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Does Altered Immune Function Cause Obesity?

sharma-obesity-adipose-tissue-macrophageThe role of proinflammatory cells in adipose tissue as a determinant of insulin resistance and altered metabolic function is now well known.

However, there is also new data suggesting that altered immune function may well be an important causal step in the accumulation of excess fat and related metabolic abnormalities.

Two studies, both in animal models, point to a role of perforin, a cytotoxic effector molecule primarily released by CD8+ T cells and natural killer (NK) cells to eliminate infected or dangerous cells via the perforin-granzyme cell death pathway. In rare cases of humans with impaired perforin-dependent cytotoxic function, one often sees excessive T-cell activation, severe hyper-inflammation and possibly death.

The first study by Xavier Revelo and colleagues from the University of Toronto, published in Diabetes, perforin-deficient mice (Prf1null), which show early increased body weight and adiposity, glucose intolerance, and insulin resistance when placed on high-fat diet (HFD) were shown to have an increased accumulation of proinflammatory IFN-γ–producing CD4+ and CD8+ T cells and M1-polarized macrophages in visceral adipose tissue.

Furthermore, transfer of CD8+ T cells from Prf1null mice into CD8-deficient mice (CD8null) resulted in worsening of metabolic parameters compared with wild-type donors, thus demonstrating a role for T-cell function in insulin resistance associated with visceral adipose tissue.

In a second independent study by Yael Zlotnikov-Klionsky and colleagues from the Weizmann Institute of Science in Rehovot, Israel, published in Immunity, showed that animals selectively lacking perforin-rich granules in their dendritic cells, progressively gained weight and exhibited features of metabolic syndrome, an effect that could be completely prevented by T cell depletion.

Both studies show that the immunoregulatory protein perforin appears to be an important regulator or body weight and metabolic function – a finding, which may well open a new door biological drivers of obesity.

Incidentally, perforin also plays a role in auto-immune diseases and this finding may thus provide a link between the common occurrence of obesity in people with auto-immune disease and has led some authors to even suggest that obesity itself may be a form of auto-immune disease.

While the therapeutic options will certainly not be as simple as replacing low levels of perforin, understanding exactly how immune function ties into the regulation of body weight may eventually lead to novel targets.

@DrSharma
Edmonton, AB

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When Identical Twins Are Different

Professor Aila Rissanen, University of Helsinki, Finland

Professor Aila Rissanen, University of Helsinki, Finland

This year’s prestigious Fredrich Wassermann Award of the European Association for the Study of Obesity presented at the 22nd European Congress on Obesity goes to Helsinki’s Aila Rissanen, Europe’s grande dame of obesity research.

I have personally known Aila for as lo as I have been involved in obesity and there is much in her work and approach to obesity that has stimulated my own thoughts on this issue.

In her acceptance address, Aila chose to focus on her work in BMI-discordant twins (among the many topics she has worked on) due to the remarkable insights into the “natre-nurture” discussion that this model offers.

Indeed, it is extremely rare to find genetically identical twins, who differ in body weight (demonstarting just how highly heritable body weight actually is). Thus, body weight in identical twins is remarkably homogeneous not only because of the heritability of weight per se but also due to heritability of weight gain.

Cining the work of her wildly successful trainee Kirsi Pietilainen, Aila described the efforts it took to identify just 30 obesity discordant (weight difference of >10 Kg) identical twins from well over 500 identical twin pairs.

These discordant twin pairs have now been extensively phenotyped with every imaginable laboratory test, measurement and tissue biopsies.

The most consistent difference between the discordant twins appears to be a greater level of physical activity in the leaner twin, which appears to precede the onset of weight gain.  In addition to voluntary physical exertion, there also appears to be a significant difference in fidgeting between the twins.

Compared to their co-twins, the obese twins had greater pro-inflammatory lipid profiles, lower antioxident activity and higher pro-coagulation markers. The reasons for these differences remains unclear.

Finally, Aila provided a brief overview of some of the exciting work that is now going on to further study the differences between these genetically identical but obesity disparate twins – metabolomics, lipidomics, epigenomics and even bacteriomics.

Although any of this has yet to translate to better obesity prevention or management, you never know where these fundamental insights into human biology may lead you.

For know, this is certainly a space I intend to watch.

@DrSharma
Prague, Czech Republic

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Targeting Gut Inflammation Can Reduce Insulin Resistance?

sharma-obesity-adipose-tissue-macrophageWith all of the recent interest in the gut microbiota as a mediator of systemic inflammation and metabolic disease, it was only a matter of time before researchers would begin targeting pro-inflammatory pathways in the gut to change metabolism.

