

  1. It might bode well for Zeta's hope (I miss Zeta. Wonder where he's at?) that someday we'll develop technology for suspended animation. Brian points out in this post that one of the challenges of suspended animation is preserving the delicate structures of the brain (particularly synapses) during cryo-suspension. RBM3 might play a role in such preservation. BTW, I came across [11], titled "Is Human Hibernation Possible?", which is a good review of the feasibility of this approach to both life extension, and short-term suspended animation (see next point).
     
  2. Understanding / leveraging how RBM3 preserves the brain during hypothermia / hypoxia may be useful in clinical practice, where temporary cooling of the body is done to given doctors more time, with the hope (and fortunately, the observation) that patients can be temporarily cooled and then rewarmed without significant deleterious effects, particularly on brain function. This clinical application of cooling is discussed in this recent popular press article on a pilot study being done here in Pittsburgh with gunshot victims who come into the hospital in critical condition. The goal is to put them into "suspended animation" for a few hours or days to give doctors more time to stabilize them and treat their injuries. Understanding and leveraging RBM3 could make this sort of short-term, medically-induced cryo-suspension safer and more effective.
     
  3. These results might help explain the amazing mammalian diving reflex (MDR),which I mentioned back in my CE Albatross post two months ago, and which I promised to discuss someday. The MDR enables animals (and people!) to recover from being submerged in cold water without oxygen for up to two hours without brain damage. It would not be at all surprising to me if scientists discover that RBM3 plays an important role protecting the brain in the MDR, although I looked and couldn't find any papers that addressed this possibility.

But the original question is a good one - If I don't think I'll be shot, fall into a frozen lake, or undergo cryo-suspension for life extension anytime soon, what use is all this RBM3 synapse preservation stuff for me now?

 

That's where the rest of [3] comes in. It turns out that cold exposure, and specifically boosting RMB3, acts as a hormetic agent - providing long-lasting protection against loss of synapses, and preserving memories.

 

Specifically, as we saw above, cooling and rewarming the AD and MCD mice once their disease had progressed was worse than useless - i.e. they lost synapses (and memories) during the cooling process which weren't restored upon rewarming. In contrast, cooling and rewarming early in the progress of the disease (i.e. just a couple weeks after the mice had been treated to induced AD or MCD) not only kept their memories from before the cooling intact immediately after rewarming - it also served as a hormetic stressor, which helped preserve their synapses for many weeks to come. Specifically, long after control mice with the AD or MCD conditions had lost their synapses and their ability to form new memories, the AD and MCD mice who had been cooled and rewarmed early on in their diseases were protected - their synapses and memory abilities were preserved much longer. In addition, they lived longer than the control mice who had either the AD or MCD treatment, but no cooling and rewarming. Don't get too excited. Their lives were still greatly shortened relative to wild-type mice who weren't messed up by the AD or MCD treatments. 

 

Further, they found that this preservation of synapses and memory performance was mediated by upregulation of RBM3. In particular, a single episode of cooling raised RBM3 levels in wild-type mice for three days, and in the AD and MCD mice, a single cooling episode "resulted in sustained several-fold increase in RBM3 expression up to 6 weeks later" [3]. When they knocked out the ability of the mice to produce RBM3 in response to cooling, it erased all the benefits - without elevated RBM3, the AD and MCD mice lost synapses and memories after cooling/rewarming at the same rate as control AD and MCD mice who hadn't been cooled/rewarmed, and they didn't live any longer either. In short, RBM3 was critical for cold-induced preservation of synapses and memories.

 

Finally, to get the real smoking gun, they skipped the cooling/rewarming and simply injected the AD and MCD mice with a virus that expresses RBM3. Yup - sure enough. Injecting this RBM3-expressing virus into the hippocampi of the AD and MCD increased hippocampal RBM3 by a factor of 3 and in the MCD mice, this boost to RBM3 preserved synapses, neurons, memories and extended survival relative MCD mice who got placebo virus injection into their hippocampi. The AD mice injected with the RBM3-expressing virus showed similar (although not identical) benefits. Finally, to cap it off:

 

RBM3 knockdown [in the absence of cooling] also reduced synapse number and 
novel object memory in wild-type mice (Extended Data Fig. 10b), thus it is
likely to be involved in synaptic maintenance under normal physiological conditions.

 

Here is that figure 10b they mentioned, showing the number of synapses (left graph) and memory performance (right graph) of wild-type mice with normal levels of RBM3 (white bars) and suppressed levels of RBM3 (yellowish bars):

6gmyBEc.png

 

 

In short, when RBM3 was cut to 70% below its usual level, normal mice kept in normal conditions (i.e. no cooling) were 50% worse at retaining memories! 

 

Here is the paper's optimistic final paragraph:

 

In conclusion, we have shown that early synapse loss in mouse models
of neurodegenerative disease results, at least in part, from defective
synaptic repair processes associated with failure to induce the cold-shock
RNA-binding protein, RBM3. This results in impaired synaptic
reassembly after cooling, but also appears to be important in the context
of protecting against ongoing synaptic toxicity during disease, and
in synaptic maintenance in wild-type mice. Our data suggest that further
understanding the mechanisms of action of cold-shock proteins
such as RBM3 may yield insights into endogenous repair processes and
bring new therapeutic targets for neuroprotection in neurodegenerative
disease.

 

In short, it appears that the cold-shock protein RBM3 can be induced by cold exposure in mice and humans. It helps to prevent cancer proliferation, sarcopenia and bone loss, boosts growth of new (hippocampal) neurons, preserves synapses and memories, and perhaps can even help prevent the onset and/or slow the progression of neurodegenerative diseases, including Alzheimer's disease.

 

Yet another pathway by which cold exposure appears good for your health!

 

--Dean

 

------

1The 5XFAD mice model of Alzheimer's disease involved genetically messed up mice who express 5 human genes associated with familial, early-onset AD, which causes them to rapidly develop amyloid-beta plaques. They lose synapses and memories first, then neurons and eventually die, just like in human AD.

