Background: AMPK activation promotes glucose and lipid metabolism. Results: Hepatic AMPK activities were decreased in fatty liver from lipodystrophic mice, and leptin activated the hepatic AMPK via the ␣-adrenergic effect. Conclusion: Leptin improved the fatty liver possibly by activating hepatic AMPK through the central and sympathetic nervous systems. Significance: Hepatic AMPK plays significant roles in the pathophysiology of lipodystrophy and metabolic action of leptin.

Seipin, encoded by BSCL2 gene, is a protein whose physiological functions remain unclear. Mutations of BSCL2 cause the most-severe form of congenital generalized lipodystrophy (CGL). BSCL2 mRNA is highly expressed in the brain and testis in addition to the adipose tissue in human, suggesting physiological roles of seipin in non-adipose tissues. Since we found BSCL2 mRNA expression pattern among organs in rat is similar to human while it is not highly expressed in mouse brain, we generated a Bscl2/seipin knockout (SKO) rat using the method with ENU (N-ethyl-N-nitrosourea) mutagenesis. SKO rats showed total lack of white adipose tissues including mechanical fat such as bone marrow and retro-orbital fats, while physiologically functional brown adipose tissue was preserved. Besides the lipodystrophic phenotypes, SKO rats showed impairment of spatial working memory with brain weight reduction and infertility with azoospermia. We confirmed reduction of brain volume and number of sperm in human patients with BSCL2 mutation. This is the first report demonstrating that seipin is necessary for normal brain development and spermatogenesis in addition to white adipose tissue development.

improves the effect of leptin on insulin sensitivity in leptin-resistant diet-induced obese mice. Am J Physiol Endocrinol Metab 302: E924 -E931, 2012. First published January 24, 2012; doi:10.1152/ajpendo.00198.2011.-Leptin enhances insulin sensitivity in addition to reducing food intake and body weight. Recently, amylin, a pancreatic ␤-cell-derived hormone, was shown to restore a weight-reducing effect of leptin in leptin-resistant dietinduced obesity. However, whether amylin improves the effect of leptin on insulin sensitivity in diet-induced obesity is unclear. Dietinduced obese (DIO) mice were infused with either saline (S), leptin (L; 500 g·kg Ϫ1 ·day Ϫ1 ), amylin (A; 100 g·kg Ϫ1 ·day Ϫ1 ), or leptin plus amylin (L/A) for 14 days using osmotic minipumps. Food intake, body weight, metabolic parameters, tissue triglyceride content, and AMP-activated protein kinase (AMPK) activity were examined. Pairfeeding and weight-matched calorie restriction experiments were performed to assess the influence of food intake and body weight reduction. Continuous L/A coadministration significantly reduced food intake, increased energy expenditure, and reduced body weight, whereas administration of L or A alone had no effects. L/A coadministration did not affect blood glucose levels during ad libitum feeding but decreased plasma insulin levels significantly (by 48%), suggesting the enhancement of insulin sensitivity. Insulin tolerance test actually showed the increased effect of insulin in L/A-treated mice. In addition, L/A coadministration significantly decreased tissue triglyceride content and increased AMPK␣2 activity in skeletal muscle (by 67%). L/A coadministration enhanced insulin sensitivity more than pairfeeding and weight-matched calorie restriction. In conclusion, this study demonstrates the beneficial effect of L/A coadministration on glucose and lipid metabolism in DIO mice, indicating the possible clinical usefulness of L/A coadministration as a new antidiabetic treatment in obesity-associated diabetes. obesity; diabetes; adenosine 5=-monophosphate-activated protein kinase LEPTIN, AN ADIPOCYTE-DERIVED HORMONE, has a weight-reducing effect accompanied by reduction in food intake and increase in energy expenditure (11,13). In general, in rodent models of diet-induced obesity and obese human, although leptin levels rise proportionally with adiposity (16, 23), the increased leptin fails to suppress the progression of obesity. Moreover, even high pharmacological doses of leptin have demonstrated only marginal, if any, effects on body weight in diet-induced obese (DIO) rodents and obese humans (8,15). This leptin ineffectiveness is called leptin resistance.Recently, it was shown that amylin, a pancreatic ␤-cellderived hormone (4), restored a weight-reducing effect of leptin and that leptin/amylin coadministration effectively reduced body weight in DIO rats (34). Moreover, in overweight/ obese humans, coadministration of the amylin analog pramlintide and the leptin analog metreleptin induced significantly greater weight ...

