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4th Canadian Obesity student Meeting (COSM 2014)

Over 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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Lack of Oxygen Can Trigger Adipose Tissue Inflammation

Lack of oxygen is a well known stressor for any living cell – this is of course also true for fat cells (adipocytes). But lack of oxygen does not just occur when there is a problem with breathing or blood flow. Lack of oxygen (hypoxia) can also occur a the cellular level, when the cellular oxygen demand exceeds supply. According to what may well be considered  a “landmark” paper by Lee and colleagues, published in CELL, it appears that increased adipocyte oxygen consumption may be the key trigger of molecular changes that cause local inflammation and systemic insulin resistance commonly associated with obesity. The paper reports on a series of animal studies with diet-induced obesity (through a high-fat diet), demonstrating that with increasing weight gain, adipocyte respiration in the mitochondria becomes “uncoupled” leading to a significant increase in oxygen consumption with relative hypoxia. This uncoupling appears to be mediated through activation of adenine nucleotide translocase 2 (ANT2), an inner mitochondrial membrane protein, by saturated fatty acids. The resulting hypoxia, in turn, activates the transcription factor HIF-1α, setting off a pro-inflammatory response which in turn leads to insulin resistance with an increased risk of diabetes. The researcher also show that blocking either ANT2 or HIF-1α can prevent these events, thereby suggesting new pharmacological targets for alleviating the pro-inflammatory and metabolic consequences of obesity. Obviously, there is always room for caution in extrapolating animal findings to humans, but this paper is likely to spawn a flurry of similar work in human fat cells. As cellular hypoxia is more likely to occur the larger the fat cell, these studies also tie in the previous observations of a positive association between adipocyte cell size and metabolic abnormalities. Certainly a topic we can expect to hear more of in the not too distant future. @DrSharma Edmonton, AB Lee YS, Kim JW, Osborne O, Oh da Y, Sasik R, Schenk S, Chen A, Chung H, Murphy A, Watkins SM, Quehenberger O, Johnson RS, & Olefsky JM (2014). Increased Adipocyte O2 Consumption Triggers HIF-1α, Causing Inflammation and Insulin Resistance in Obesity. Cell, 157 (6), 1339-52 PMID: 24906151

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The Colour Of Fat

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,… Read More »

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Liraglutide Improves Metabolism in Liver and Fat Tissue

Insulin resistance in liver and fat tissue are common findings in obese individuals and often related to other metabolic defects including abnormalities in glucose and lipid metabolism. Now a small but elegantly done phase 2 study by Matthew Armstrong and colleagues from the University of Birmingham, UK, published in The Lancet, shows that liraglutide, a glucagon-like peptide 1 (GLP-1) analogue that significantly improves glycaemic control, weight, and hepatic steatosis also improves insulin sensitivity (hepatic, muscle, adipose), hepatic lipogenesis, and markers of inflammation in fat tissue. In this study, 14 patients with biopsy-proven non-alcoholic steatohepatitis (NASH) were randomly assigned to either 1·8 mg liraglutide or placebo for 12 weeks As expected, liraglutide significantly decreased weight, waist circumference, HbA1c, fasting glucose, LDL, and liver enzymes compared with placebo. However, liraglutide also significantly increased insulin sensitivity in the liver as indicated by increased suppression of hepatic glucose production with low-dose insulin, decreased circulating non-esterified fatty acid (NEFA) in the fasting, low-dose, and high-dose insulin states. Similarly, in fat tissue, liraglutide significantly reduced the insulin concentration required to half-maximally suppress circulating NEFA and significantly decrease adipose tissue lipolysis. Furthermore, liraglutide significantly improved serum markers of adipose inflammation—namely, leptin, adiponectin, and chemokine ligand 2. The researchers also performed in vitro studies showing that liraglutide directly reduces de-novo lipogenesis in primary cultures of human hepatocytes. Together, these findings provide strong evidence that liraglutide significantly reduces metabolic and pro-inflammatory signals associated with excess weight and may provide a novel treatment for patients with fatty liver disease. Although these findings will need to be confirmed in larger trials, if true, this may point to a new treatment for a condition commonly associated with obesity for which we currently have no good medical treatments. @DrSharma Copenhagen, DK Disclaimer: I am a consultant for Novo Nordisk, the makers of liraglutide

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Hindsight: Epicardial Fat and Cardiovascular Risk

In 2005 I was joined by Gianluca Iacobellis at McMaster, with whom I published a paper in Nature Clinical Practice: Cardiovascular Medicine on the anatomic, biomolecular and clinical role of epicardial fat. In this paper we reviewed the growing evidence that epicardial fat is a metabolically active organ that generates various bioactive molecules, which could well affect cardiac function. We speculated that, although relatively small, this ‘visceral’ fat depot is a rich source of free fatty acids and a number of bioactive molecules, such as adiponectin, resistin and inflammatory cytokines, which could affect the coronary artery response. We also noted that epicardial fat mass might reflect intra-abdominal visceral fat and proposed that echocardiographic assessment of this tissue could serve as a reliable marker of visceral adiposity. Furthermore, epicardial adipose tissue is clinically related to left ventricular mass and other features of the metabolic syndrome, such as concentrations of LDL cholesterol, fasting insulin and adiponectin, and arterial blood pressure. Thus, we suggested that echocardiographic assessment of epicardial fat could serve as a simple and practical tool for cardiovascular risk stratification in clinical practice and research. While assessment of epicardial fat is not yet part of routine clinical assessment, since we published this paper, interest in this tissue has grown substantially and new research on the function of this tissue are now a recurring topic of interest at cardiovascular conferences around the world. AMS Edmonton, Alberta

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