 

----------

[1] Neuroscience. 2015 Oct 1;305:268-78. doi: 10.1016/j.neuroscience.2015.08.012.

Epub 2015 Aug 8.
 
Cold stress protein RBM3 responds to temperature change in an ultra-sensitive
manner in young neurons.
 
Jackson TC(1), Manole MD(2), Kotermanski SE(3), Jackson EK(3), Clark RS(4),
Kochanek PM(4).
 
Extremely mild hypothermia to 36.0 °C is not thought to appreciably differ
clinically from 37.0 °C. However, it is possible that 36.0 °C stimulates highly
sensitive hypothermic signaling mechanism(s) and alters biochemistry. To the best
of our knowledge, no such ultra-sensitive pathway/mechanisms have been described.
Here we show that cold stress protein RNA binding motif 3 (RBM3) increases in
neuron and astrocyte cultures maintained at 33 °C or 36 °C for 24 or 48 h,
compared to 37 °C controls. Neurons cultured at 36 °C also had increased global
protein synthesis (GPS). Finally, we found that melatonin or fibroblast growth
factor 21 (FGF21) augmented RBM3 upregulation in young neurons cooled to 36 °C.
Our results show that a 1 °C reduction in temperature can induce pleiotropic
biochemical changes by upregulating GPS in neurons which may be mediated by RBM3 
and that this process can be pharmacologically mimicked and enhanced with
melatonin or FGF21.
 
Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
 
PMCID: PMC4570027 [Available on 2016-10-01]
PMID: 26265550

 

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

[2] Williams DR, Epperson LE, Li W, Hughes MA, Taylor R, Rogers J, Martin SL, Cossins AR, Gracey AY (2005) Seasonally hibernating phenotype assessed through transcript screening. Physiol Genomics 24(1):13–22. doi:10.​1152/​physiolgenomics.​00301.​2004 PubMedCrossRef

 

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

[3] Nature. 2015 Feb 12;518(7538):236-9. doi: 10.1038/nature14142. Epub 2015 Jan 14.

 
RBM3 mediates structural plasticity and protective effects of cooling in
neurodegeneration.
 
Peretti D(1), Bastide A(1), Radford H(1), Verity N(1), Molloy C(1), Martin MG(1),
Moreno JA(1), Steinert JR(1), Smith T(1), Dinsdale D(1), Willis AE(1), Mallucci
GR(2).
 
 
Comment in
    Nat Rev Neurosci. 2015 Mar;16(3):124.
    Nature. 2015 Feb 12;518(7538):177-8.
    Nat Rev Neurol. 2015 Mar;11(3):124.
 
In the healthy adult brain synapses are continuously remodelled through a process
of elimination and formation known as structural plasticity. Reduction in synapse
number is a consistent early feature of neurodegenerative diseases, suggesting
deficient compensatory mechanisms. Although much is known about toxic processes
leading to synaptic dysfunction and loss in these disorders, how synaptic
regeneration is affected is unknown. In hibernating mammals, cooling induces loss
of synaptic contacts, which are reformed on rewarming, a form of structural
plasticity. We have found that similar changes occur in artificially cooled
laboratory rodents. Cooling and hibernation also induce a number of cold-shock
proteins in the brain, including the RNA binding protein, RBM3 (ref. 6). The
relationship of such proteins to structural plasticity is unknown. Here we show
that synapse regeneration is impaired in mouse models of neurodegenerative
disease, in association with the failure to induce RBM3. In both prion-infected
and 5XFAD (Alzheimer-type) mice, the capacity to regenerate synapses after
cooling declined in parallel with the loss of induction of RBM3. Enhanced
expression of RBM3 in the hippocampus prevented this deficit and restored the
capacity for synapse reassembly after cooling. RBM3 overexpression, achieved
either by boosting endogenous levels through hypothermia before the loss of the
RBM3 response or by lentiviral delivery, resulted in sustained synaptic
protection in 5XFAD mice and throughout the course of prion disease, preventing
behavioural deficits and neuronal loss and significantly prolonging survival. In 
contrast, knockdown of RBM3 exacerbated synapse loss in both models and
accelerated disease and prevented the neuroprotective effects of cooling. Thus,
deficient synapse regeneration, mediated at least in part by failure of the RBM3 
stress response, contributes to synapse loss throughout the course of
neurodegenerative disease. The data support enhancing cold-shock pathways as
potential protective therapies in neurodegenerative disorders.
 
PMCID: PMC4338605
PMID: 25607368
 
----------
[4] Cell Mol Life Sci. 2016 May 4. [Epub ahead of print]
 
Cold-inducible proteins CIRP and RBM3, a unique couple with activities far beyond
the cold.
 
Zhu X(1), Bührer C(2), Wellmann S(3,)(4).
 
 
Cold-inducible RNA-binding protein (CIRP) and RNA-binding motif protein 3 (RBM3) 
are two evolutionarily conserved RNA-binding proteins that are transcriptionally 
upregulated in response to low temperature. Featuring an RNA-recognition
motif (RRM) and an arginine-glycine-rich (RGG) domain, these proteins display
many similarities and specific disparities in the regulation of numerous
molecular and cellular events. The resistance to serum withdrawal, endoplasmic
reticulum stress, or other harsh conditions conferred by RBM3 has led to its
reputation as a survival gene. Once CIRP protein is released from cells, it
appears to bolster inflammation, contributing to poor prognosis in septic
patients. A variety of human tumor specimens have been analyzed for CIRP and RBM3
expression. Surprisingly, RBM3 expression was primarily found to be positively
associated with the survival of chemotherapy-treated patients, while CIRP
expression was inversely linked to patient survival. In this comprehensive
review, we summarize the evolutionary conservation of CIRP and RBM3 across
species as well as their molecular interactions, cellular functions, and roles in
diverse physiological and pathological processes, including circadian rhythm,
inflammation, neural plasticity, stem cell properties, and cancer development.
 
