Decreased fatty acid esterification compensates for the reduced lipolytic activity in hormone-sensitive lipase-deficient white adipose tissue

doi:10.1194/jlr.M300190-JLR200

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Decreased fatty acid esterification compensates for the reduced lipolytic activity in hormone-sensitive lipase-deficient white adipose tissue

Robert Zimmermann, Guenter Haemmerle, Elke M. Wagner, Juliane G. Strauss, Dagmar Kratky, and Rudolf Zechner

Inst. of Mol. Biol., Biochem. and Microbiology, Graz 8010

Corresponding Author: robert.zimmermann{at}kfunigraz.ac.at

Hormone-sensitive lipase deficient (HSL-ko) mice exhibit a marked decrease of acylglyceride hydrolase activity in white adipose tissue (WAT). The decreased lipolytic activity would be expected to cause accumulation of triglycerides (TG) and abnormally low levels of non-esterified fatty acids (NEFA) in WAT. In contrast to these expectations, HSL-ko mice exhibited reduced WAT mass and unchanged intracellular NEFA levels compared to control animals. These observations suggested that HSL-deficiency not only causes changes in TG lipolysis but also affects lipogenesis. Here we demonstrate that the downregulation of lipogenic processes leads to the reduced fat mass in HSL-ko mice. First, cellular TG synthesis as measured by the incorporation of NEFA into TG in ex vivo fat pads is markedly reduced due to downregulation of the enzymes responsible for glycerophosphate acyltransferase, dihydroxyacetonphosphate acyltransferase, lysophosphatidate acyltransferase and diacylglycerol acyltransferase activity. Second, fatty acid de novo synthesis is decreased due to reduced cellular glucose uptake, reduced glucose incorporation into adipose tissue lipids and reduced activities of the major enzymes involved in fatty acid synthesis, acetyl CoA carboxylase and fatty acid synthase. Third, phosphoenolpyruvate-carboxykinase (PEPCK), acyl-CoA synthetase (ACS) and glucose 6-phosphate dehydrogenase, the enzymes that provide glycerol-3-phosphate, acyl-CoA, and NADPH for TG synthesis, respectively, are also reduced in HSL-ko mice. The decreased expression of the PPARg target genes PEPCK, ACS, and aP2 as well as reduced mRNA levels of PPARg itself suggested the involvement of this transcription factor in the downregulation of lipogenesis. Taken together these results provide evidence that in the absence of HSL, the reduced NEFA production resulting from decreased TG hydrolysis and de novo NEFA synthesis is counteracted by a drastic reduction of NEFA reesterification to maintain normal intracellular NEFA levels. These metabolic adaptations result in decreased fat mass in HSL-ko mice.

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