Leptin Activates Hepatic 5′-AMP-activated Protein Kinase through Sympathetic Nervous System and α1-Adrenergic Receptor

Miyamoto, Licht; Ebihara, Ken; Kusakabe, Toru; Aotani, Daisuke; Yamamoto-Kataoka, Sachiko; Sakai, Toshiyasu; Aizawa-Abe, Megumi; Yamamoto, Yuji; Fujikura, Junji; Hayashi, Tatsuya; Hosoda, Kiminori; Nakao, Kazuwa

doi:10.1074/jbc.m112.384545

Cited by 69 publications

(57 citation statements)

References 38 publications

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“…Novel peptides mimicking the a2 AMPK domain increase the AMPK phosphorylation in the skeletal muscle but not in the liver, which leads to reduced adipose tissue mass and triglyceride levels in the skeletal muscle and increased liver triglyceride levels (44). Furthermore, AMPK activity in skeletal muscle and liver is differentially regulated in lipodystrophic A-ZIP/F-1 mice, in which AMPK activity in the skeletal muscle of A-ZIP/F-1 mice is unchanged, while AMPK activity in liver is reduced (45). In contrast to our results, hemin reduces lipid accumulation in the liver of Zucker rats and db/db mice, which is accompanied with reduced expression of inflammatory cytokine (15,46).…”

Section: Discussionmentioning

confidence: 99%

Hemin Improves Insulin Sensitivity in Skeletal Muscle in High Fat–Fed Mice

Kwon

Kim

et al. 2014

J Pharmacol Sci

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Abstract. The present study examined whether hemin could prevent the development of high-fat diet-induced insulin resistance in the liver and skeletal muscle using a hyperinsulinemic-euglycemic clamp. A four-week high-fat feeding to mice increased the body weight, fat mass, and plasma levels of insulin and lipid, which were reduced by hemin. High-fat diet reduced whole body glucose uptake, which were increased by hemin. Insulin-stimulated hepatic glucose production (HGP) was increased by high-fat diet, but hemin had no significant effect on HGP. Skeletal muscle glucose uptake was reduced by high-fat diet, and hemin normalized the glucose uptake. High-fat diet increased triglyceride levels and mRNA levels of lipogenic enzymes, and decreased mRNA levels of enzymes involved in lipid b-oxidation, which was reversed by hemin. Phosphorylated AMPactivated protein kinase levels were increased in the skeletal muscle of high fat-fed hemin-injected mice. High-fat diet reduced mRNA levels of antioxidant enzymes and increased mRNA levels of inflammatory cytokines and nitrotyrosine levels, which was normalized by hemin in the skeletal muscle. However, hemin had no significant effect on these factors in the liver. These results suggest that hemin prevents the development of high-fat diet-induced insulin resistance by increased insulin sensitivity in the skeletal muscle.

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Section: Discussionmentioning

confidence: 99%

Hemin Improves Insulin Sensitivity in Skeletal Muscle in High Fat–Fed Mice

Kwon

Kim

et al. 2014

J Pharmacol Sci

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“…Because leptin affects 5-AMP-activated protein kinase and FA oxidation in the liver by stimulating the hepatic α 1 -AR, negative feedback regulation of ADRA1 mRNA might occur by the leptin status in the liver of neonatal calves. Therefore, adrenergic effects on hepatic FA oxidation might be mediated by α 1 -and β 2 -AR as well as plasma leptin concentrations (Lafontan and Berlan, 1993;Miyamoto et al, 2012).…”

mentioning

confidence: 99%

Effects of colostrum versus formula feeding on hepatic glucocorticoid and α1- and β2-adrenergic receptors in neonatal calves and their effect on glucose and lipid metabolism