PMID: 27147467
 
----------
[5] Wellmann S, Buhrer C, Moderegger E, Zelmer A, Kirschner R, Koehne P, Fujita J, Seeger K (2004) Oxygen-regulated expression of the RNA-binding proteins RBM3 and CIRP by a HIF-1-independent mechanism. J Cell Sci 117(Pt 9):1785–1794. doi:10.​1242/​jcs.​01026 PubMedCrossRef
---------
[6] Smart F, Aschrafi A, Atkins A, Owens GC, Pilotte J, Cunningham BA, Vanderklish PW (2007) Two isoforms of the cold-inducible mRNA-binding protein RBM3 localize to dendrites and promote translation. J Neurochem 101(5):1367–1379. doi:10.​1111/​j.​1471-4159.​2007.​04521.​x PubMedCrossRef
----------
[7] Selkoe, D. J. Alzheimer’s disease is a synaptic failure. Science 298, 789–791 (2002).
 
-------------
[8] Mallucci, G. R. Prion neurodegeneration: starts and stops at the synapse. Prion 3, 195–201 (2009).

 

-------

[9] Magarin˜ os, A. M., McEwen, B. S., Saboureau, M. & Pevet, P. Rapid and reversible

changes in intrahippocampal connectivity during the course of hibernation in
European hamsters. Proc. Natl Acad. Sci. USA 103, 18775–18780 (2006).
 
---------
[10] Popov, V. I. & Bocharova, L. S. Hibernation-induced structural changes in synaptic
contacts between mossy fibres and hippocampal pyramidal neurons.
Neuroscience 48, 53–62 (1992).

 

-----------

[11] Annu Rev Med. 2008;59:177-86. doi: 10.1146/annurev.med.59.061506.110403.

Is human hibernation possible?

Lee CC(1).

Full text: 10.1146/annurev.med.59.061506.110403

The induction of hypometabolism in cells and organs to reduce ischemia damage
holds enormous clinical promise in diverse fields, including treatment of stroke
and heart attack. However, the thought that humans can undergo a severe
hypometabolic state analogous to hibernation borders on science fiction. Some
mammals can enter a severe hypothermic state during hibernation in which
metabolic activity is extremely low, and yet full viability is restored when the
animal arouses from such a state. To date, the underlying mechanism for
hibernation or similar behaviors remains an enigma. The beneficial effect of
hypothermia, which reduces cellular metabolic demands, has many well-established
clinical applications. However, severe hypothermia induced by clinical drugs is
extremely difficult and is associated with dramatically increased rates of
cardiac arrest for nonhibernators. The recent discovery of a biomolecule, 5'-AMP,
which allows nonhibernating mammals to rapidly and safely enter severe
hypothermia could remove this impediment and enable the wide adoption of
hypothermia as a routine clinical tool.

PMID: 18186703


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

#286 Sthira

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Posted 16 May 2016 - 05:30 PM


Marijuana (Component) Promotes Browning of White Fat Too!

I'm not sure if Sthira (or anyone but Kenton and Tom?) are still reading this thread, but I suspect he'll be pleased to hear about this ....


Jah mon.. I know I'm completely alone here, but personally I don't like these crazy high thc sativa strains. I prefer the mellow indicas -- admittedly without much BAT consideration -- rich cbd indica strains like Stephen Hawking kush, Darkstar, Remedy... Hey, no leaf expert; but I do know some sweet and sour widow will definitely brown-down some white fat, well, anecdotally of course since science likes mice studies. That's great news that Pennsylvania of all places is legalizing -- did I read that correctly?

#287 AlPater

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Posted 16 May 2016 - 05:42 PM

So cold-inducible RNA-binding protein (CIRP) and RBM3 are the Dr/ Jekyll and Mr. Hyde of' of cold exposure?

 

Heat shock proteins have some nice things to be said of them too, I believe

 

Khurram quoted earlier in the thread:

 

"Connie - So you found this protein, RBM3 - where do you go now?

 
Giovanna - So, we didn’t find the protein; I mean the proteins a known cold shock protein.  What we’ve done is associate it with the failure of structural plasticity in neurodegenerative disease in Alzheimer type mouse models and what we now want to do is understand the relevance for human disease.  Because what we found in the mice is that if you put the protein back in it’s incredibly protective, it gives them new synapses, it stops them getting neurodegeneration, it stops them getting memory loss, and it protects them in the long term and you can do that by either cooling the mice early to boost their indodgenous or their own RBM3 levels, or by putting it in artificially.  So now, obviously, this is a way in for neuroprotection for human disease but cooling itself is not realistic or practical in the long term.  It is used medically; it’s used in newborn babies that have had hypoxic damage; it’s used in post-stroke and it’s used in cardiac surgery, and in many forms of neurosurgery.  So we thinks that that’s acting through RBM3 and our ideal would be to be able to manipulate RBM3 levels for protection without having to cool."


#288 Dean Pomerleau

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Posted 16 May 2016 - 06:40 PM

Thanks Al,

 

So cold-inducible RNA-binding protein (CIRP) and RBM3 are the Dr/ Jekyll and Mr. Hyde of' of cold exposure?

 
Yes - CIRP doesn't look as friendly as RBM3 - e.g. CIRP is associated with worse cancer prognosis. Fortunately RBM3 is induced by mild cold exposure, while CIRP appears to kick in more for quite severe cold, and not much at all in the brain, as this Western Blot analysis from [1] shows:
 
HeulhV7.png
 
As you can see, RBM3 kicks in strongly in the brain even from a modest drop in body temperature from normal (37 °C) to 36 °C, While CIRP (= CIRBP) is nowhere to be seen.
 

Khurram quoted earlier in the thread: ...

