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.
Highlights
Leptin is essential for energy homeostasis and regulation of food intake
Leptin did not reverse the lack of macroscopic white and brown adipose tissue in the Agpat2Ϫ/Ϫ mice, but it resulted in significant reduction of food intake in the Agpat2Ϫ/Ϫ mice
Since metabolic changes in the Agpat2Ϫ/Ϫ mice could entirely be dependent on reductions in energy intake, a group of Agpat2Ϫ/Ϫ mice was infused with saline and their food intake was restricted to the level of Agpat2Ϫ/Ϫ leptin-infused mice (Fig. 1G)
Summary
Animals Generation of Agpat2Ϫ/Ϫ mouse and genotyping is described elsewhere [25]. Animals were euthanized at the end of the dark cycle by isoflurane overdose; blood and tissues were harvested in less than 1 min. At the end of the fourth week, the animals were euthanized and blood and liver were harvested for analysis. Individual animals were housed in calorimetric cages (CLAMS, Columbus Instruments, Columbus, OH) and allowed to acclimate for one week. Osmotic minipumps, filled either with leptin (1 mg/ml, n = 6) or a saline solution (PBS, n = 6), were implanted in Agpat2Ϫ/Ϫ mice at the beginning of the second week. In the three weeks, food access was unlimited for the leptin-treated mice, whereas it was limited for the saline-infused ones. Q-PCR expression levels were normalized to the expression level of cyclophilin and the fold change was estimated by the ⌬⌬CT method
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