Abstract
It has been observed previously that hormone-sensitive lipase-deficient (HSL-ko) mice have reduced white adipose tissue (WAT) stores compared to control mice. These findings contradict the expectation that the decreased lipolytic activity in WAT of HSL-ko mice would cause accumulation of triglycerides (TGs) in that tissue. Here we demonstrate that the cellular TG synthesis in HSL-deficient WAT is markedly reduced due to downregulation of the enzymatic activities of glycerophosphate acyltransferase, dihydroxyacetonphosphate acyltransferase, lysophosphatidate acyltransferase, and diacylglycerol acyltransferase. Fatty acid de novo synthesis is also decreased due to reduced cellular glucose uptake, reduced glucose incorporation into adipose tissue lipids, and reduced activities of acetyl:CoA carboxylase and fatty acid synthase. Finally, the activities of 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 decreased in HSL-ko mice. The reduced expression of the peroxisome proliferator-activated receptor gamma (PPAR gamma) target genes PEPCK, ACS, and aP2, as well as reduced mRNA levels of PPAR gamma itself, suggest the involvement of this transcription factor in the downregulation of lipogenesis. Taken together, these results establish that in the absence of HSL, the reduced NEFA production is counteracted by a drastic reduction of NEFA reesterification that provides sufficient quantities of NEFA for release into the circulation. These metabolic adaptations result in decreased fat mass in HSL-ko mice.
Highlights
It has been observed previously that hormonesensitive lipase-deficient (HSL-ko) mice have reduced white adipose tissue (WAT) stores compared to control mice
To gain information about the transcriptional mechanisms leading to the downregulation of fatty acid and lipid synthesis in Hormone-sensitive lipase (HSL)-ko WAT, we investigated the contribution of the transcription factors peroxisome proliferator-activated receptor ␥ (PPAR␥) and sterol regulatory element binding protein (SREBP)-1 in these processes
The major process to provide nonesterified fatty acids (NEFAs) to the vascular system during fasting is the induction of TG lipolysis, and HSL is responsible for the hydrolysis of acylglycerides in fat cells
Summary
It has been observed previously that hormonesensitive lipase-deficient (HSL-ko) mice have reduced white adipose tissue (WAT) stores compared to control mice. To assess whether decreased fatty acid esterification and synthesis of TG and PL are responsible for the maintenance of normal steady-state NEFA concentrations in HSL-deficient WAT, the incorporation of [3H]9,10-oleic acid into the lipid moiety was measured in ex vivo fat pads from control and HSL-ko mice. To determine mRNA levels for the enzymes involved in the esterification of fatty acids, Northern blot analysis was performed in WAT from fed animals, with specific probes for mouse DGAT-1, DGAT-2, GPAM, LPAAT, and GNPAT.
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