 

I'd totally forgotten about that post from Khurram back in January. I guess that's what happens when a thread stretches to over 450 8.5x11 pages! The "Giovanna" person in interview transcript he posted is Giovanna Mallucci one of the authors of PMID 25607368, which was the main reference [3] from my RBM3 post above. Here is the full text of the transcript Khurram posted:

 

Though the idea of a long sleep may sound pretty tempting, animals actually put themselves through an awful lot. They are continually cooling and reheating their bodies, putting huge stress on their organs, and some even make themselves diabetic. Hibernation is clearly no picnic, and things get even Neuronsworse as, in an attempt to save energy, animals will dismantle the synapses in their brains. These are the parts of the neuron that send and receive signals and without them we’re all pretty useless. But what’s even more amazing is that when it’s time to “wake up”  they’ll put them back together again, just as they were. Professor Giovanna Mallucci is a clinical neuroscientist at Cambridge University and she explains to Connie Orbach how this actually works.

 
Giovanna -  I think you’ve heard already from our other speakers, that there’s lots of processes that slow down and are shut down for hibernation including metabolism.  And one way to save energy is to stop the brain using its energy and the dismantling of synaptic connections between brain cells is a way of doing that.  What happens is, on cooling there is a retraction of what we call the “dendritic arbour”, you know all the connections and branches of a brain cell that’s connecting to another and the actual contacts - it’s like unplugging a plug from its socket, they are just removed so that no energy flows.  When they rewarm there’s a signal to reconnect these structures; how that exactly happens is absolutely not known and very, very interesting to us but we do know a lot about the processes that drive that regenerative capacity.
 
Connie - Is this happening all over the brain?
 
Giovanna - Yes, it’s happening all over the brain and all of us all the time.  So there’s a balance between pruning and generation or regeneration to maintain a sort of status quo and learning and memory need new synapses and then you prune and get rid of all your excess synapses when you sleep and other conditions.  But the capacity for regenerating synapses and refreshing them is part of repair and it’s called “structural synaptic plasticity.”
 
Connie - So let me just get this right. So what’s happening with animals in hibernation is a much more extreme version of actually something that’s happening all the time in humans and animals?
 
Giovanna - Correct, that’s exactly right.
 
Connie - So how have you been using this then in your work?
 
Giovanna -   So we know that in neurodegenerative diseases like Alzheimer’s, which is the prototypical disease but also many of the others.  The earliest thing that happens, before you get the brain cell degeneration, is that synapses are lost and as synapses are lost memory goes down - what we call cognitive function goes down, and it’s just not clear why this is early loss of synapses which is such an important stage in these diseases, and it’s important a) because it give you symptoms and b) because it's reversible.  So that’s the stage before the brain cells have died, before the neurons have died when, actually, if you can increase synapse number you can restore memory so it’s a very attractive, targetable point of intervention.  And our starting hypothesis was that the reason that synapses are lost early in Alzheimer’s disease and early in Parkinson’s disease and other disorders is because there’s a failure of this regenerative capacity that is part of our normal structural plasticity.  We used hibernation or induced laboratory hibernation in mice to test the ability of synapses to regenerate themselves in mouse neurodegeneration models.
 
Connie - And what did you find out - what’s happening?
 
Giovanna - So first of all we found very interestingly that mice which don’t normally hibernate, can hibernate in all the ways that you would normally expect.  So if you cool them: they’ll drop their body temperature, they’ll dismantle their synapses and they’ll go into torpor and then, when you re-warm them, they come completely back to normal again.  And what we found out was that normal mice dismantle and reassemble their synapses but the mice that we used that had neurodegeneration models - that’s Alzheimer type mice, and mice with prion disease - that’s another neurodegenerative disease.  They failed to reassemble their synapses so they could unplug the plugs but they couldn’t put them back in again and this lack of degenerative capacity gives us a good idea of why there’s such an early loss in synapses.
 
Connie - Did you get a bit deeper into this?  Did you get to see the protein that’s involved - is that right?
 
Giovanna - Yes we did. So hibernating and cooling does two things to you: it shuts down metabolism and it shuts down protein synthesis, but there’s a group of proteins that are upregulated and these are called “cold-shock proteins,” and they’re a relatively new family of proteins.  And one of these which is called “RBM3”, which is RNA Binding Motif Protein 3, is highly expressed in the brain and by being upregulated during hibernation that protein keeps a number of really important critical Messenger RNAs, that you need for survival, ready to make into proteins when you wake up.  And we found out that RBM3 is failing in the Alzheimer’s brain, and if we put it back in, we can rescue them.
 
Connie - So you found this protein, RBM3 - where do you go now?
 
Giovanna - So, we didn’t find the protein; I mean the proteins a known cold shock protein.  What we’ve done is associate it with the failure of structural plasticity in neurodegenerative disease in Alzheimer type mouse models and what we now want to do is understand the relevance for human disease.  Because what we found in the mice is that if you put the protein back in it’s incredibly protective, it gives them new synapses, it stops them getting neurodegeneration, it stops them getting memory loss, and it protects them in the long term and you can do that by either cooling the mice early to boost their indodgenous or their own RBM3 levels, or by putting it in artificially.  So now, obviously, this is a way in for neuroprotection for human disease but cooling itself is not realistic or practical in the long term.  It is used medically; it’s used in newborn babies that have had hypoxic damage; it’s used in post-stroke and it’s used in cardiac surgery, and in many forms of neurosurgery.  So we thinks that that’s acting through RBM3 and our ideal would be to be able to manipulate RBM3 levels for protection without having to cool.

 

Thanks Al and Khurram!

 

--Dean

 

-------

[1] Neuroscience. 2015 Oct 1;305:268-78. doi: 10.1016/j.neuroscience.2015.08.012.

Epub 2015 Aug 8.
 
Cold stress protein RBM3 responds to temperature change in an ultra-sensitive
manner in young neurons.
 
Jackson TC(1), Manole MD(2), Kotermanski SE(3), Jackson EK(3), Clark RS(4),
Kochanek PM(4).
 
Author information: 
(1)University of Pittsburgh School of Medicine, Safar Center for Resuscitation
Research, 200 Hill Building, 3434 Fifth Avenue, Pittsburgh, PA 15260, United
States; University of Pittsburgh School of Medicine, Department of Critical Care 
Medicine, 3550 Terrace Street, Pittsburgh, PA 15261, United States. Electronic
address: jacksontc@upmc.edu.
 
