Monday, April 7, 2014

The Molecular Mechanism of Sleeve Gastrectomy

sharma-obesity-verticalsleevegastrectomyIn recent year, vertical sleeve gastrectomy (VSG), which involves removing large parts of the stomach, thereby reducing it to the size of a small banana, has gained in popularity in bariatric surgery.

Although slightly less efficacious, it is a far simpler procedure to perform than the “classic” Roux-en-Y gastric bypass.

According to popular wisdom, the reason why VSG works has to do with mechanically reducing the volume of the stomach (thereby creating a physical “restriction”), whereby effect on gastric ghrelin secretion may or may not also play a role in reducing hunger (the science on this is somewhat unclear).

Now, a paper by Karen Ryan and colleagues from the University of Cincinnati, published in Nature, provides a completely new explanation for the molecular mechanism by which this surgery appears to work.

The study was prompted by the observation that VBG leads to profound changes in circulating bile acids. Bile acids are now known to bind to a nuclear receptor (farsenoid-X-receptor or FXR for short) which plays an important role in fat and glucose metabolism.

Using a rather elegant series of studies in mice, Ryan and colleagues demonstrate that the weight loss effect of sleeve gastrectomy has little to do with reducing the size of the stomach. Rather, almost all of its effect on body weight appears to be mediated by the effect of this surgery on circulating bile acids and accompanying changes in gut microbial flora.

The researchers also clearly demonstrate that much of the weight loss with SVG is dependent on a functional FXR, without which (as in FXR knockout mice) the surgery has little effect on body weight or glucose metabolism.

This demonstration of the importance of bile acids and FXR signalling as an important molecular mechanism for why VSG actually works is important because it means that this surgery could possibly be mimicked by pharmacological interventions that target bile acid and/or FXR.

In fact drugs that stimulate FXR (e.g. obeticholic acid) are already being considered for other indications including fatty liver disease and type 2 diabetes.

Given the remarkable efficacy of VSG surgery, the possibility of providing the same benefits in a pill are clearly attractive.

@DrSharma
Edmonton, AB

ResearchBlogging.orgRyan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, Wilson-Pérez HE, Sandoval DA, Kohli R, Bäckhed F, & Seeley RJ (2014). FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature PMID: 24670636

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Thursday, March 27, 2014

Three Essential Ways in Which Melatonin Links to Energy Balance

sharma-obesity-pineal-glandAs a regular reader, you will be quite familiar with the emerging recognition of sleep (or rather lack thereof) as an important determinant of weight gain.

Melatonin, an evolutionary ancient molecule that, in mammals, is secreted from the pineal gland, is a hormone that plays a major role as a key regulator of the circadian cycle, along which  virtually all metabolic activities are coordinated.

A paper by José Cipolla-Neto and colleagues, published in the Journal of Pineal Research, provides a fascinating overview of how melatonin plays a significant role in energy metabolism.

Its first role relates to insulin secretion and action. Thus, melatonin is not only necessary for the proper synthesis and secretion of insulin, it also plays a role in the insulin-signalling pathway through its effects on GLUT4 receptors.

Secondly, as a powerful chronobiotic, it helps coordinate various metabolic processes so that the activity/feeding phase of the day is associated with higher insulin sensitivity whereas the rest/fasting phase is synchronized to lower insulin sensitivity.

Thirdly, melatonin plays an important role in regulating energy flow to and from fat stores and directly regulating the energy expenditure through the activation of brown adipose tissue and participating in the browning process of white adipose tissue.

The paper discusses how the reduction in melatonin production, as seen during aging, shift-work or night-time light exposure can induce insulin resistance, glucose intolerance, sleep disturbance and metabolic circadian disorganization, which together can lead to weigh gain.

Thus, the available data supports the notion that melatonin replacement therapy may provide a novel strategy to influence metabolism, at least in people with disruptions in their melatonin system.

