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.

Copenhagen, DK

Disclaimer: I am a consultant for Novo Nordisk, the makers of liraglutide

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Saturday, October 6, 2012

Hindsight: Epicardial Fat and Cardiovascular Risk

Dr. Gianluca Iacobellis

Dr. Gianluca Iacobellis

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.

Edmonton, Alberta

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Saturday, September 15, 2012

Hindsight: Monocyte Activation and Adipose Tissue Inflammation

It is now well recognised that infiltration of adipose tissue with pro-inflammatory macrophages (white blood cells) is an important factor in the development of the metabolic complications of obesity.

In a paper we published in HYPERTENSION in 2005, we examined the relationship between markers of macrophage activitation (DC11b) on circulating monocytes and expression of pro-inflammatory genes in adipose tissue biopsies. We also used in-vivo microdialysis to examine glucose metabolism in adipose tissue.

We found that participants with higher CD11b expression on monocytes also had increased expression of the macrophage marker CD68 in adipose tissue.

Although we found no differences in systemic insulin sensitivity, subjects with higher peripheral CD11b expression also showed a markedly augmented increase in dialysate glucose in adipose tissue during oral glucose tolerance testing as well as increased adipose tissue lipolysis.

Thus, out data showed that human monocyte activation is associated with tissue-specific changes in glucose and lipid metabolism, which may in part be explained by monocyte/macrophage infiltration of adipose tissue.

Since then, the concept of adipose tissue inflammation and its relation to metabolic complications of obesity have been well characterized and this continues to be a hot area of research.

Indeed, there is now much data to support the notion that it may well be that the presence or absence of adipose tissue inflammatory response is the key defining difference between those who are considered metabolically ‘healthy’ obese and those who develop metabolic complications.

Edmonton, Alberta

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Saturday, June 16, 2012

Hindsight: Endothelial Cell Specific Molecule-1 in Adipocytes

Back in 2003, laboratories around the world were busy identifying a dizzying array of factors secreted by fat cells. Ever since the discovery of leptin, adipose tissue had become well established as an ‘endocrine organ’ that secreted a range of molecules commonly now referred to as ‘adipokines’.

In a paper published in 2003 in Hormone and Metabolic Research, we reported that endothelial cell specific molecule (ESM)-1, originally identified in lung and kidney endothelial cells, where its expression is regulated by cytokines, was also expressed in fat cells.

Previous in vitro studies had shown that ESM-1 interferes with the molecular mechanisms of immune cell migration by binding to adhesion molecules.

In our study, we explored the expression of ESM-1 in isolated human adipocytes and in rat adipose tissue depots. Human primary adipocytes were cultivated after collagenase digestion and used for in vitro incubation studies. Adipocytes were also isolated from different fat depots of Sprague-Dawley rats.

Using gene expression techniques and confocal microscopy, we demonstrated that ESM-1 was expressed in both human and rat adipose tissue and showed that its expression was stimulated by phorbol ester, an activator of protein kinase C, and by retinoic acid, an activator of nuclear receptors.

The highest expression was found in subcutaneous rat adipose tissue – two-fold compared to epididymal and six-fold compared to intrascapular brown adipose tissue.

Based on the emerging evidence that obesity is related to systemic inflammation, we speculated that the formation of ESM-1 in adipocytes and its activation by protein kinase C may play a role in the regulation of inflammatory processes in fat tissue.

Judging by the rather modest 17 citations of this paper, our finding of ESM-1 in fat tissue may not have been quite that important a discovery after all.

Edmonton, Alberta

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Saturday, June 2, 2012

Hindsight: Adiponectin and Inflammation



Back in 1996, a protein now widely referred to as adiponectin, was found to be secreted in large amounts by fat cells. Paradoxically, however, secretion of this protein, which has positive effects on glucose and lipid metabolism as well as anti-inflammatory effects, was found to be suppressed in obese individuals.

In 2003, we published a paper in DIABETES, in which we examined the relationship between adiponectin and mediators of inflammation in blood and subcutaneous adipose tissue samples from 65 postmenopausal healthy women.

As expected, adiponectin plasma levels and adipose-tissue gene expression were significantly lower in obese subjects.

However, we also found that the levels of adiponectin were inversely correlated with obesity-associated variables, including high-sensitive C-reactive protein (hs-CRP) and interleukin-6 (IL-6).

Despite adjustment for obesity-associated variables, plasma levels of adiponectin were significantly correlated to adiponectin gene expression and the inverse correlation between plasma levels of hs-CRP and plasma adiponectin remained significant despite correction for obesity-associated variables, whereas the inverse correlation between adiponectin plasma levels or adiponectin gene expression in adipose tissue with plasma IL-6 were largely dependent on the clustering of obesity-associated variables.

Thus, our data suggested a transcriptional mechanism leading to decreased adiponectin plasma levels in obese women and showed that low levels of adiponectin are associated with higher levels of hs-CRP and IL-6, two inflammatory mediators and markers of increased cardiovascular risk.

While the exact mechanism by which adiponectin secretion is reduced in obesity remains only partially understood, at the time, this study certainly suggested that low levels of adiponectin may well play a role in the increased systemic inflammation often found in obese individuals.

In the meantime, there is data to suggest that in fact the opposite may be true – increased inflammation (particularly in adipose tissue) may well be the mechanism through with adiponectin secretion is suppressed in obesity.

According to Google Scholar, this paper has been cited 344 times.

Edmonton, Alberta

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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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