Thursday, August 21, 2014

The Grizzly Truth About Healthy Obesity

While we continue to debatgrizzly-bear_566_600x450e the incidence and physiology of healthy obesity (i.e. adiposity without any evident health problems), there are ample examples of adiposity in the animal kingdom, where the accumulation of vast amounts of fat tissue are entirely compatible with good health.

One of these fascinating example is the grizzly bear, which accumulates enough fat to last all winter without any apparent ill-effects on its health – indeed, the accumulation of fat to a level that would be considered “morbidly obese” in humans in vital to its survival.

Thus, not only is “healthy” obesity possible in mammals, it may also be an important area of study to better understand healthy obesity (or lack of it) in humans.

Insights into healthy obesity comes from a fascinating study by Lynne Nelson and colleagues from Washington State University, in a paper published in Cell Metabolism.

The researchers studied metabolism in four adult female grizzly bears, trained to “voluntarily” allow blood samples to be drawn for this study (for a video on how exactly this was done click here).

Their study shows that as grizzly bears accumulate fat in preparation for hibernation, they become exquisitely insulin sensitive, only to switch to a state of insulin resistance as they enter hibernation. This process reverses as they emerge from hibernation months later.

While the paper describes in detail the metabolic and hormonal pathways involved in this modulation of insulin sensitivity (via PTEN/AKT signaling in adipose tissue, it suggests that it is the ability to maintain insulin sensitivity in the face of increased adipose tissue that allows these animals to remain metabolically healthy.

As readers may recall, this is akin to the finding in humans that healthy obese individuals also display high levels of insulin sensitivity compared to metabolically unhealthy obese individuals, who display the more typical insulin resistance.

While much of this ability to maintain insulin sensitivity in a state of adiposity may be genetic (as in the rare case of humans with PTEN haploinsufficiency) other factors that enhance insulin sensitivity (e.g. regular aerobic exercise) may also help prevent or alleviate the metabolic consequences of excess fat.

Other factors may well include the actual location of the expanded fat depots, with peripheral accumulation of subcutaneous fat being far less likely to cause metabolic problems (and perhaps even protect against) than visceral or ectopic fat.

Now I guess, we need a study to see how well healthy obese humans do in hibernation.

@DrSharma
Edmonton, AB

Hat tip to Susan Jelinski for pointing me to this paper

ResearchBlogging.orgNelson OL, Jansen HT, Galbreath E, Morgenstern K, Gehring JL, Rigano KS, Lee J, Gong J, Shaywitz AJ, Vella CA, Robbins CT, & Corbit KC (2014). Grizzly Bears Exhibit Augmented Insulin Sensitivity while Obese Prior to a Reversible Insulin Resistance during Hibernation. Cell metabolism, 20 (2), 376-82 PMID: 25100064

 

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Friday, August 8, 2014

Healthy Obesity: More Questions Than Answers?

sharma-obesity-visceral-fat-mriRegular readers will be well aware of the evidence that a subset of people living with obesity can be remarkably healthy despite carrying a rather large amount of body fat.

This issue of “healthy obesity” was the topic of the 13th Stock Conference of the International Association of the Study of Obesity, the proceeding of which are now published in Obesity Reviews.

As the authors note,

“The ‘healthy obese’ phenotype was described in the 1980s, but major advancements in its characterization were only made in the past five years. During this time, several new mechanisms that may be involved in health preservation in obesity were proposed through the use of transgenic animal models, use of sophisticated imaging techniques and in vivo measurements of insulin sensitivity. However, the main obstacle in advancing our understanding of the metabolically healthy obese phenotype and its related long-term health risks is the lack of a standardized definition.”

The latter is a real problem because finding people with obesity, who are truly metabolically and otherwise healthy becomes harder the higher the BMI gets – this makes the study of this phenomenon rather challenging.

Nevertheless,

“One of the most consistent characteristics of metabolic health in obesity across studies in humans is reduced liver lipid. This is likely the consequence of increased capacity for storing fat coupled with improved mitochondrial function in adipose tissue and decreased de novo lipogenesis in liver. This can also result in decreased deposition of lipids, including bioactive species, in skeletal muscle. Decreased adipose tissue inflammation with decreased macrophages and a unique T-cell signature with an anti-inflammatory circulating milieu were also suggested to characterize metabolic health in obesity. Anecdotal data support a possible role for healthier lifestyle, including increased level of physical activity and healthier diet. It remains to be established whether a favourable metagenomic signature is a characteristic of metabolic health in obesity.”

