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OBJECTIVE - To investigate the role of desnutrin in adipose tissue triacylglycerol (TAG) and fatty acid metabolism.
RESEARCH DESIGN AND METHODS- We generated transgenic mice overexpressing desnutrin (also called adipose triglyceride lipase [ATGL]) in adipocytes (aP2-desnutrin) and also performed adenoviral-mediated overexpression of desnutrin in 3T3-L1CARΔ1 adipocytes.
RESULTS - aP2-desnutrin mice were leaner with decreased adipose tissue TAG content and smaller adipocyte size. Overexpression of desnutrin increased lipolysis but did not result in increased serum nonesterified fatty acid levels or ectopic TAG storage. We found increased cycling between diacylglycerol (DAG) and TAG and increased fatty acid oxidation in adipocytes from these mice, as well as improved insulin sensitivity.
CONCLUSIONS - We show that by increasing lipolysis, desnutrin overexpression causes reduced adipocyte TAG content and attenuation of diet-induced obesity. Desnutrin-mediated lipolysis promotes fatty acid oxidation and re-esterification within adipocytes. Diabetes 58:855-866, 2009
In mammals, white adipose tissue (WAT) is the primary energy storage depot, accumulating fuel reserves in the form of triacylglycerol (TAG) during times of energy excess (1). However, unlike TAG synthesis that also occurs at high levels in liver for VLDL production, lipolysis for the provision of fatty acids (FAs) as an energy source for use by other organs is unique to adipocytes. The release of FA from TAG proceeds in an orderly and regulated manner. TAG is hydrolyzed first to form diacylglycerol (DAG) and then monoacylglycerol (MAG) that is hydrolyzed to liberate the final FA and glycerol (1-4).
We and others have recently identified a TAG lipase that belongs to the patatin-like domain-containing family of proteins (5-7). We named this enzyme desnutrin (also called PNPLA2, adipose triglyceride lipase, TTS2.2, and iPLA^sub 2^ζ) because it is induced during a low nutritional state in mice (i.e., fasting) and it belongs to the same patatin-like domain-containing family as another nutritionally regulated protein, adiponutrin. Desnutrin is highly expressed in adipose tissue but is also found at low levels in other tissues (6). Understanding the role of desnutrin in fat metabolism, specifically in adipose tissue, is of critical importance, because dysregulated adipocyte TAG lipolysis may cause elevated circulating FA concentrations that are associated with severe metabolic derangements, including the development of insulin resistance and type 2 diabetes (8). Central to this understanding is the question of the metabolic...