Diabetes mellitus can affect spermatogenesis at various levels, which can cause male-factor infertility.

Optimal control of hepatic lipid metabolism is critical for organismal metabolic fitness. In liver, adipose triglyceride lipase (ATGL) serves as a major triacylglycerol (TAG) lipase and controls the bulk of intracellular lipid turnover. However, regulation of ATGL expression and its functional implications in hepatic lipid metabolism, particularly in the context of fatty liver disease, is unclear. We show that E3 ubiquitin ligase COP1 (also known as RFWD2) binds to the consensus VP motif of ATGL and targets it for proteasomal degradation by K-48 linked polyubiquitination, predominantly at the lysine 100 residue. COP1 thus serves as a critical regulator of hepatocyte TAG content, fatty acid mobilization, and oxidation. Moreover, COP1-mediated regulation of hepatic lipid metabolism requires optimum ATGL expression for its metabolic outcome. In vivo, adenovirus-mediated depletion of COP1 ameliorates high-fat diet-induced steatosis in mouse liver and improves liver function. Our study thus provides new insights into the regulation of hepatic lipid metabolism by the ubiquitin-proteasome system and suggests COP1 as a potential therapeutic target for nonalcoholic fatty liver disease.

Adipose triglyceride lipase (ATGL) maintains an optimum mitochondrial function putatively by generating cognate ligands for peroxisome proliferator-activated receptor α (PPARα), which, together with PPARγ coactivator-1α (PGC1α), regulate muscle mitochondrial biogenesis. However, the cross-talk between ATGL and PPARα in skeletal muscle mitochondrial metabolism and its implication in chronological aging is poorly understood. The role of ATGL in muscle mitochondrial metabolism was studied by overexpressing and depleting the gene and studying its downstream effect in cultured myotubes and in murine skeletal muscle. We found that PPARα directly induces ATGL expression during myogenesis. Overexpression of ATGL significantly enhanced while depletion of ATGL attenuated mitochondrial oxidative phosphorylation and fatty acid oxidation without alteration in mitochondrial content, and it rendered PPARα and PGC1α redundant in promoting mitochondrial oxidative function. However, ATGL did not alter PPARα-dependent lipid accumulation and insulin sensitivity. In middle-aged rats, ATGL expression was higher and correlated with PPARα expression and sustained fatty acid oxidation in oxidative soleus muscle. Fenofibrate feeding further induced ATGL expression selectively in this muscle compartment. These findings illustrate that PPARα and ATGL constitute a regulatory pathway in skeletal muscle, suggesting their role as a mitochondrial metabolic reserve.-Biswas, D., Ghosh, M., Kumar, S., Chakrabarti, P. PPARα-ATGL pathway improves muscle mitochondrial metabolism: implication in aging.