Clearly, these notions need to be tested in well-controlled randomised trials but there certainly appears to be ample data to suggest that such a trial may well be worthwhile.

If you have taken melatonin or prescribed it to your patients, I’d certainly like to hear about your experience.

@DrSharma
Edmonton, AB

Hat tip to Sukie for pointing me to this article.

ResearchBlogging.orgCipolla-Neto J, Amaral FG, Afeche SC, Tan DX, & Reiter RJ (2014). Melatonin, Energy Metabolism and Obesity: a Review. Journal of pineal research PMID: 24654916

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Wednesday, March 26, 2014

How The FTO Gene Affects Body Weight

sharma-obesity-dna_molecule9Body weight is one of the most heritable of physiological traits – in fact (believe it or not), it is just as heritable as body height.

Among the many genes associated with body weight, data for the FTO gene have been most consistent.

But these finding have puzzled researchers, as genetic manipulations of the coding regions of the FTO gene have large effects on body weight, without any apparent change in the function of this gene.

Now, a paper by Scott Smemo and colleagues, published in NATURE, suggests a mechanism for how variants of the FTO gene may affect body composition.

The answer lies in the way that the region of the FTO gene associated with obesity directly interacts with another gene IRX3, located a few megabases away on the same chromosome. This interaction appears conserved across species all the way back to the zebrafish.

Consistent with this finding, it turns out that the obesity-associated single nucleotide polymorphisms of the FTO gene are associated with changes in the expression of IRX3, but not FTO, in human brains.

Also consistent with this idea is the fact that IRX3-deficient mice have a 30% lower body weight, primarily due to less fat mass and an increase in basal metabolic rate with browning of white adipose tissue. The animals also appear resistant to the effects of a high-fat diet and appear protected against diabetes.

Furthermore, expression of a dominant-negative form of IRX3 in the hypothalamus reproduces the metabolic phenotypes of Irx3-deficient mice.

Thus, these findings suggest that FTO exerts its effect on body weight through its functional impact on the IRX3 gene, a gene that has so far not been linked to body weight regulation.

This is of particular significance, as IRX3 appears to be a “master gene” that controls the expression of other genes in many tissues including the brain and fat cells.

Given that variants of the FTO gene are frequent in the population and consistently linked to obesity (and type 2 diabetes), these findings may take us one step closer to a molecular target for anti-obesity interventions.

@DrSharma
Edmonton, AB
ResearchBlogging.orgSmemo S, Tena JJ, Kim KH, Gamazon ER, Sakabe NJ, Gómez-Marín C, Aneas I, Credidio FL, Sobreira DR, Wasserman NF, Lee JH, Puviindran V, Tam D, Shen M, Son JE, Vakili NA, Sung HK, Naranjo S, Acemel RD, Manzanares M, Nagy A, Cox NJ, Hui CC, Gomez-Skarmeta JL, & Nóbrega MA (2014). Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature, 507 (7492), 371-5 PMID: 24646999

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Tuesday, March 11, 2014

Liraglutide Improves Metabolism in Liver and Fat Tissue

sharma-obesity-fatty-liver-disease1Insulin 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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Friday, March 7, 2014

Leipzig Forging Its Way As Leaders in Obesity Research

Seal Faculty of Medicine, University of Leipzig, GermanyThis week, for the 5th consecutive year, I have had the privilege of participating in an extensive review of the obesity research program at the University of Leipzig.

I believe that it is fair to say, that starting from scratch, this centre has certainly shown a most remarkable growth and advancement in both fundamental and clinical aspects of obesity research.

It is indeed an honour to have had the opportunity to help evaluate and guide this world-class research program over the past five years.

It is particularly heartwarming to see how much emphasis this program has placed on supporting the career development of the next generation of obesity researchers in Germany.

As the program goes into the renewal phase for hopefully acquiring funding for the next five years, here is a link to past posts on their achievements.

@DrSharma
Leipzig, Germany

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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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