Adipose tissue plays a critical role in storing triglycerides and also secretes adipokines mediating lipid metabolism and insulin sensitivity in peripheral tissues. Understanding the mechanisms underlying control of chemical energy storage and utilization in adipocytes is central to containing the epidemic of obesity. While mitochondrial fatty acid oxidation is tightly coupled to ATP synthesis, peroxisomal fatty acid oxidation generates heat at the expense of chemical energy and may work as an uncoupling process that limits adipocyte expansion. In peroxisomes, FA can undergo ? as well as a oxidation. It is known that peroxisomal a oxidation is important for catabolism of branched chain FA and also for very long chain FA (VLCFA). Recent data also support the role of a oxidation pathway in LCFA oxidation but its contribution to catabolism of these FA in vivo and its overall role in adipocyte energy homeostasis remain largely unknown. Using electrospray ionization mass spectrometry (ESI/MS), we demonstrated an increased activity of peroxisomal FA a oxidation during differentiation of 3T3-L1 cells to adipocytes, which was reflected in accumulation of odd numbered shorter acyl moieties in major lipid species. The physiological significance of such a change in lipid composition is unexplored. We hypothesize that LCFA a oxidation affects lipid accumulation through futile cycling of the FA generated by lipogeneis and that it may mediate some of the action of leptin to increase FA catabolism in adipose tissue. Another effect of active a oxidation is to increase the proportion of lipids with shorter acyl chains. Since intracellular lipid trafficking is highly dependent on the chemical property of acyl chains, we also hypothesize that LCFA a oxidation may alter trafficking of glucose transporters in response to insulin signaling. Accordingly, Aim 1 seeks to define how LCFA a oxidation is regulated in adipocytes, its substrate selectivity and dependence on SCD-1 activity.
Aim 2 will study the role of LCFA a oxidation in energy homeostasis and lipid accumulation by examining cultured adipocytes where a oxidation is manipulated by chemical inhibition, gene knock down and protein over-expression. Obese mice (ob/ob and db/db), mice resistant to diet induced obesity (CD36 null and SCD-1 null) and mice of different ages are employed to confirm its function in vivo.
Aim 3 will investigate LCFA a oxidation-mediated trafficking of glucose transporter in response to insulin signaling in adipocytes. Insights gained from this work will enhance our knowledge related to the role of a previously underappreciated pathway in the regulation of adipocyte lipid and energy metabolism. The work may lead to new concepts related to the etiology of adiposity and guide novel strategies aiming to prevent obesity and its associated complications, diabetes, and cardiovascular disease.
Obesity and diabetes are affecting an alarming proportion of the population in industrialized nations. Our study will gain significant insights into a novel pathway of fatty acid metabolism and the etiology of obesity and diabetes and will aid in the discovery of novel targets for treatment of these metabolic diseases.
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| Guo, Lin; Zhou, Dequan; Pryse, Kenneth M et al. (2010) Fatty acid 2-hydroxylase mediates diffusional mobility of Raft-associated lipids, GLUT4 level, and lipogenesis in 3T3-L1 adipocytes. J Biol Chem 285:25438-47 |
