Leptin and the control of respiratory gene expression in muscle.
Leptin plays a central role in the regulation of fatty acid homeostasis, promoting lipid storage in adipose tissue and fatty acid oxidation in peripheral tissues. Loss of leptin signaling leads to accumulation of lipids in muscle and loss of insulin sensitivity secondary to obesity. In this study, we examined the direct and indirect effects of leptin signaling on mitochondrial enzymes including those essential for peripheral fatty acid oxidation. We assessed the impact of leptin using the JCR:LA-cp rat, which lacks functional leptin receptors. The activities of marker mitochondrial enzymes citrate synthase (CS) and cytochrome oxidase (COX) were similar between wild-type (+/?) and corpulent (cp/cp) rats. In contrast, several tissues showed variations in the fatty acid oxidizing enzymes carnitine palmitoyltransferase II (CPT II), long-chain acyl-CoA dehydrogenase (LCAD) and 3-hydroxyacyl-CoA dehydrogenase (HOAD). It was not clear if these changes were due to loss of leptin signaling or to insulin insensitivity. Consequently, we examined the effects of leptin on cultured C(2)C(12) and Sol8 cells. Leptin (3 days at 0, 0.2, or 2.0 nM) had no direct effect on the activities of CS, COX, or fatty acid oxidizing enzymes. Leptin treatment did not affect luciferase-based reporter genes under the control of transcription factors involved in mitochondrial biogenesis (nuclear respiratory factor-1 (NRF-1), nuclear respiratory factor-2 (NRF-2)) or fatty acid enzyme expression (peroxisome proliferator-activated receptors (PPARs)). These studies suggest that leptin exerts only indirect effects on mitochondrial gene expression in muscle, possibly arising from insulin resistance.
McClelland
G B
GB
Department of Biology, Queen's University, Kingston, Ontario, Canada K7L 3N6.
Kraft
C S
CS
Michaud
D
D
Russell
J C
JC
Mueller
C R
CR
Moyes
C D
CD
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000096:biosynthesis; D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000096:biosynthesis; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000096:biosynthesis; D002478:Cells, Cultured; D002950:Citrate (si)-Synthase / Q000096:biosynthesis; D003576:Electron Transport Complex IV / Q000096:biosynthesis; D005786:Gene Expression Regulation; D066298:In Vitro Techniques; D020738:Leptin / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000201:enzymology; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000201:enzymology / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D014162:Transfection
D020738:Leptin; D012333:RNA, Messenger; D015094:3-Hydroxyacyl CoA Dehydrogenases; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D003576:Electron Transport Complex IV; D002334:Carnitine O-Palmitoyltransferase; D002950:Citrate (si)-Synthase