Role of SENP2 in leptin-induced fatty acid oxidation in skeletal muscle

Abstract

Leptin is an adipokine produced predominantly in adipose tissue, and plays an important role in maintaining adipose mass by regulating both food intake and energy expenditure. Leptin binds to leptin receptor long form (LepRb) and enhances Janus kinase 2 (JAK2)/ signal transducer and activator of transcription 3 (STAT3) signaling. Leptin binds to LepR in hypothalamus and inhibits food intake by promotion of anorexigenic factors and inhibiting orexigenic factors. In arcuate region of hypothalamus, pro-opiomelanocortin (POMC) neurons activate peptide which is a hormone inhibiting food intake, and POMC/ cocaine and amphetamine-regulated transcript (CART) is known for decreasing food intake. Leptin increases energy expenditure in skeletal muscle by activation of AMP-activated protein kinase and resultant increase in fatty acid oxidation. Our group recently demonstrated that leptin increases SUMO specific protease 2 (SENP2) expression through leptin receptor/STAT3 signaling in C2C12 myotubes. SENP2 desumoylates peroxisome proliferator-activated receptors (PPAR) δ and PPARγ, which increases transcription of PPAR target genes to produce fatty acid oxidation(FAO)-associated enzymes such as acyl-CoA synthetase 1 (ACSL1) and carnitine palmitoyl transferase-1 (CPT1b). In this study, I aimed to verify the role of SENP2 on the effect of leptin in skeletal muscles in vivo. Intraperinoteal injection of leptin (3mg/kg, body weight) significantly increased mRNA levels of SENP2 in soleus muscle but not in gastrocnemius muscles (GM) of C57BL/6J mice. Leptin did not increase SENP2 expression in soleus muscle of db/db mice which have defective leptin long form receptors. Incubation of isolated soleus muscles of C57BL/6J mice with leptin (3mg/kg, body weight) increase phosphorylation of STAT3 from 30 minutes to 2 hours. These results suggest that leptin increases SENP2 expression through the leptin receptor/STAT3 signaling pathway in skeletal muscle. Leptin administration also increased the mRNA levels of ACSL1 and CPT1b and FAO in soleus muscles of C57BL/6J mice. However, leptin did not increase FAO-associated enzymes expression and FAO in GM muscle of C57BL/6J mice as well as soleus muscles of db/db mice. These data suggest that leptin increases FAO in skeletal

muscle and leptin induced SENP2 expression contribute to in vivo effect of leptin on FAO.

Keywords: SUMO-specific protease 2, Leptin, Leptin receptor, fatty acid oxidation, obesity