Follow me on

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. AMS Edmonton, Alberta

Full Post

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. AMS Edmonton, Alberta

Full Post

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. AMS Edmonton, Alberta

Full Post

Weekend Roundup, September 9, 2011

As not everyone may have a chance during the week to read every post, here’s a roundup of last week’s posts: Should We Outsource Obesity Treatments To Weight Watchers? Alberta’s Obesity Initiative: Not Just Diet and Exercise Is There Any Path For Approval of Anti-Obesity Drugs? GLP-1 Receptor Agonists, Obesity and Psoriasis Bariatric Surgery For Osteoarthritis of Hips and Knees? Have a great Sunday! (or what’s left of it) AMS London, UK You can now also follow me and post your comments on Facebook

Full Post

GLP-1 Receptor Agonists, Obesity And Psoriasis

I have previously discussed the not too uncommon association between obesity and psoriasis, a chronic, autoimmune disease that causes red, scaly patches to appear on the skin, and affects 2-3% of the population in Western countries. Hogan and colleagues, St Vincent’s University Hospital, University College Dublin, Ireland, in a paper just published in Diabetologia, now report improvement of psoriasis in three obese patients with type 2 diabetes several weeks after the initiation of therapy with the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists exenatide and liraglutide. Regular readers may recall that GLP-1 receptor agonists were recently introduced for the treatment of diabetes and are currently under investigation for the treatment of obesity. In addition to the clinical improvement, with reduced itching and/or a reduction in Psoriasis Area and Severity Index (PASI) scores, they also provide evidence that GLP-1 receptor agonist treatment had immunological effects in that it increased the number of natural killer T (NKT) cells in the circulation and reduced the number of invariant NKT cells in the psoriatic plaques. In an accompanying commentary, Drucker and Rosen from the University of Toronto, point out that apart from the ‘classical’ metabolic effects of GLP-1 (e.g. on the secretion of insulin and glucagon), GLP-1 receptors are also found in numerous immune cell subpopulations, including thymoyctes, splenocytes, bone marrow-derived cells, and regulatory T cells. It is therefore biologically ‘plausible’ that administration of GLP-1 analogues could have anti-inflammatory effects on psoriasis (and perhaps other inflammatory abnormalities). Obviously, a few cases do not yet make an indication, but they certainly suggest that this hypothesis may well be worthy of further study. I certainly wonder, if any of my readers have experienced similar improvements in inflammatory conditions like psoriasis with the use of GLP-1 analogues. AMS Edmonton, Alberta Hogan AE, Tobin AM, Ahern T, Corrigan MA, Gaoatswe G, Jackson R, O’Reilly V, Lynch L, Doherty DG, Moynagh PN, Kirby B, O’Connell J, & O’Shea D (2011). Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis. Diabetologia PMID: 21744074 Drucker DJ, & Rosen CF (2011). Glucagon-like peptide-1 (GLP-1) receptor agonists, obesity and psoriasis: diabetes meets dermatology. Diabetologia PMID: 21892687

Full Post