 
Extremely mild hypothermia to 36.0 °C is not thought to appreciably differ
clinically from 37.0 °C. However, it is possible that 36.0 °C stimulates highly
sensitive hypothermic signaling mechanism(s) and alters biochemistry. To the best
of our knowledge, no such ultra-sensitive pathway/mechanisms have been described.
Here we show that cold stress protein RNA binding motif 3 (RBM3) increases in
neuron and astrocyte cultures maintained at 33 °C or 36 °C for 24 or 48 h,
compared to 37 °C controls. Neurons cultured at 36 °C also had increased global
protein synthesis (GPS). Finally, we found that melatonin or fibroblast growth
factor 21 (FGF21) augmented RBM3 upregulation in young neurons cooled to 36 °C.
Our results show that a 1 °C reduction in temperature can induce pleiotropic
biochemical changes by upregulating GPS in neurons which may be mediated by RBM3 
and that this process can be pharmacologically mimicked and enhanced with
melatonin or FGF21.
 
Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
 
PMCID: PMC4570027 [Available on 2016-10-01]
PMID: 26265550

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#289 Dean Pomerleau

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Posted 25 May 2016 - 12:37 PM

Micronutrients in Broccoli, Citrus and Honey Promote Browning of White Fat

 

The list of beneficial compounds that appear to boost brown/beige fat just keeps getting longer and more impressive.

 

In this new study [1], sulforaphane (SFN), the cancer-fighting active ingredient in broccoli, was found to turn white fat cells to brown in vitro, by increasing both the number of mitochondria and their expression of UCP-1, and their SIRT1 level. SFN also enhanced both glucose and lipid uptake and utilization. 

 

Similarly, study [2] found limonene, one of the most important compounds in citrus fruit and especially in the peels, does the exact same thing - turning white fat cells to brown, at least in a petri dish. As you can see from the graph below, limonene increased expression of UCP1 in isolated WAT cells by about 250%, and upregulated expression of a number of genes associated with mitochondrial biogenesis:

 

GVREFQG.png

 

 

But the most striking effect was that limonene increased fat cells' expression of Fibroblast Growth Factor 21 (FGF21) by over 1000%! Recall from this post, increased FGF21 expression (via genetic manipulation) resulted in mice that lived dramatically longer, and also recall that cold-exposure increases FGF21.

 

Beyond the graphs, [2] contains visually compelling micrographs of control (top) and limonene-treated (bottom) cells stained for either UCP-1 (left) or mitochondrial content (right). As you can see below, the effect of limonene on the promotion of these two metrics of fat brownness are quite dramatic:

 

hBHyEJB.png

Interestingly, the researchers in [2] found the browning effect of limonene was entirely suppressed by a β3-adrenergic receptor blocker, so the mechanism of browning appears to be through increased signalling of the sympathetic nervous system, just like we've seen previous with capsaicin, and of course, the granddaddy of all fat browning interventions - cold exposure.

 

The same research group from [2], another flavonoid called chrysin, rich in certain flowers as well as honey (not surprisingly) , had the same effect - turning white fat cells to brown in vitro [3]. Interestingly it worked through a slightly different pathway, by upregulating AMP-activated protein kinase (AMPK) - the pathway by which resveratrol has also been shown turn white fat to brown [4], as I've discussed elsewhere.

 

Finally, recall in this post I added curcumin to the list of brown fat inducers, based on indirect evidence - namely that it increases FGF21, which in turn results in fat browning. This new study [5] from the same group as [2] and [3] tested the browning effects of curcumin directly, and found that it also turns white fat cells to brown through the same mechanism (upregulating AMPK) as chrysin and resveratrol. Those researchers from Daegu University in South Korea are a busy bunch - recall they were also the team that found cannabidiol (from hemp & marijuana) also promotes fat browning, as I discussed here.

 

I've added all the micronutrients & foods discussed in this post to the master list of fat browning agents below. With the addition of broccoli, citrus peels, honey and confirmation of curcumin as brown fat inducers, it has become even more of a "who's who" list of healthy foods, supplements and lifestyle interventions. In fact, there aren't many things that are known to be good for you that aren't on the list of brown fat promoters - to the point where it is almost uncanny.

 

It would be a logical fallacy to try to argue that since all these good-for-you things also induce fat browning, that fat browning must good for you too. That would be like trying to argue that since jogging causes blisters on your feet and jogging is good for you, blisters on your feet must make you healthy. But unlike blisters, there are a number of plausible causal mechanisms by which brown/beige fat, and increased thermogenesis can improve health and potentially boost longevity - as discussed throughout this thread, and especially in the CE-Albatross and subsequent posts.

 

Also, foot blisters are associated with only one health-promoting activity, making the hypothesis that blisters are a mere side-effect (and not causally involved) pretty plausible. In contrast, with so many different and widely-varing health promoters acting to increase brown/beige fat and thermogenesis, it seems much harder to take seriously the idea that increased brown fat is just a coincidental side effect of all these things and not causally involved in their benefits.

 

Finally, look at it this way. By eating many of the foods and engaging in the activities listed below, health-conscious people are already promoting brown/beige fat and thermogenesis to some degree. It therefore does not seem unreasonable to think that boosting brown/beige fat and thermogenesis directly and through the most effective means possible (i.e. cold exposure) will be health-promoting as well. 

 

--Dean

 

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

Here is the latest full list of modifiable and [nonmodifiable] factors associated with increased brown/beige adipose tissue and/or thermogenesis, with the factors mentioned in this post highlighted in red:

  • 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
  • Sulforaphane-rich foods - Broccoli, brussels sprouts, cabbage
  • 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 peels / ursolic acid; Citrus fruit / citrus peels / limonene; Honey / chrysin
  • Beverages - green tea, roasted coffee, red wine, cacao beans / chocolate
  • Drugs / Supplements - metformin, caffeine, creatine, nicotinamide riboside (NAD), resveratrol, ginseng,cannabidiol / hemp oil / medicinal marijuana
  • 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] Mol Nutr Food Res. 2016 May 24. doi: 10.1002/mnfr.201500915. [Epub ahead of

print]
 
Sulforaphane induces adipocyte browning and promotes glucose and lipid
utilization.
 
