In vivo regulation of SREBP-1c in skeletal muscle: effects of nutritional status, glucose, insulin, and leptin.
Sterol regulatory element binding protein-1c (SREBP-1c), a transcription factor that is important for mediating insulin effects on metabolic gene expression in liver during the fasted-to-fed transition, is also expressed in skeletal muscle. However, the regulation and role of SREBP-1c in skeletal muscle are poorly understood. The present study compared the effects of nutritional status, physiological hyperinsulinemic clamps, and adenovirus-mediated hyperleptinemia (HLEP) in rats on expression of SREBP-1c and other metabolic genes in skeletal muscle. Three- and 6-h refeeding of 18-h-fasted animals increased levels of SREBP-1c mRNA and the SREBP-1 protein (full length and mature) in gastrocnemius muscle (P < 0.05). Fatty acid synthase (FAS) and hexokinase II (HKII) mRNA levels were also increased by refeeding, and uncoupling protein 3 (UCP3) mRNA level was decreased (all P < 0.05). Surprisingly, 3-h hyperinsulinemic clamps did not increase gastrocnemius muscle SREBP-1c and FAS mRNA levels or SREBP-1 protein levels but did increase HKII mRNA levels and decrease UCP3 mRNA levels (P < 0.05). HLEP reduced refeeding-induced increases of SREBP-1c and FAS mRNA levels but did not reduce the level of SREBP-1 protein. We conclude that 1) skeletal muscle SREBP-1c gene expression is regulated by nutritional status in a fashion similar to that observed in liver and adipose tissue, 2) physiological hyperinsulinemia is not sufficient to imitate the effects of refeeding on SREBP-1c gene expression, and 3) leptin suppresses refeeding effects on SREBP-1c mRNA levels.
Department of Medicine, Division of Endocrinology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261, USA.
S Renee
SR
Commerford
Li
L
Peng
John J
JJ
Dubé
Robert M
RM
O'Doherty
D000818:Animals; D001786:Blood Glucose / Q000502:physiology*; D015152:Blotting, Northern; D001835:Body Weight / Q000187:drug effects; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004435:Eating / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000502:physiology*; D020738:Leptin / Q000097:blood / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D009752:Nutritional Status / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors
D001786:Blood Glucose; D022762:CCAAT-Enhancer-Binding Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D007328:Insulin; D020738:Leptin; D012333:RNA, Messenger; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors