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SUMO-specific protease 2 mediates leptin-induced fatty acid oxidation in skeletal muscle.
Metabolism. 2019 06; 95:27-35.M

Abstract

BACKGROUND AND PURPOSE

In addition to the central nervous system-mediated action, leptin also directly induces fatty acid oxidation in skeletal muscle. Rapid induction of FAO by leptin is mediated by the AMP-activated protein kinase (AMPK) pathway, but the mechanism of prolonged FAO by leptin was previously unknown. In an earlier study, we showed that free fatty acids increase transcription of small ubiquitin-like modifier (SUMO) specific protease 2 (SENP2) in skeletal muscle, and that SENP2 stimulates expression of FAO-associated enzymes by deSUMOylating peroxisome proliferator-activated receptors, PPARδ and PPARγ. In this study, we examine whether SENP2 is involved in prolonged stimulation of FAO by leptin.

METHODS

The Effect of leptin on expression of SENP2 and on SENP2-mediated FAO was investigated by using western blotting and real time qPCR of C2C12 myotubes, and of C2C12 myotubes in which expression of specific genes was knocked down using siRNAs. Additionally, muscle-specific SENP2 knockout mice were generated to test the involvement of SENP2 in leptin-induced FAO in vivo.

RESULTS

We show that leptin treatment of C2C12 myotubes causes signal transducer and activator of transcription 3 (STAT3) to bind to the Senp2 promoter, inducing SENP2 expression. We also show that leptin increases the binding of PPARδ and PPARγ to PPRE sites in the promoters of two FAO-associated genes: long-chain acyl-CoA synthetase 1 (Acsl1) or carnitine palmitoyl transferase 1b (Cpt1b). When SENP2 is knocked down in myotubes, leptin-induced expression of FAO-associated enzymes and prolonged increase of FAO are suppressed, but rapid increase of FAO is unaffected. In addition, leptin-induced expression of FAO-associated enzymes was not observed in muscle tissue of SENP2 knockout mice.

CONCLUSIONS

We demonstrate that the peripheral actions of leptin on FAO are mediated by two different pathways: AMPK causes a rapid increase in FAO, and SENP2 of the STAT3 pathway causes a slow, prolonged increase in FAO.

Authors+Show Affiliations

Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, College of Medicine, Seoul National University, Seoul, Republic of Korea.Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, College of Medicine, Seoul National University, Seoul, Republic of Korea; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea. Electronic address: suschung@snu.ac.kr.Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, College of Medicine, Seoul National University, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: kspark@snu.ac.kr.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30902749

Citation

Koo, Young Do, et al. "SUMO-specific Protease 2 Mediates Leptin-induced Fatty Acid Oxidation in Skeletal Muscle." Metabolism: Clinical and Experimental, vol. 95, 2019, pp. 27-35.
Koo YD, Lee JS, Lee SA, et al. SUMO-specific protease 2 mediates leptin-induced fatty acid oxidation in skeletal muscle. Metab Clin Exp. 2019;95:27-35.
Koo, Y. D., Lee, J. S., Lee, S. A., Quaresma, P. G. F., Bhat, R., Haynes, W. G., Park, Y. J., Kim, Y. B., Chung, S. S., & Park, K. S. (2019). SUMO-specific protease 2 mediates leptin-induced fatty acid oxidation in skeletal muscle. Metabolism: Clinical and Experimental, 95, 27-35. https://doi.org/10.1016/j.metabol.2019.03.004
Koo YD, et al. SUMO-specific Protease 2 Mediates Leptin-induced Fatty Acid Oxidation in Skeletal Muscle. Metab Clin Exp. 2019;95:27-35. PubMed PMID: 30902749.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SUMO-specific protease 2 mediates leptin-induced fatty acid oxidation in skeletal muscle. AU - Koo,Young Do, AU - Lee,Ji Seon, AU - Lee,Seung-Ah, AU - Quaresma,Paula G F, AU - Bhat,Ratan, AU - Haynes,William G, AU - Park,Young Joo, AU - Kim,Young-Bum, AU - Chung,Sung Soo, AU - Park,Kyong Soo, Y1 - 2019/03/19/ PY - 2019/01/10/received PY - 2019/02/28/revised PY - 2019/03/15/accepted PY - 2019/3/25/pubmed PY - 2019/11/26/medline PY - 2019/3/24/entrez KW - Fatty acid oxidation KW - Leptin KW - PPAR KW - SUMO KW - SUMO-specific protease SP - 27 EP - 35 JF - Metabolism: clinical and experimental JO - Metab. Clin. Exp. VL - 95 N2 - BACKGROUND AND PURPOSE: In addition to the central nervous system-mediated action, leptin also directly induces fatty acid oxidation in skeletal muscle. Rapid induction of FAO by leptin is mediated by the AMP-activated protein kinase (AMPK) pathway, but the mechanism of prolonged FAO by leptin was previously unknown. In an earlier study, we showed that free fatty acids increase transcription of small ubiquitin-like modifier (SUMO) specific protease 2 (SENP2) in skeletal muscle, and that SENP2 stimulates expression of FAO-associated enzymes by deSUMOylating peroxisome proliferator-activated receptors, PPARδ and PPARγ. In this study, we examine whether SENP2 is involved in prolonged stimulation of FAO by leptin. METHODS: The Effect of leptin on expression of SENP2 and on SENP2-mediated FAO was investigated by using western blotting and real time qPCR of C2C12 myotubes, and of C2C12 myotubes in which expression of specific genes was knocked down using siRNAs. Additionally, muscle-specific SENP2 knockout mice were generated to test the involvement of SENP2 in leptin-induced FAO in vivo. RESULTS: We show that leptin treatment of C2C12 myotubes causes signal transducer and activator of transcription 3 (STAT3) to bind to the Senp2 promoter, inducing SENP2 expression. We also show that leptin increases the binding of PPARδ and PPARγ to PPRE sites in the promoters of two FAO-associated genes: long-chain acyl-CoA synthetase 1 (Acsl1) or carnitine palmitoyl transferase 1b (Cpt1b). When SENP2 is knocked down in myotubes, leptin-induced expression of FAO-associated enzymes and prolonged increase of FAO are suppressed, but rapid increase of FAO is unaffected. In addition, leptin-induced expression of FAO-associated enzymes was not observed in muscle tissue of SENP2 knockout mice. CONCLUSIONS: We demonstrate that the peripheral actions of leptin on FAO are mediated by two different pathways: AMPK causes a rapid increase in FAO, and SENP2 of the STAT3 pathway causes a slow, prolonged increase in FAO. SN - 1532-8600 UR - https://www.unboundmedicine.com/medline/citation/30902749/SUMO_specific_protease_2_mediates_leptin_induced_fatty_acid_oxidation_in_skeletal_muscle_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0026-0495(19)30060-5 DB - PRIME DP - Unbound Medicine ER -