21 research outputs found
Induction of glucose uptake in skeletal muscle by central leptin is mediated by muscle β2-adrenergic receptor but not by AMPK
Leptin increases glucose uptake and fatty acid oxidation (FAO) in red-type skeletal muscle. However, the mechanism remains unknown. We have investigated the role of β2-adrenergic receptor (AR), the major β-AR isoform in skeletal muscle, and AMPK in leptin-induced muscle glucose uptake of mice. Leptin injection into the ventromedial hypothalamus (VMH) increased 2-deoxy-D-glucose (2DG) uptake in red-type skeletal muscle in wild-type (WT) mice accompanied with increased phosphorylation of the insulin receptor (IR) and Akt as well as of norepinephrine (NE) turnover in the muscle. Leptin-induced 2DG uptake was not observed in β-AR-deficient (β-less) mice despite that AMPK phosphorylation was increased in the muscle. Forced expression of β2-AR in the unilateral hind limb of β-less mice restored leptin-induced glucose uptake and enhancement of insulin signalling in red-type skeletal muscle. Leptin increased 2DG uptake and enhanced insulin signalling in red-type skeletal muscle of mice expressing a dominant negative form of AMPK (DN-AMPK) in skeletal muscle. Thus, leptin increases glucose uptake and enhances insulin signalling in red-type skeletal muscle via activation of sympathetic nerves and β2-AR in muscle and in a manner independent of muscle AMPK
Activation of AMPK-Regulated CRH Neurons in the PVH is Sufficient and Necessary to Induce Dietary Preference for Carbohydrate over Fat
Food selection is essential for metabolic homeostasis and is influenced by nutritional state, food palatability, and social factors such as stress. However, the mechanism responsible for selection between a high-carbohydrate diet (HCD) and a high-fat diet (HFD) remains unknown. Here, we show that activation of a subset of corticotropin-releasing hormone (CRH)-positive neurons in the rostral region of the paraventricular hypothalamus (PVH) induces selection of an HCD over an HFD in mice during refeeding after fasting, resulting in a rapid recovery from the change in ketone metabolism. These neurons manifest activation of AMP-activated protein kinase (AMPK) during food deprivation, and this activation is necessary and sufficient for selection of an HCD over an HFD. Furthermore, this effect is mediated by carnitine palmitoyltransferase 1c (CPT1c). Thus, our results identify the specific neurons and intracellular signaling pathway responsible for regulation of the complex behavior of selection between an HCD and an HFD
Mitochondrial UCP2 in the central regulation of metabolism
Uncoupling protein 2 (UCP2) is a mitochondrial anion carrier protein, which uncouples the oxidative phosphorylation from ATP production by dissipating the proton gradient generated across the mitochondrial inner membrane. UCP2 regulates not only mitochondrial ATP production, but also the generation of reactive oxygen species (ROS), considered important second-messenger signals within the cell. The importance of UCP2 was firstly reported in macrophages and pancreatic beta cells. However, several studies have revealed the important role of UCP2 in the Central Nervous System (CNS) in the regulation of homeostatic mechanisms including food intake, energy expenditure, glucose homeostasis and reward behaviors. The mechanisms by which central UCP2 affect these processes seem to be associated with synaptic and mitochondrial plasticity. In this review, we will describe recent findings on central UCP2 and discuss its role in CNS regulation of homeostasis
Distinct effects of leptin and melanocortin agonist in medial hypothalamic nuclei on glucose uptake in peripheral tissues
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UCP2 Regulates Mitochondrial Fission and Ventromedial Nucleus Control of Glucose Responsiveness
The ventromedial nucleus of the hypothalamus (VMH) plays a critical role in regulating systemic glucose homeostasis. How neurons in this brain area adapt to the changing metabolic environment to regulate circulating glucose levels is ill-defined. Here we show that glucose load results in mitochondrial fission and reduced reactive oxygen species in VMH neurons mediated by dynamin-related peptide 1 (DRP1) under the control of uncoupling protein 2 (UCP2). Probed by genetic manipulations and chemical-genetic control of VMH neuronal circuitry, we unmasked that this mitochondrial adaptation determines the size of the pool of glucose-excited neurons in the VMH, and, that this process regulates systemic glucose homoeostasis. Thus, our data unmasked a critical cellular biological process controlled by mitochondrial dynamics in VMH regulation of systemic glucose homeostasis