Central Melanocortin Signaling Restores Skeletal Muscle AMP-Activated Protein Kinase Phosphorylation in Mice Fed a High-Fat Diet

Tanaka, Tomohiro; Masuzaki, Hiroaki; Yasue, Shintaro; Ebihara, Ken; Shiuchi, Tetsuya; Ishii, Takako; Arai, Naoki; Hirata, Masakazu; Yamamoto, Hiroshi; Hayashi, Tatsuya; Hosoda, Kiminori; Minokoshi, Yasuhiko; Nakao, Kazuwa

doi:10.1016/j.cmet.2007.04.004

Cited by 57 publications

(56 citation statements)

References 34 publications

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“…The CNS-mediated activation of AMPK involves the stimulation of ␣-adrenergic signaling (336) and is dependent on the melanocortin (MC) system, since intracerebroventricular delivery of an MC4 receptor antagonist inhibits leptin activation of AMPK in skeletal muscle while a melanocortin agonist increases AMPK (487). Contrary to the situation in muscle, leptin administration results in suppression of AMPK activity in the paraventricular and arcuate sections of the hypothalamus (15,335).…”

Section: Leptinmentioning

confidence: 99%

AMPK in Health and Disease

Steinberg¹,

Kemp²

2009

Physiological Reviews

1,443

1,419

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The function and survival of all organisms is dependent on the dynamic control of energy metabolism, when energy demand is matched to energy supply. The AMP-activated protein kinase (AMPK) αβγ heterotrimer has emerged as an important integrator of signals that control energy balance through the regulation of multiple biochemical pathways in all eukaryotes. In this review, we begin with the discovery of the AMPK family and discuss the recent structural studies that have revealed the molecular basis for AMP binding to the enzyme's γ subunit. AMPK's regulation involves autoinhibitory features and phosphorylation of both the catalytic α subunit and the β-targeting subunit. We review the role of AMPK at the cellular level through examination of its many substrates and discuss how it controls cellular energy balance. We look at how AMPK integrates stress responses such as exercise as well as nutrient and hormonal signals to control food intake, energy expenditure, and substrate utilization at the whole body level. Lastly, we review the possible role of AMPK in multiple common diseases and the role of the new age of drugs targeting AMPK signaling.

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Section: Leptinmentioning

confidence: 99%

AMPK in Health and Disease

Steinberg¹,

Kemp²

2009

Physiological Reviews

1,443

1,419

View full text Add to dashboard Cite

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“…Liver and skeletal muscle triacylglycerol content Tissue triacylglycerol content was measured as described previously [7,8], with modifications. Liver and quadriceps muscle were isolated at the end of the leptin infusion experiment, immediately frozen in liquid nitrogen and lipids extracted with isopropyl alcohol/heptane (1:1 vol./vol.).…”

Section: Leptin Infusion Experimentsmentioning

confidence: 99%

“…We previously generated transgenic skinny mice (LepTg) overexpressing leptin under the control of the liver-specific human serum amyloid P component promoter [6]. LepTg mice showed elevated plasma leptin levels comparable to those of obese human individuals, providing a unique experimental model to investigate various actions of leptin [6][7][8][9][10][11]. LepTg mice exhibited increased glucose metabolism and insulin sensitivity with augmented liver and skeletal muscle insulin receptor signalling [6].…”

Section: Introductionmentioning

confidence: 99%

“…LepTg mice also exhibited increased lipid metabolism accompanied by increased lipoprotein lipase activity and clearance of triacylglycerol [7]. In addition, LepTg mice had reduced tissue triacylglycerol content along with increased energy expenditure through augmented phosphorylation of AMP-activated protein kinase (AMPK), a key enzyme that mediates the leptin effect on fatty acid β-oxidation in skeletal muscle [8,9]. Therefore, these findings led us to hypothesise that leptin acts as a glucose-lowering drug with a lipid-lowering effect in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and a high-fat diet