Leptin is one of the key molecules in maintaining energy homeostasis. Although genetically leptin-deficient Lep(ob)/Lep(ob) mice have greatly contributed to elucidating leptin physiology, the use of more than one species can improve the accuracy of analysis results. Using the N-ethyl-N-nitrosourea mutagenesis method, we generated a leptin-deficient Lep(mkyo)/Lep(mkyo) rat that had a nonsense mutation (Q92X) in leptin gene. Lep(mkyo)/Lep(mkyo) rats showed obese phenotypes including severe fatty liver, which were comparable to Lep(ob)/Lep(ob) mice. To identify genes that respond to leptin in the liver, we performed microarray analysis with Lep(mkyo)/Lep(mkyo) rats and Lep(ob)/Lep(ob) mice. We sorted out genes whose expression levels in the liver of Lep(mkyo)/Lep(mkyo) rats were changed from wild-type (WT) rats and were reversed toward WT rats by leptin administration. In this analysis, livers were sampled for 6 h, a relatively short time after leptin administration to avoid the secondary effect of metabolic changes such as improvement of fatty liver. We did the same procedure in Lep(ob)/Lep(ob) mice and selected genes whose expression patterns were common in rat and mouse. We verified their gene expressions by real-time quantitative PCR. Finally, we identified eight genes that primarily respond to leptin in the liver commonly in rat and mouse. These genes might be important for the effect of leptin in the liver.

restores the insulinotropic effect of exenatide in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and high-fat diet. Am J Physiol Endocrinol Metab 307: E712-E719, 2014. First published August 26, 2014; doi:10.1152/ajpendo.00272.2014.-Leptin may reduce pancreatic lipid deposition, which increases with progression of obesity and can impair ␤-cell function. The insulinotropic effect of glucagon-like peptide-1 (GLP-1) and the efficacy of GLP-1 receptor agonist are reduced associated with impaired ␤-cell function. In this study, we examined whether leptin could restore the efficacy of exenatide, a GLP-1 receptor agonist, in type 2 diabetes with increased adiposity. We chronically administered leptin (500 g·kg Ϫ1 ·day Ϫ1 ) and/or exenatide (20 g·kg Ϫ1 ·day Ϫ1 ) for 2 wk in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and highfat diet (STZ/HFD mice). The STZ/HFD mice exhibited hyperglycemia, overweight, increased pancreatic triglyceride level, and reduced glucose-stimulated insulin secretion (GSIS); moreover, the insulinotropic effect of exenatide was reduced. However, leptin significantly reduced pancreatic triglyceride level, and adding leptin to exenatide (LEP/EX) remarkably enhanced GSIS. These results suggested that the leptin treatment restored the insulinotropic effect of exenatide in the mice. In addition, LEP/EX reduced food intake, body weight, and triglyceride levels in the skeletal muscle and liver, and corrected hyperglycemia to a greater extent than either monotherapy. The pair-feeding experiment indicated that the marked reduction of pancreatic triglyceride level and enhancement of GSIS by LEP/EX occurred via mechanisms other than calorie restriction. These results suggest that leptin treatment may restore the insulinotropic effect of exenatide associated with the reduction of pancreatic lipid deposition in type 2 diabetes with increased adiposity. Combination therapy with leptin and exenatide could be an effective treatment for patients with type 2 diabetes with increased adiposity. drug therapy; combination; insulin secretion LEPTIN, AN ADIPOCYTE-DERIVED hormone, has therapeutic potential for treating diabetes and obesity (7, 13 19, 27, 32, 34). In our previous clinical trial in patients with lipodystrophy (6), we confirmed the therapeutic usefulness of leptin as a glucose-lowering agent, and it was first approved for the treatment of lipodystrophy in Japan in March 2013. Given these glucoregulatory effects of leptin, we and others have reported the therapeutic usefulness of leptin for various forms of diabetes, including type 2 diabetes, in rodent models (20,23,26,28,47). The glucoregulatory effects of leptin are associated with the reduction of ectopic lipid deposition, which increases with progression of obesity (36,39,46). The reduction of ectopic lipid deposition in the liver and skeletal muscle could improve insulin sensitivity (42). In the pancreas, the reduction of ectopic lipid deposition could improve ␤-cell function ...