Finland’s, Dr Kirsi Pietiläinen explained that,

“..three energy dissipation pathways, oxidative phosphorylation, fat oxidation and amino acid catabolism showed preserved pathway activities in subjects who are MHO at a level similar to their lean counterparts. In contrast, these pathways were significantly down-regulated in adipose samples from obese twins with metabolic disturbances. Another potential hallmark of metabolic health, a favourable inflammatory profile of the adipose tissue was also observed in the MHO twins. Also, the fat cells of the MHO twins were smaller with evidence of more active differentiation processes within the fat tissue. As multiple mitochondrial pathways are vital in adipocyte differentiation [29], it is possible that mitochondrial malfunction impairs the development of new fat cells, which in turn results in an inability of the adipose tissue to expand under conditions of energy excess. This failure of fat cell proliferation has long been suspected to constitute the framework for ectopic fat storage, insulin resistance and type 2 diabetes.”

Other speakers discussed other aspects including immune function and microbiata in this phenomenon.

Finally, the authors concluded that,

“identifying underlying factors and mechanisms associated with this phenotype will eventually be invaluable in helping the scientific and medical community understand factors that predispose, delay or protect obese individuals from metabolic disturbances. It is essential to underscore that the MHO concept presently only address the cardio-metabolic risks associated with obesity; it is therefore important that patients who are MHO are still very likely to present many other obesity-related complications such as altered physical and/or physiological functional status, sleep problems, articulation and postural problems, stigma, etc. Importantly, the MHO concept supports the fact that classification based on excess adiposity per se (e.g. BMI or body composition if available) should be supplemented with obesity-related comorbidities, e.g. with fasting insulin as proposed by the Edmonton obesity classification system.”

Certainly a space to watch as we learn more and more about the “healthy obesity” phenotype.

@DrSharma
Edmonton, AB

ResearchBlogging.orgSamocha-Bonet D, Dixit VD, Kahn CR, Leibel RL, Lin X, Nieuwdorp M, Pietiläinen KH, Rabasa-Lhoret R, Roden M, Scherer PE, Klein S, & Ravussin E (2014). Metabolically healthy and unhealthy obese – the 2013 Stock Conference report. Obesity reviews : an official journal of the International Association for the Study of Obesity PMID: 25059108

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Thursday, July 31, 2014

Low Adipocyte Formation Is Associated With Abdominal Obesity

sharma-obesity-adipocytes3One of the key concepts about the deposition of visceral and ectopic fat is the inability of “healthy” subcutaneous to readily expand to accommodate excess calories. This is why people with large fat cells and those with less or no subcutaneous fat (as in partial or complete lipodystrophy) display features of the metabolic syndrome.

In line with these observations, a study by Andre Tchernof and colleagues from the University of Laval, Quebec, in a paper published in ADIPOCYTE show that low adipogenic capacity of subcutaneous adipose tissue is associated with visceral obesity, visceral adipocyte hypertrophy, and a dysmetabolic state.

The researchers studied adipocytes and preadipocytes isolated from subcutaneous and visceral fat samples from 35 women undergoing gynecological surgery and assessed body fat distribution by CT as well as fasting plasma lipids and glycemia.

Using an in vitro differentiation assay, they found that lower adipogenic rates were strongly associated with increased visceral cell size and dyslipidemia.

In addition, When matched for BMI, women with low subcutaneous preadipocyte adipogenic rates had a higher visceral adipose tissue area, omental adipocyte hypertrophy, higher VLDL-lipid content and higher fasting glycemia.

All of these findings are in line with the notion that low subcutaneous preadipocyte differentiation capacity in vitro is associated with visceral obesity, visceral adipocyte hypertrophy, and a dysmetabolic state.

Once again, as regular readers should be aware, not all fat is equal.

@DrSharma
Edmonton, AB

ResearchBlogging.orgLessard J, Laforest S, Pelletier M, Leboeuf M, Blackburn L, & Tchernof A (2014). Low abdominal subcutaneous preadipocyte adipogenesis is associated with visceral obesity, visceral adipocyte hypertrophy, and a dysmetabolic state. Adipocyte, 3 (3), 197-205 PMID: 25068086

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Wednesday, June 18, 2014

4th Canadian Obesity student Meeting (COSM 2014)

Uwaterloo_sealOver the next three days, I will be in Waterloo, Ontario, attending the 4th biennial Canadian Obesity Student Meeting (COSM 2014), a rather unique capacity building event organised by the Canadian Obesity Network’s Students and New Professionals (CON-SNP).

CON-SNP consist of an extensive network within CON, comprising of over 1000 trainees organised in about 30 chapters at universities and colleges across Canada.

Students and trainees in this network come from a wide range of backgrounds and span faculties and research interests as diverse as molecular genetics and public health, kinesiology and bariatric surgery, education and marketing, or energy metabolism and ingestive behaviour.

Over the past eight years, since the 1st COSM was hosted by laval university in Quebec, these meetings have been attended by over 600 students, most presenting their original research work, often for the first time to an audience of peers.