et al. 2009

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Aims/hypothesisWe have previously demonstrated the therapeutic usefulness of leptin in lipoatrophic diabetes and insulin-deficient diabetes in mouse models and could also demonstrate its dramatic effects on lipoatrophic diabetes in humans. The aim of the present study was to explore the therapeutic usefulness of leptin in a mouse model of type 2 diabetes with increased adiposity. Methods To generate a mouse model mimicking human type 2 diabetes with increased adiposity, we used a combination of low-dose streptozotocin (STZ, 120 μg/g body weight) and high-fat diet (HFD, 45% of energy as fat). Recombinant mouse leptin was infused chronically (20 ng [g body weight] −1 h −1 ) for 14 days using a mini-osmotic pump. The effects of leptin on food intake, body weight, metabolic variables, tissue triacylglycerol content and AMP-activated protein kinase (AMPK) activity were examined. Results Low-dose STZ injection led to a substantial reduction of plasma insulin levels and hyperglycaemia. Subsequent HFD feeding increased adiposity and induced insulin resistance and further augmentation of hyperglycaemia. In this model mouse mimicking human type 2 diabetes (STZ/HFD), continuous leptin infusion reduced food intake and body weight and improved glucose and lipid metabolism with enhancement of insulin sensitivity. Leptin also decreased liver and skeletal muscle triacylglycerol content accompanied by an increase of α2 AMPK activity in skeletal muscle. Pairfeeding experiments demonstrated that leptin improved glucose and lipid metabolism independently of the food intake reduction. Conclusions/interpretation This study demonstrates the beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity, indicating the possible clinical usefulness of leptin as a new glucose-lowering drug in humans.

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“…3). Intravenous injection of leptin induced a biphasic effect on the activity of AMPK containing the α2 catalytic subunit (α2 AMPK) in red-type skeletal muscle such as the soleus, with a twofold increase being apparent at ~15 min, a return to baseline by 60 min, and a second twofold increase at 6 h. Injection of leptin into the medial hypothalamus including the VMH and ARC also increased the activity of α2 AMPK in red-type skeletal muscle, with this effect peaking at 1 h and persisting for up to 6 h. The activity of α1 AMPK in soleus muscle was not affected MCR in the brain participates in the hypothalamic effect of leptin on α2 AMPK activity in soleus muscle 33) . An icv injection of the MCR agonist MT-II thus activated AMPK in muscle, whereas the MCR antagonist SHU9119 blunted the effect of leptin.…”

Section: Leptin Regulates Insulin Sensitivity In Skeletal Muscle and mentioning

confidence: 86%

Hypothalamic control of glucose and lipid metabolism in skeletal muscle

Minokoshi

2017

JPFSM

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The hypothalamus controls glucose and lipid metabolism in peripheral tissues.Recent studies have revealed that the ventromedial hypothalamus (VMH) and arcuate nucleus (ARC) of the hypothalamus play an important role in the regulation of glucose and lipid metabolism in skeletal muscle and the liver. The fat-derived hormone leptin was thus shown to stimulate glucose uptake and fatty acid oxidation in red-type skeletal muscle by activating VMH neurons -likely mediated in part by augmentation of synaptic plasticity between leptin receptor and proopiomelanocortin (POMC)-expressing neurons in the ARC and melanocortin receptor (MCR)-expressing VMH neurons -and consequent activation of sympathetic nerves innervating the muscle tissue. The VMH -sympathetic nerve axis was also found to be activated by orexin-positive neurons in mediation of hedonic feeding-induced glucose uptake in redtype skeletal muscle. The effects of orexin and leptin on glucose metabolism in skeletal muscle are interconnected with those of insulin, with the action of VMH also being necessary for the beneficial effects of exercise on metabolism. Leptin ameliorates diabetic phenotypes in animals with uncontrolled insulin-deficient diabetes as well as in patients with or animal models of lipodystrophy through the central nervous system (CNS). Finally, a single injection of fibroblast growth factor 1 (FGF1) into the lateral ventricle was shown to induce sustained remission of hyperglycemia in several animal models of type 2 diabetes, at least in part by increasing glucose uptake in skeletal muscle. The CNS thus plays an important role in the control of glucose and lipid metabolism, with the VMH as well as POMC neurons being implicated as key regulators of such metabolism in skeletal muscle.

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Central Melanocortin Signaling Restores Skeletal Muscle AMP-Activated Protein Kinase Phosphorylation in Mice Fed a High-Fat Diet

Cited by 57 publications

References 34 publications

AMPK in Health and Disease

AMPK in Health and Disease

Beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and a high-fat diet

Hypothalamic control of glucose and lipid metabolism in skeletal muscle

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