title: Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2-/- lipodystrophic mice independent of hepatocyte leptin receptors.
abstract: Leptin is essential for energy homeostasis and regulation of food intake. Patients with congenital generalized lipodystrophy (CGL) due to mutations in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) and the CGL murine model (Agpat2(-/-) mice) both have severe insulin resistance, diabetes mellitus, hepatic steatosis, and low plasma leptin levels. In this study, we show that continuous leptin treatment of Agpat2(-/-) mice for 28 days reduced plasma insulin and glucose levels and normalized hepatic steatosis and hypertriglyceridemia. Leptin also partially, but significantly, reversed the low plasma thyroxine and high corticosterone levels found in Agpat2(-/-) mice. Levels of carbohydrate response element binding protein (ChREBP) were reduced, whereas lipogenic gene expression were increased in the livers of Agpat2(-/-) mice, suggesting that deregulated ChREBP contributed to the development of fatty livers in these mice and that this transcription factor is a target of leptin's beneficial metabolic action. Leptin administration did not change hepatic fatty acid oxidation enzymes mRNA levels in Agpat2(-/-) mice. The selective deletion of leptin receptors only in hepatocytes did not prevent the positive metabolic actions of leptin in Agpat2(-/-) mice, supporting the notion that the majority of metabolic actions of leptin are dependent on its action in nonhepatocyte cells and/or the central nervous system.
authors.affiliation: Department of Molecular Genetics, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Víctor A
authors.initials: VA
authors.lastname: Cortés
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Cautivo
authors.forename: Shunxing
authors.initials: S
authors.lastname: Rong
authors.forename: Abhimanyu
authors.initials: A
authors.lastname: Garg
authors.forename: Jay D
authors.initials: JD
authors.lastname: Horton
authors.forename: Anil K
authors.initials: AK
authors.lastname: Agarwal
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D003345:Corticosterone / Q000097:blood; D005227:Fatty Acids / Q000096:biosynthesis / Q000378:metabolism; D005234:Fatty Liver / Q000097:blood / Q000150:complications* / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D007333:Insulin Resistance; D020738:Leptin / Q000494:pharmacology*; D008060:Lipodystrophy / Q000150:complications*; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013974:Thyroxine / Q000097:blood; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D005227:Fatty Acids; D020738:Leptin; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D054411:Receptors, Leptin; D014157:Transcription Factors; D014280:Triglycerides; D006003:Glycogen; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose; D013974:Thyroxine; D003345:Corticosterone
keywords: acyltransferase; diabetes mellitus; phospholipids