title: Recovered insulin response by 2 weeks of leptin administration in high-fat fed rats is associated with restored AS160 activation and decreased reactive lipid accumulation.
abstract: Leptin is an adipokine that increases fatty acid (FA) oxidation, decreases intramuscular lipid stores, and improves insulin response in skeletal muscle. In an attempt to elucidate the underlying mechanisms by which these metabolic changes occur, we administered leptin (Lep) or saline (Sal) by miniosmotic pumps to rats during the final 2 wk of a 6-wk low-fat (LF) or high-fat (HF) diet. Insulin-stimulated glucose transport was impaired by the HF diet (HF-Sal) but was restored with leptin administration (HF-Lep). This improvement was associated with restored phosphorylation of Akt and AS160 and decreased in reactive lipid species (ceramide, diacylglycerol), known inhibitors of the insulin-signaling cascade. Total muscle citrate synthase (CS) activity was increased by both leptin and HF diet, but was not additive. Leptin increased subsarcolemmal (SS) and intramyofibrillar (IMF) mitochondria CS activity. Total muscle, sarcolemmal, and mitochondrial (SS and IMF) FA transporter (FAT/CD36) protein content was significantly increased with the HF diet, but not altered by leptin. Therefore, the decrease in reactive lipid stores and subsequent improvement in insulin response, secondary to leptin administration in rats fed a HF diet was not due to a decrease in FA transport protein content or altered cellular distribution.
authors.affiliation: Dept. of Human Health and Nutritional Sciences, University of Guelph, Ontario, Canada, N1G 2W1.
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Stefanyk
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Gulli
authors.forename: Ian R
authors.initials: IR
authors.lastname: Ritchie
authors.forename: Adrian
authors.initials: A
authors.lastname: Chabowski
authors.forename: Laelie A
authors.initials: LA
authors.lastname: Snook
authors.forename: Arend
authors.initials: A
authors.lastname: Bonen
authors.forename: David J
authors.initials: DJ
authors.lastname: Dyck
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D001823:Body Composition / Q000187:drug effects / Q000502:physiology; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects* / Q000502:physiology; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D004041:Dietary Fats; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D020738:Leptin; C533101:TBC1D4 protein, rat; D002950:Citrate (si)-Synthase; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D000091162:AMP-Activated Protein Kinase Kinases