Indeed, it is the peer-led nature of this meeting that makes it so unique. COSM is entirely organised by CON-SNP – the students select the site, book the venues, review the abstracts, design the program, chair the sessions, and lead the discussions.

Although a few senior faculty are invited, they are largely observers, at best participating in discussions and giving the odd plenary lecture. But 85% of the program is delivered by the trainees themselves.

Apart from the sheer pleasure of sharing in the excitement of the participants, it has been particularly rewarding to follow the careers of many of the trainees who attended the first COSMs – many now themselves hold faculty positions and have trainees of their own.

As my readers are well aware, I regularly attend professional meetings around the world – none match the excitement and intensity of COSM.

I look forward to another succesful meeting as we continue to build the next generation of Canadian obesity researchers, health professionals and policy makers.

You can follow live tweets from this meeting at #COSM2014

@DrSharma
Waterloo, Ontario

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Wednesday, May 7, 2014

The Colour Of Fat

Brown Fat Cells in White Fat Tissue

Brown Fat Cells in White Fat Tissue

As a regular reader you will be well aware that body fat is not body fat. Much depends on its exact location, but also on the cellular structure and biological function of the different types of fat depots.

This is the subject of a paper by Brian Owens, a science editor from New Brunswick, Canada, published in the recent Nature Outlook supplement on Obesity.

Although, the predominant form of fat tissue in humans is white fat (which, is in fact yellow), we also have other types of fat cells that are either brown or beige.

While the primary function of white fat cells is to store fat, brown(ish) fat cells specialize in burning it.

This may lead us to believe that brown fat cells are the “good guys” whereas white fat cells are the “bad guys” but this could not be further from the truth.

As Owens explains (quoting Patrick Seale), the white fat cells actually play a key role in keeping us safe from the ill-effects of excess fat by safely sequestering it away:

“Healthy white fat protects the body by providing a ‘safe home’ for lipids, which can be toxic to other tissues such as muscle or the liver. So these fat cells hold on to the lipids until the energy they are storing is needed, when they release them into the blood.”

Thus, white fat actually plays an important role in protecting us from metabolic disease. This is most evident in people who genetically (or in the case of anti-retroviral treatment) lack sufficient white fat cells. These folks end up depositing their excess fat in those other tissues (e.g. liver, pancreas, muscle, etc), thereby causing exactly the same metabolic problems that are commonly associated with obesity.

So why do some people with excess white fat develop these problems?

Here Owens quotes Philipp Scherer, who explains that cell size may have something to do with this:

“Problems arise when white fat cells store too much lipid. They begin expanding and proliferating rapidly in a process that resembles the growth of a solid tumour….The blood supply cannot keep up with this expansion, and the cells begin to suffer from lack of oxygen. This hypoxia attracts the protein HIF-1α, which in fat tissue stimulates the extracellular matrix surrounding the cells, leading to fibrosis. The huge, oxygen-starved fat cells do not have enough room to expand and get squeezed to death, releasing their lipid cargo. As the cells start to die, macrophages swarm to the fat depots to try and clean up the mess by carrying away the lipid droplets. The problem is that the macrophages cannot clear up the lipids fast enough, and so they begin to spill over into other tissues, such as the liver and pancreas.”

As for brown fat – it has a completely different function, namely to help regulate body temperature by burning off calories to generate heat.

But researchers have discovered yet an additional type of fat cell – one that lies some where between typical white and brown fat. In fact, it seems that most the brown fat in humans is actually beige – these seem to be cells recruited from white fat depots that transform themselves into “brownish” cells with certain stimuli (e.g. cold exposure, physical exercise).

These beige cells may also be important protectors against metabolic disease. The article quotes work by Bruce Spiegelman showing that selectively disabling beige fat in mice by targeting the protein PRDM16, which is found only in these cells, leaving the white and brown fat intact leads to animals with severe metabolic dysfunction — obesity, insulin resistance and fatty livers.

Thus it appears that the loss of the beige fat destroys the protective abilities of subcutaneous white fat – at least in mice.

If nothing else, these studies show that we have yet much to learn about fat cells. In fact, there may be other subtypes of fat cells specific to the different fat depots in the body (of which there are many), that may each have their unique importance and functions.

Whether or not we can harness this new knowledge to find better treatments for obesity remains to be seen – simply destroying fat cells willy-nilly can certainly do more harm than good.

@DrSharma
New York, NY

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In The News

Diabetics in most need of bariatric surgery, university study finds

Oct. 18, 2013 – Ottawa Citizen: "Encouraging more men to consider bariatric surgery is also important, since it's the best treatment and can stop diabetic patients from needing insulin, said Dr. Arya Sharma, chair in obesity research and management at the University of Alberta." Read article

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