A proof-of-principle, that this is indeed possible, is presented by Helen Luck and colleagues from the University of Toronto in a paper published in Cell Metabolism.

Using mice models, the researchers not only show that a high-fat diet can alter the gut immune system but also that the chronic phenotypic pro-inflammatory shift in bowel lamina propria immune cell populations is reduced in genetically altered mice that lack beta7 integrin-deficient mice (Beta7null), a driver of gut inflammatory response.

Further more, treatment of high-fat-fed normal mice with the local gut anti-inflammatory agent 5-aminosalicyclic acid (5-ASA), reverses bowel inflammation and improves metabolic parameters including insulin resistance (although it had no effect on body weight).

These beneficial effects are are associated with reduced gut permeability and endotoxemia as well as decreased visceral adipose tissue inflammation.

Moreover, treatment with ASA also improved antigen-specific tolerance to luminal antigens.

Thus, as the authors conclude,

“…the mucosal immune system affects multiple pathways associated with systemic insulin resistance and represents a novel therapeutic target in this disease.”

Clearly gut inflammation both in relationship to gut microbiota as well as response to dietary factors is likely to be a hot topic in obesity and metabolic research for the foreseeable future.

@DrSharma
Edmonton, AB

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Can Dietary Emulsifiers Promote Obesity?

2013 Super Chefs Nat'l Obesity Summit 0001Emulsifiers are amongst the most commonly used food additives to improve the texture and palatability of foods ranging from margarine and mayonnaise to ice cream and baked goods.

Now a study by Benoit Chassaing and colleagues published in NATURE, suggests that dietary emulsifiers may promote weight gain and the metabolic syndrome by altering the composition of intestinal microbes.

The researchers hypothesized that emulsifiers may increase bacterial translocation across intestinal mucosa, thereby promoting local and systemic inflammation as well as affecting the composition of gut bacteria.

Their study in mice show that relatively low concentrations of two commonly used emulsifiers (carboxymethylcellulose and polysorbate-80) can induce low-grade systemic inflammation, weight gain and features of the metabolic syndrome, as well as promote intestinal inflammation in mice susceptible to inflammatory bowel disease.

Importantly, they used germ-free mice and faecal transplants to show that these changes can be induced simply by transferring the gut microbes from emulsifier-treated animals to controls.

As the authors note,

“These results support the emerging concept that perturbed host-microbiota interactions resulting in low-grade inflammation can promote adiposity and its associated metabolic effects. Moreover, they suggest that the broad use of emulsifying agents might be contributing to an increased societal incidence of obesity/metabolic syndrome and other chronic inflammatory diseases.”

While these findings (if replicated in humans) certainly point to the industrial use of food emulsifiers as a potential cause of the global increase in obesity and inflammatory bowel disease, given that these compounds are present in virtually all processed foods, they may well be difficult to avoid.

Guess it’s back to home cooking with raw ingredients.

@DrSharma
Edmonton, AB

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Social Network Analysis of the Obesity Research Boot Camp

bootcamp_pin_finalRegular readers may recall that for the past nine years, I have had the privilege and pleasure of serving as faculty of the Canadian Obesity Network’s annual Obesity Research Summer Bootcamp.

The camp is open to a select group of graduate and post-graduate trainees from a wide range of disciplines with an interest in obesity research. Over nine days, the trainees are mentored and have a chance to learn about obesity research in areas ranging from basic science to epidemiology and childhood obesity to health policy.

Now, a formal network analysis of bootcamp attendees, published by Jenny Godley and colleagues in the Journal of Interdisciplinary Healthcare, documents the substantial impact that this camp has on the careers of the trainees.

As the analysis of trainees who attended this camp over its first 5 years of operation (2006-2010) shows, camp attendance had a profound positive impact on their career development, particularly in terms of establishing contacts and professional relationships.

Thus, both the quantitative and the qualitative results demonstrate the importance of interdisciplinary training and relationships for career development in obesity researcher (and possibly beyond).

Personally, participation at this camp has been one of the most rewarding experiences of my career and I look forward to continuing this annual exercise for years to come.

To apply for the 2015 Bootcamp, which is also open to international trainees – click here.

@DrSharma
Toronto, ON

ResearchBlogging.orgGodley J, Glenn NM, Sharma AM, & Spence JC (2014). Networks of trainees: examining the effects of attending an interdisciplinary research training camp on the careers of new obesity scholars. Journal of multidisciplinary healthcare, 7, 459-70 PMID: 25336965

 

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