Zhang HQ(1,)(2), Chen SY(1,)(3), Wang AS(1), Yao AJ(1), Fu JF(1), Zhao JS(1),
Chen F(4), Zou ZQ(1), Zhang XH(1), Shan YJ(5), Bao YP(6).
 
SCOPE: Obesity is closely related to the imbalance of white adipose tissue
storing excess calories, and brown adipose tissue dissipating energy to produce
heat in mammals. Recent studies revealed that acquisition of brown
characteristics by white adipocytes, termed "browning," may positively contribute
to cellular bioenergetics and metabolism homeostasis. The goal was to investigate
the putative effects of natural antioxidant sulforaphane
(1-isothiocyanate-4-methyl-sulfonyl butane; SFN) on browning of white adipocytes.
METHODS AND RESULTS: 3T3-L1 mature white adipocytes were treated with SFN for 48 
h, and then the mitochondrial content, function, and energy utilization were
assessed. SFN was found to induce 3T3-L1 adipocytes browning based on the
increased mitochondrial content and activity of respiratory chain enzymes,
whereas the mechanism involved the upregulation of nuclear factor E2-related
factor 2/ sirtuin1/ peroxisome proliferator-activated receptor gamma coactivator 
1 alpha signaling. SFN enhanced uncoupling protein 1 expression, a marker for
brown adipocyte, leading to the decrease in cellular ATP. SFN also enhanced
glucose uptake and oxidative utilization, lipolysis and fatty acid oxidation in
3T3-L1 adipocytes.
CONCLUSION: SFN-induced browning of white adipocytes enhanced the utilization of 
cellular fuel, and SFN is a promising strategy to combat obesity and
obesity-related metabolic disorder. This article is protected by copyright. All
rights reserved.
 
This article is protected by copyright. All rights reserved.
 
PMID: 27218607
 
------------
[2] Life Sci. 2016 May 15;153:198-206. doi: 10.1016/j.lfs.2016.04.010. Epub 2016 Apr 
9.
 
Monoterpene limonene induces brown fat-like phenotype in 3T3-L1 white adipocytes.
 
Lone J(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.
 
 
AIMS: Several dietary compounds that are able to induce the brown fat-like
phenotype in white adipocytes have been considered for treatment of obesity due
to their ability to increase energy expenditure. Here, we report that limonene
induces the brown fat-like phenotype in 3T3-L1 adipocytes by increasing
expression of brown adipocyte-specific genes and proteins.
MAIN METHODS: Limonene-induced browning in white adipocytes was investigated by
determining expression levels of brown fat-specific genes and proteins by
real-time RT-PCR, immunoblot analysis, and immunocytochemical staining.
KEY FINDINGS: Limonene enhanced mitochondrial biogenesis, as evidenced by
increased mitochondrial content and immunofluorescent intensity. Limonene also
significantly elevated protein levels of HSL, PLIN, p-AMPK, p-ACC, ACO, COX4,
CPT1, and CYT C, suggesting its possible role in enhancement of lipolysis and
lipid catabolism. Increased expression of PRDM16, UCP1, C/EBPβ, and other brown
fat-specific markers by limonene was possibly mediated by activation of
β3-adnergenic receptor (β3-AR), as inhibition of β3-AR inhibited up-regulation of
brown fat-specific markers. Similarly, limonene-mediated activation of ERK and
up-regulation of key brown adipocyte specific markers were eliminated by
treatment with ERK antagonist.
SIGNIFICANCE: Taken together, these results suggest that limonene induces
browning of 3T3-L1 adipocytes via activation of β3-AR and the ERK signaling
pathway. In conclusion, our findings suggest that limonene plays a dual
modulatory role in induction of the brown adipocyte-like phenotype as well as
promotion of lipid metabolism and thus may have potential therapeutic
implications for treatment of obesity.
 
Copyright © 2016 Elsevier Inc. All rights reserved.
 
PMID: 27071835
 
-------
[3] Nutrition. 2016 Mar 9. pii: S0899-9007(16)00109-X. doi:
10.1016/j.nut.2016.02.007. [Epub ahead of print]
 
Chrysin induces brown fat-like phenotype and enhances lipid metabolism in 3T3-L1 
adipocytes.
 
Choi JH(1), Yun JW(2).
 
Author information: 
(1)Department of Biotechnology, Daegu University, Kyungsan, Kyungbuk, Republic of
Korea. (2)Department of Biotechnology, Daegu University, Kyungsan, Kyungbuk,
Republic of Korea. Electronic address: Jwyun@daegu.ac.kr.
 
 
OBJECTIVES: Many studies have to do with promising therapeutic phytochemicals
such as flavonoids to treat obesity and related complications, and a number of
dietary compounds have been proposed as tools for increasing energy expenditure
and decreasing fat accumulation in mammals. Here, we show that the flavonoid
chrysin induces browning of 3T3-L1 adipocytes via enhanced expression of brown
fat-specific genes and proteins as well as enhances lipid metabolism.
METHODS: Chrysin-induced fat browning was investigated by determining expression 
levels of brown fat-specific genes and proteins by real-time polymerase chain
reaction and immunoblot analysis, respectively.
RESULTS: Chrysin enhanced expression of brown fat-specific markers and increased 
protein levels of peroxisome proliferator-activated receptor (PPAR)α, PPARγ,
PPARδ, phosphorylated AMP-activated protein kinase (p-AMPK), phosphorylated
acetyl-CoA carboxylase, hormone sensitive lipase, perilipin, carnitine
palmitoyltransferase 1, acyl-coenzyme A oxidase 1, peroxisome
proliferator-activated receptor-1 alpha (PGC-1α), and uncoupling protein 1
(UCP-1), suggesting its possible role in augmentation of lipolysis, fat
oxidation, and thermogenesis as well as reduction of lipogenesis. Increased
expression of UCP-1 and other brown fat-specific markers was possibly mediated by
chrysin-induced activation of AMPK based on the fact that inhibition of AMPK by
dorsomorphin abolished expression of PR domain-containing 16, UCP-1, and PGC-1α
while the activator 5-aminoimidazole-4-carboxamide ribonucleotide elevated
expression of these brown marker proteins.
CONCLUSION: Our findings suggest that chrysin plays a dual modulatory role in the
form of inducing the brown-like phenotype as well as enhancing lipid metabolism
and thus may be explored as a potentially promising food additive for prevention 
of obesity.
 
