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

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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

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Leptin Receptors
Leptin
Insulin Resistance
Hepatocytes
Insulin
Liver
Congenital Generalized Lipodystrophy
Response Elements
Plasmas
1-Acylglycerol-3-Phosphate O-Acyltransferase
Carrier Proteins
Carbohydrates
Appetite Regulation
Hypertriglyceridemia
Neurology
Fatty Liver
Medical problems
Corticosterone
Thyroxine
Gene expression

Keywords

  • Acyltransferase
  • Diabetes mellitus
  • Phospholipids

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

Cite this

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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 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. -Cort{\'e}s, 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.",
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T1 - Leptin ameliorates insulin resistance and hepatic steatosis in Agpat2-/-lipodystrophic mice independent of hepatocyte leptin receptors

AU - Cortés, Víctor A.

AU - Cautivo, Kelly M.

AU - Rong, Shunxing

AU - Garg, Abhimanyu

AU - Horton, Jay D.

AU - Agarwal, Anil K.

PY - 2014/2

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N2 - 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.

AB - 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.

KW - Acyltransferase

KW - Diabetes mellitus

KW - Phospholipids

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