New actors in adipocyte function -Focusing on PDEs, CART and superantigen

Sammanfattning: Obesity is increasing rapidly in all parts of the world and is now considered to be a global epidemic. Obesity is a major risk factor for several health issues such as type 2 diabetes (T2D) and cardiovascular disease. The adipose tissue is central in the maintenance of a normal energy homeostasis in the body for instance via regulating lipid storage and release. Besides being an important energy reserve, the adipose tissue is also an endocrine organ releasing a variety of molecules collectively called adipokines, able to affect many different tissues. During weight gain, an expanding adipose tissue may result in dysfunctional adipocytes with unbalanced lipid metabolism, dysregulated release of adipokines, infiltration of immune cells into the adipose tissue and subsequent low grade inflammation. This may result in both local and peripheral insulin resistance, hyperglycemia and the development of T2D. In this thesis we focus on several new players in adipocyte function and energy metabolism. For the first time we report that the phosphodiesterase (PDE) isoforms PDE9A and PDE10A are expressed in adipocytes. When investigating PDE activity in human obesity we found that total-, PDE3-, PDE4- and PDEn activity were downregulated in adipose tissue from obese patients. Inhibition of certain PDEs has previously been shown to result in a healthier adipocyte phenotype and we hypothesize that the reduced PDE activity in obesity is an attempt to create a healthier adipose tissue. We also report for the first time that the peptide hormone cocaine- and amphetamine-regulated transcript (CART) is expressed in adipocytes. When investigating the effects of CART on adipocyte metabolism we demonstrate that stimulating isolated adipocytes with CART results in several changes in adipocyte lipid- and glucose metabolism. In addition, adipocytes isolated from mice with β-cell-specific overexpression of CART, CARTtg mice, displayed altered adipocyte metabolism. Since CART can be found in blood and was found to be expressed in adipocytes, CART is a potential new adipokine able to affect neighboring cells as well as other tissues via the circulation. Regarding the effect of superantigen on adipocyte function, SEA was observed to bind to the cytokine receptor gp130 on primary rat adipocytes and activate downstream signaling through phosphorylation of STAT3. Incubation with SEA also resulted in reduced insulin sensitivity, in line with previously reported IL-6-induced adipocyte insulin resistance. This thesis has revealed many interesting data regarding new players in adipocyte metabolism and will hopefully lead to more research concerning the exact role of these players in adipocyte function as well as in obesity and T2D.