Copyright © 2016 Elsevier Inc. All rights reserved.
 
PMID: 27133810
 
--------
[4] Wang S, Liang X, Yang Q, Fu X, Rogers CJ, Zhu M, et al. Resveratrol induces brown-like adipocyte formation in white fat through activation of AMP-activated protein kinase (AMPK)α1. Int J Obes 2015;39:967-76. 

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

#290 BrianA

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Posted 27 May 2016 - 03:10 PM

Hi,

 

Question to Dean, Gordo, anyone else experimenting with CE: in regards to improved glucose readings, have you found that CE primarily is improving the postprandial readings, or is it also improving fasting readings? I ask because so far most readings I've seen posted here, and also discussed at other sites like the cool fat burner seem to be demonstrating postprandial improvements.

 

I actually have obtained the basic cool fat burner vest and have begun experimenting, along with a few other mild CE lifestyle changes.



#291 Dean Pomerleau

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Posted 28 May 2016 - 11:28 AM

BrianA,

 

Welcome to the CR Forums! I'm glad to hear you too are experimenting with cold exposure.

 

I don't know about Gordo (who has seen the most dramatic improvements in glucose), but I haven't seen much change in my fasting blood glucose level - it remains mid 70s to low 80s mg/dl, which I'm happy with.

 

--Dean


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

#292 Todd S

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Posted 28 May 2016 - 10:45 PM

It was good to see Dean (and others!) at the recent CR Society Conference in Tucson. I mentioned to him that I was intrigued enough to experiment with Cold Exposure -- and had implemented a relatively lower-cost solution than the vests that had been mentioned here previously. Dean suggested that I post about it -- so that's the reason for this post.

 

This solution uses 4 x $12.99 (from Target) TheraPearl "Back Wrap with Strap" items. [The $12.99 price is Target's online price -- which you can get matched at any Target store by requesting the online price at the Customer Service counter.] The original packaging box looks like this:

 

http://imgur.com/UztnE1r

 

Each two of the four "back wraps" are combined to form a sash the covers both the back and the front. Both sashes folded and each put into a plastic bag intended for a Sunday newspaper looks like this:

 

http://imgur.com/hFgbmYW

 

Unfolding the two sashes (including the straps) looks like this:

 

http://imgur.com/OIljiws

 

This is an important step:  To combine two "back wraps" into a sash, put the "slot" ends together, flip over one of the wraps (enabling the velcro to be useful when putting the sash on), and use tie-wraps (shown in red") to fasten the "slot" ends together. This shows the detail of the tie-wraps:

 

http://imgur.com/Wg0pamk

 

For each sash, the straps wrap around the body in opposite directions and come around to connect together. Here is what it looks like after putting on both sashes but before adding a light "Members Only" jacket on top to insulate from the outside temperature.

 

http://imgur.com/OmptL9t

 

Thanks,

Todd



#293 gracezw

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Posted 29 May 2016 - 12:06 AM

Dean, is your current cold vest the original style? Or do you have both the original style and the "gut buster" style?

 

I read the first case study on their website. It looks that having brown fat is good and white fat is bad. Is white fat subcutaneous fat? Where is the good brown fat located in one's body? How is it related to visceral fat? I am really confused.

 

It may be nice to have a thing like that which would keep me cool when I sweat on my future recumbent bike. Is it summer time now. I just want to confirm with you that the vest would cool me down. Also I have a weight vest. And this vest is not a weight vest, right?

 

the Cool Fat Burner (CFB). It comes in two styles and a variety of sizes. The "original" style costs $86 including tax and shipping.

 

It comes in two styles:

 

                     Original ($86 incl S&H)     "Gut Buster" Vest ($106 incl S&H)            

 

cfb.jpgcgb-208x240.jpg

 

 



#294 gracezw

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Posted 29 May 2016 - 12:14 AM

Todd, it was nice having seen you to at the Tuscon conference! Also it is great to see that you are posting on the forums too! Thank you for posting this. How long have you been using this solution?

 

It was good to see Dean (and others!) at the recent CR Society Conference in Tucson. ...



#295 gracezw

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Posted 29 May 2016 - 12:35 AM

Todd, I have another question. When you wear your solution on your back, is it in contact with any back rest?

 

I am also thinking of your solution for my future recumbent bike. It has a back rest. I wonder how comfortable it would be.



#296 Todd S

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Posted 29 May 2016 - 12:53 AM

Grace,

 

I enjoyed meeting and talking to you at the Tucson Conference. I've only used my Cold Exposure solution a few times so far. I think that the TheraPearls solution is more comfortable because it does not form a solid block, but on the other hand it may not sustain the cold temperature as long as a simple non-pearled coldpack gel. I used it tonight while leaning back in a Lazy Boy recliner someone gave me -- and it was comfortable.  I actually purchased 8 "back wraps" rather than just 4, so I have a replacement pair of sashes for when the first pair gets too warm. I used both of them tonight. It is very comfortable when the outside temperatures are high -- although I'm not sure that this provides the conditions necessary for the benefits that Dean has described.

 

Thanks,

Todd



#297 Dean Pomerleau

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Posted 29 May 2016 - 03:47 AM

Todd,

You've come up with another, very create solution for a cooling vest! Thanks for sharing it. My only reservation about your solution would be how long the pearled coldpacks remain charged. For anyone interested here is my full review of the Cool Fat Burner vest I use.

