Role of SUMO-Specific Protease 2 in Leptin-Induced Fatty Acid Metabolism in White Adipocytes

Abstract

Background: Leptin is a 16-kDa fat-derived hormone with a primary role in controlling adipose tissue levels. Leptin increases fatty acid oxidation (FAO) acutely through adenosine monophosphate-activated protein kinase (AMPK) and on delay through the SUMO-specific protease 2 (SENP2)–peroxisome proliferator-activated receptor δ/γ (PPARδ/γ) pathway in skeletal muscle. Leptin also directly increases FAO and decreases lipogenesis in adipocytes; however, the mechanism behind these effects remains unknown. Here, we investigated the role of SENP2 in the regulation of fatty acid metabolism by leptin in adipocytes and white adipose tissues.Methods: The effects of leptin mediated by SENP2 on fatty acid metabolism were tested by siRNA-mediated knockdown in 3T3-L1 adipocytes. The role of SENP2 was confirmed <i>in vivo</i> using adipocyte-specific <i>Senp2</i> knockout (<i>Senp2</i>-aKO) mice. We revealed the molecular mechanism involved in the leptin-induced transcriptional regulation of carnitine palmitoyl transferase 1b (<i>Cpt1b</i>) and long-chain acyl-coenzyme A synthetase 1 (<i>Acsl1</i>) using transfection/reporter assays and chromatin immunoprecipitation.Results: SENP2 mediated the increased expression of FAO-associated enzymes, <i>CPT1b</i> and <i>ACSL1</i>, which peaked 24 hours after leptin treatment in adipocytes. In contrast, leptin stimulated FAO through AMPK during the initial several hours after treatment. In white adipose tissues, FAO and mRNA levels of <i>Cpt1b</i> and <i>Acsl1</i> were increased by 2-fold 24 hours after leptin injection in control mice but not in <i>Senp2</i>-aKO mice. Leptin increased PPARα binding to the <i>Cpt1b</i> and <i>Acsl1</i> promoters in adipocytes through SENP2.Conclusion: These results suggest that the SENP2-PPARα pathway plays an important role in leptin-induced FAO in white adipocytes.