Schäff

Rohrbeck

Steinhoff‐Wagner

et al. 2014

Journal of Dairy Science

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Neonatal energy metabolism in calves has to adapt to extrauterine life and depends on colostrum feeding. The adrenergic and glucocorticoid systems are involved in postnatal maturation of pathways related to energy metabolism and calves show elevated plasma concentrations of cortisol and catecholamines during perinatal life. We tested the hypothesis that hepatic glucocorticoid receptors (GR) and α 1 -and β 2 -adrenergic receptors (AR) in neonatal calves are involved in adaptation of postnatal energy metabolism and that respective binding capacities depend on colostrum feeding. Calves were fed colostrum (CF; n = 7) or a milk-based formula (FF; n = 7) with similar nutrient content up to d 4 of life. Blood samples were taken daily before feeding and 2 h after feeding on d 4 of life to measure metabolites and hormones related to energy metabolism in blood plasma. Liver tissue was obtained 2 h after feeding on d 4 to measure hepatic fat content and binding capacity of AR and GR. Maximal binding capacity and binding affinity were calculated by saturation binding assays using [3 H]-prazosin and [ 3 H]-CGP-12177 for determination of α 1 -and β 2 -AR and [ 3 H]-dexamethasone for determination of GR in liver. Additional liver samples were taken to measure mRNA abundance of AR and GR, and of key enzymes related to hepatic glucose and lipid metabolism. Plasma concentrations of albumin, triacylglycerides, insulin-like growth factor I, leptin, and thyroid hormones changed until d 4 and all these variables except leptin and thyroid hormones responded to feed intake on d 4. Diet effects were determined for albumin, insulin-like growth factor I, leptin, and thyroid hormones. Binding capacity for GR was greater and for α 1 -AR tended to be greater in CF than in FF calves. Binding affinities were in the same range for each receptor type. Gene expression of α 1 -AR (ADRA1) tended to be lower in CF than FF calves. Binding capacity of GR was related to parameters of glucose and lipid metabolism, whereas β 2 -AR binding capacity was negatively associated with glucose metabolism. In conclusion, our results indicate a dependence of GR and α 1 -AR on milk feeding immediately after birth and point to an involvement of hepatic GR and AR in postnatal adaptation of glucose and lipid metabolism in calves.

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“…However, whether these reductions in hepatic and muscle steatosis are secondary to decreased caloric intake and weight loss, or due to a direct effect on fatty acid oxidation in non-adipose tissue, cannot be determined from these studies. Based on recent experimental data in lipodystrophic mice, which showed that increase in 5´-AMP activated protein kinase activity in liver and skeletal muscle after leptin treatment [43], it is likely that leptin exerts its effects by both central and peripheral mechanisms, the relative importance of each needs to be determined by future controlled experiments.…”

Section: Mechanisms Of Leptin Actionmentioning

confidence: 99%

Metreleptin for metabolic disorders associated with generalized or partial lipodystrophy

Simha

2014

Expert Review of Endocrinology & Metabolism

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Lipodystrophy is a group of acquired and inherited disorders characterized by selective loss of adipose tissue. Despite wide genotypic and phenotypic variety, many patients with lipodystrophy have similar metabolic complications including insulin resistance, diabetes mellitus, hypertriglyceridemia and hepatic steatosis. Often, these metabolic abnormalities are severe and difficult to treat with conventional glucose and lipid-lowering therapies. Lack of adipose tissue also results in marked hypoleptinemia, and there has recently been much interest in using leptin-replacement therapy to treat the metabolic complications of lipodystrophy. Administration of metreleptin, the human recombinant leptin analogue, has been shown in prospective, open-label studies to improve glucose control, dyslipidemia and steatohepatitis. This article summarizes the current evidence for the safety and efficacy of leptin-replacement therapy in patients with lipodystrophy.

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Leptin Activates Hepatic 5′-AMP-activated Protein Kinase through Sympathetic Nervous System and α1-Adrenergic Receptor

Cited by 69 publications

References 38 publications

Hemin Improves Insulin Sensitivity in Skeletal Muscle in High Fat–Fed Mice

Hemin Improves Insulin Sensitivity in Skeletal Muscle in High Fat–Fed Mice

Effects of colostrum versus formula feeding on hepatic glucocorticoid and α1- and β2-adrenergic receptors in neonatal calves and their effect on glucose and lipid metabolism

Metreleptin for metabolic disorders associated with generalized or partial lipodystrophy

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