Grace, I have both the original and the "gut buster" models of the Cool Fat Burner, and will probably start using them both simultaneously now that it is getting quite warm in Pittsburgh. They do a great job of keeping one cool while exercising on a bike (desk), walking on a treadmill (desk), or simply sitting around in a warm house.

As for comfort while riding on your recumbent bike (with backrest) - I use the flexible (blue) coldpacks I purchased with my Cool Fat Burner in the back pockets for just this reason. They are quite comfortable when leaning back. I put the white (rigid) coldpacks in the front two pockets of the vest.

Regarding fats and the distribution of brown fat. The largest concentrations of brown fat in humans are located around the neck, shoulders, upper chest and upper back. White fat can be either subcutaneous (what we refer to as "love handles") or visceral (located in the abdomen surrounding our organs). Visceral fat is much more detrimental health-wise than subcutaneous fat, since it releases more inflammatory cytokines.

It appears from evidence I've presented earlier in this thread that both subcutaneous and visceral white fat can be converted to brown fat through cold exposure either overall or localized (i.e. spot cooling of specific white fat deposits). In fact, there is a specific name for white fat thus converted. It's called "beige" or "brite" fat to distinguish it from white fat and from fat cells which were born brown.

--Dean


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

#298 gracezw

gracezw
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Posted 29 May 2016 - 10:07 AM

Todd, thanks again for all the sharing! I really appreciate it!

 

I am glad that your solution was so nice and comfortable for you in your lazy boy recliner.

 

I am afraid that I won't be able to follow your tutorial steps with four images to make this happen for me independently. But I really like your idea of having anothr spare set handy to replace the set in use.

 

Grace,

 

I enjoyed meeting and talking to you at the Tucson Conference. I've only used my Cold Exposure solution a few times so far. I think that the TheraPearls solution is more comfortable because it does not form a solid block, but on the other hand it may not sustain the cold temperature as long as a simple non-pearled coldpack gel. I used it tonight while leaning back in a Lazy Boy recliner someone gave me -- and it was comfortable.  I actually purchased 8 "back wraps" rather than just 4, so I have a replacement pair of sashes for when the first pair gets too warm. I used both of them tonight. It is very comfortable when the outside temperatures are high -- although I'm not sure that this provides the conditions necessary for the benefits that Dean has described.

 

Thanks,

Todd



#299 gracezw

gracezw
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Posted 29 May 2016 - 10:33 AM

Dean, what can the gut buster model do that the original can not?

 

Thanks for explaining about the brown fat, white fat and how they are related to subcutaneous fat and visceral fat. That is great to know!

 


 

 

Todd,
 
You've come up with another, very create solution for a cooling vest! Thanks for sharing it. My only reservation about your solution would be how long the pearled coldpacks remain charged. For anyone interested here is my full review of the Cool Fat Burner vest I use.
 
Grace, I have both the original and the "gut buster" models of the Cool Fat Burner, and will probably start using them both simultaneously now that it is getting quite warm in Pittsburgh. They do a great job of keeping one cool while exercising on a bike (desk), walking on a treadmill (desk), or simply sitting around in a warm house.
 
As for comfort while riding on your recumbent bike (with backrest) - I use the flexible (blue) coldpacks I purchased with my Cool Fat Burner in the back pockets for just this reason. They are quite comfortable when leaning back. I put the white (rigid) coldpacks in the front two pockets of the vest.
 
Regarding fats and the distribution of brown fat. The largest concentrations of brown fat in humans are located around the neck, shoulders, upper chest and upper back. White fat can be either subcutaneous (what we refer to as "love handles") or visceral (located in the abdomen surrounding our organs). Visceral fat is much more detrimental health-wise than subcutaneous fat, since it releases more inflammatory cytokines. 
 
It appears from evidence I've presented earlier in this thread that both subcutaneous and visceral white fat can be converted to brown fat through cold exposure either overall or localized (i.e. spot cooling of specific white fat deposits). In fact, there is a specific name for white fat thus converted. It's called "beige" or "brite" fat to distinguish it from white fat and from fat cells which were born brown.
 
--Dean

 

 

ound in a warm house.
 
As for comfort while riding on your recumbent bike (with backrest) - I use the flexible (blue) coldpacks I purchased with my Cool Fat Burner in the back pockets for just this reason. They are quite comfortable when leaning back. I put the white (rigid) coldpacks in the front two pockets of the vest.
 
Regarding fats and the distribution of brown fat. The largest concentrations of brown fat in humans are located around the neck, shoulders, upper chest and upper back. White fat can be either subcutaneous (what we refer to as "love handles") or visceral (located in the abdomen surrounding our organs). Visceral fat is much more detrimental health-wise than subcutaneous fat, since it releases more inflammatory cytokines. 
 
It appears from evidence I've presented earlier in this thread that both subcutaneous and visceral white fat can be converted to brown fat through cold exposure either overall or localized (i.e. spot cooling of specific white fat deposits). In fact, there is a specific name for white fat thus converted. It's called "beige" or "brite" fat to distinguish it from white fat and from fat cells which were born brown.
 
--Dean

 



#300 Dean Pomerleau

Dean Pomerleau
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Posted 29 May 2016 - 11:17 AM

Grace,

 

First, stop quoting the entire message you are responding. It adds nothing to your posts. Either quote small sections or don't quote at all.

 

Second, you ask:

 

Dean, what can the gut buster model do that the original can not?

 

Grace, you've been hanging out here long enough, and I know you have a thick enough skin, so I'm not afraid to tell you this is a silly question you should be able to answer for yourself based on my Cool Fat Burner review and the Cool Fat Burner website. Think independently Grace, and save your questions for the really tough ones, which I'm happy to try to answer.

 

But to answer your current question, I consider the original Cool Fat Burner as better at targeting the areas where the most BAT is located, but the "Gut Buster" model a good addition to the original to increase overall body cooling and to target the abdominal region with localized cooling in order to encourage the subcutaneous fat in that region to turn from white to brown.

 

--Dean


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





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