title: Central leptin activates mitochondrial function and increases heat production in skeletal muscle.
abstract: Leptin acts on the brain to increase postprandial heat production in skeletal muscle of sheep. To determine a mechanism for this effect, we examined the role of mitochondrial uncoupling and AMP-activated protein kinase (AMPK). Ovariectomized ewes (n=4/group) received infusion lines into the lateral cerebral ventricle, and leptin (10 μg/h) was infused to increase heat production in skeletal muscle. In animals that were program fed (1100-1600 h), skeletal muscle biopsies were taken after either central infusion of leptin or vehicle to measure the expression of uncoupling protein (UCP) mRNA and the phosphorylation status of AMPK. Respiratory function was also quantified in mitochondria isolated from skeletal muscle. Leptin infusion increased the expression of UCP2 and UCP3 mRNA as well as UCP3 protein but not UCP1 mRNA in muscle. Leptin also increased substrate-driven, coupled (ADP-driven), and uncoupled (oligomycin) respiration but had no effect on the total respiratory capacity. The respiratory control ratio was lower in leptin-treated (vs. vehicle-treated) animals, indicating a predominant effect on uncoupled respiration. There was no effect of central leptin treatment on AMPK phosphorylation. We then infused 5-aminoimidazole-4-carboxamide-1β-riboside (AICAR) (10 mg/h for 6 h) directly into the femoral artery and measured skeletal muscle temperature; muscle was also collected for isolated mitochondria studies. AICAR had no effect on heat production or substrate-driven, uncoupled, or total respiratory states in skeletal muscle mitochondria. However, AICAR increased ADP-driven (coupled) respiration in mitochondria. In conclusion, leptin acts at the brain to increase heat production in muscle through altered mitochondrial function, indicative of adaptive thermogenesis.
authors.affiliation: Department of Physiology, Monash University, Building 13F, Wellington Road, Clayton, Victoria 3800, Australia. belinda.henry@monash.edu
authors.forename: Belinda A
authors.initials: BA
authors.lastname: Henry
authors.forename: Zane B
authors.initials: ZB
authors.lastname: Andrews
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rao
authors.forename: Iain J
authors.initials: IJ
authors.lastname: Clarke
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D057967:Infusions, Intraventricular; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000008:administration & dosage / Q000502:physiology*; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage; D034561:Sheep, Domestic; D022722:Thermogenesis / Q000187:drug effects; D014475:Uncoupling Agents / Q000494:pharmacology; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
chemical_list: D007473:Ion Channels; D020738:Leptin; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; C000604389:UCP2 protein, human; C000604392:UCP3 protein, human; D014475:Uncoupling Agents; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D000244:Adenosine Diphosphate; D055372:AMP-Activated Protein Kinases