UC Berkeley

Adipose tissue is the major energy storage depot in mammals, storing energy in the form triacylglycerol (TAG) during times of energy excess, and mobilizing TAG, via lipolysis, during times of energy need to generate fatty acids. Desnutrin (also known as ATGL) is a novel TAG hydrolase expressed highly only in white and brown adipose tissue (WAT and BAT). To investigate the role of desnutrin in vivo, transgenic mice that overexpress desnutrin predominantly in adipose tissue (aP2-desnutrin mice) were generated. aP2-desnutrin mice had increased lipolysis in adipose tissue and were resistant to diet-induced obesity. Surprisingly, this increased lipolysis in adipose tissue did not result in higher levels of serum non-esterified fatty acids (NEFA), but instead promoted fatty acid oxidation directly within adipocytes resulting in higher energy expenditure and a leaner phenotype. To further investigate the adipose-specific role of desnutrin, gene targeting by homologous recombination in embryonic stem cells was performed to generate adipose-specific conditional desnutrin knockout mice (desnutrin ASKO mice). In contrast to aP2-desnutrin mice, these mice had markedly decreased lipolysis in both WAT and BAT with massive accumulation of TAG in these tissues. These mice had impaired thermogenesis and decreased oxygen consumption. Notably, BAT in these mice was drastically enlarged, and resembled WAT, indicating that desnutrin may be important in the conversion of WAT to BAT.

While the classic model of the endocrine regulation of lipolysis by catecholamines and insulin has been extensively studied, the local regulation of lipolysis in adipose tissue by autocrine/paracrine factors is not well understood. Identification of adipose-specific phospholipase A2 (AdPLA) revealed a surprisingly important and dominant role for adipocyte-derived PGE2 in the autocrine/paracrine regulation of lipolysis. As a PLA2, AdPLA catalyzes the release of fatty acids from the sn-2 position of phospholipids that is typically enriched in arachidonic acid, providing substrate for the initial, rate-limiting step in the synthesis of eicosanoids. To investigate the role of AdPLA in vivo, AdPLA null mice were generated. Through the PGE2/EP3/cAMP pathway, AdPLA dominantly regulates lipolysis in adipose tissue in an autocrine/paracrine manner. The unrestrained adipocyte lipolysis in AdPLA null mice resulted in resistance to both diet-induced and genetic obesity. Consistent with results from aP2-desnutrin mice, despite elevated lipolysis in adipose tissue, serum NEFA levels were not elevated in AdPLA null mice and fatty acid oxidation was increased in WAT, resulting in higher energy expenditure and resistance to obesity. Taken together, findings from aP2-desnutrin mice, desnutrin ASKO mice, and AdPLA null mice have led to the discovery of novel players in the lipolytic cascade, and revealed an unexpected link between lipolysis and the ability of adipose tissue to oxidize fatty acids and release heat, rather than to provide useful energy for work.