Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2-/-lipodystrophic mice independent of hepatocyte leptin receptors

Víctor A. Cortés, Kelly M. Cautivo, Shunxing Rong, Abhimanyu Garg, Jay D. Horton, Anil K. Agarwal

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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 signifi- cantly, 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. -Cortés, V. A., K. M. Cautivo, S. Rong, A. Garg, J. D. Horton, and A. K. Agarwal. Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2 - / - lipodystrophic mice independent of hepatocyte leptin receptors.

Original languageEnglish (US)
Pages (from-to)276-288
Number of pages13
JournalJournal of lipid research
Volume55
Issue number2
DOIs
StatePublished - Feb 2014

Keywords

  • Acyltransferase
  • Diabetes mellitus
  • Phospholipids

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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