SUMO-specific protease 2 mediates leptin-induced fatty acid oxidation in skeletal muscle.
AMP-Activated Protein Kinases
/ metabolism
Animals
Carnitine O-Palmitoyltransferase
/ genetics
Cells, Cultured
Coenzyme A Ligases
/ genetics
Cysteine Endopeptidases
/ biosynthesis
Fatty Acids
/ metabolism
Gene Knockdown Techniques
Leptin
/ pharmacology
Male
Metabolic Networks and Pathways
/ drug effects
Mice
Mice, Inbred C57BL
Muscle Fibers, Skeletal
/ metabolism
Muscle, Skeletal
/ drug effects
Oxidation-Reduction
Fatty acid oxidation
Leptin
PPAR
SUMO
SUMO-specific protease
Journal
Metabolism: clinical and experimental
ISSN: 1532-8600
Titre abrégé: Metabolism
Pays: United States
ID NLM: 0375267
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
10
01
2019
revised:
28
02
2019
accepted:
15
03
2019
pubmed:
25
3
2019
medline:
26
11
2019
entrez:
24
3
2019
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 30902749
pii: S0026-0495(19)30060-5
doi: 10.1016/j.metabol.2019.03.004
pmc: PMC7398119
mid: NIHMS1610755
pii:
doi:
Substances chimiques
Fatty Acids
0
Leptin
0
CPT1B protein, mouse
EC 2.3.1.21
Carnitine O-Palmitoyltransferase
EC 2.3.1.21
AMP-Activated Protein Kinases
EC 2.7.11.31
Cysteine Endopeptidases
EC 3.4.22.-
Senp2 protein, mouse
EC 3.4.22.68
ACSL1 protein, mouse
EC 6.2.1.-
Coenzyme A Ligases
EC 6.2.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
27-35Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK083567
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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