Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity

Parton, Laure E; Ye, Chianping; Coppari, Roberto; Enriori, Pablo J.; Choi, Brian; Zhang, Chenyu; Xu, Chun; Vianna, Cláudia Pereira; Balthasar, Nina; Lee, Charlotte E.; Elmquist, Joel K.; Cowley, Michael A.; Lowell, Bradford B.

doi:10.1038/nature06098

Cited by 624 publications

(591 citation statements)

References 30 publications

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“…For instance, a recent study reported that transgenic expression in POMC neurons of a constitutively active Kir6.2 subunit, which generates K ATP channels that can no longer be regulated by glucose, led to complete unresponsiveness of these neurons to elevations in extracellular glucose concentration. 89 The feeding behavior of these mice was however normal, suggesting that glucose sensing by these cells was not critical for the physiological control of feeding. The metabolic sensor AMP-activated kinase, which is activated by low glucose concentrations, may also participate in the control by glucose of feeding through a regulation of the melanocortin pathway.…”

Section: Feeding Controlmentioning

confidence: 92%

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

Thorens

2008

Int J Obes

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The control of body weight and of blood glucose concentrations depends on the exquisite coordination of the function of several organs and tissues, in particular the liver, muscle and fat. These organs and tissues have major roles in the use and storage of nutrients in the form of glycogen or triglycerides and in the release of glucose or free fatty acids into the blood, in periods of metabolic needs. These mechanisms are tightly regulated by hormonal and nervous signals, which are generated by specialized cells that detect variations in blood glucose or lipid concentrations. The hormones insulin and glucagon not only regulate glycemic levels through their action on these organs and the sympathetic and parasympathetic branches of the autonomic nervous system, which are activated by glucose or lipid sensors, but also modulate pancreatic hormone secretion and liver, muscle and fat glucose and lipid metabolism. Other signaling molecules, such as the adipocyte hormones leptin and adiponectin, have circulating plasma concentrations that reflect the level of fat stored in adipocytes. These signals are integrated at the level of the hypothalamus by the melanocortin pathway, which produces orexigenic and anorexigenic neuropeptides to control feeding behavior, energy expenditure and glucose homeostasis. Work from several laboratories, including ours, has explored the physiological role of glucose as a signal that regulates these homeostatic processes and has tested the hypothesis that the mechanism of glucose sensing that controls insulin secretion by the pancreatic beta-cells is also used by other cell types. I discuss here evidence for these mechanisms, how they integrate signals from other nutrients such as lipids and how their deregulation may initiate metabolic diseases.

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Section: Feeding Controlmentioning

confidence: 92%

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

Thorens

2008

Int J Obes

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“…In addition, peripheral hyperglycemia in rats increased hypothalamic glucose levels and suppressed EGP, whereas inhibiting central metabolism of lactate partially abolished suppression of EGP by hyperglycemia (16). Further studies showed that transgenic mice with impaired glucose sensing by pro-opiomelanocortin (POMC) neurons due to expression of a mutant Kir6.2 subunit developed impaired glucose tolerance (18). Additionally, obese mice on a high fat diet developed similarly impaired firing of POMC neurons in response to glucose (19).…”

Section: Evidence For Cns Nutrient and Hormone Sensing In Animalsmentioning

confidence: 99%

Evidence for Central Regulation of Glucose Metabolism

Carey

Kehlenbrink

Hawkins

2013

Journal of Biological Chemistry

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Evidence for central regulation of glucose homeostasis is accumulating from both animal and human studies. Central nutrient and hormone sensing in the hypothalamus appears to coordinate regulation of whole body metabolism. Central signals activate ATP-sensitive potassium (K ATP ) channels, thereby down-regulating glucose production, likely through vagal efferent signals. Recent human studies are consistent with this hypothesis. The contributions of direct and central inputs to metabolic regulation are likely of comparable magnitude, with somewhat delayed central effects and more rapid peripheral effects. Understanding central regulation of glucose metabolism could promote the development of novel therapeutic approaches for such metabolic conditions as diabetes mellitus.The estimated global prevalence of Type 2 diabetes (T2DM) 2 is 347 million (1). Because glycemic control is achieved in only ϳ40% of patients, additional therapeutic strategies are needed (2). Increased endogenous glucose production (EGP) is the main source of fasting hyperglycemia (3, 4), contributing ϳ80% of diurnal hyperglycemia in T2DM (5). Apart from insulin, there is no treatment targeting basal EGP. Better understanding its regulation would have important therapeutic implications. We will examine the evidence for central sensing of nutritional and hormonal signals in animal models and humans, focusing on CNS regulation of glucose metabolism. Evidence for CNS Nutrient and Hormone Sensing in AnimalsUnlike other organs, the brain is an obligate consumer of glucose (6). Central regulation of EGP would therefore be teleologically advantageous. Since the first demonstration by Claude Bernard (7) that lesions in the floor of the fourth ventricle altered blood glucose levels, the ability of central glucose sensing to regulate peripheral glucose homeostasis has been extensively examined in animal models. There are glucosesensing neurons in many areas of the brain (8), particularly the hypothalamus (9). Specifically, the ventromedial hypothalamus (VMH) and arcuate nucleus (10) integrate hormonal and nutrient signals impacting peripheral metabolism (Fig. 1). Central signals appear to activate hypothalamic ATP-sensitive potassium (K ATP ) channels (9,11,12) composed of an inward rectifier potassium ion channel Kir6.2 subunit and a sulfonylurea receptor (SUR) subunit. Pharmacologic compounds including diazoxide activate and thereby close hypothalamic K ATP channels, whereas sulfonylureas inhibit and thereby open them, ultimately modulating EGP (12).Glucose-Elegant studies in rats showed that direct infusion of D-glucose into the VMH inhibited counterregulatory hormonal responses to systemic hypoglycemia during a hypoglycemic clamp, indicating that VMH glucose sensing is needed for the systemic response to peripheral hypoglycemia (13). VMH infusion of L-lactate, a byproduct of glucose metabolism and an alternate fuel source for neurons in conditions of glucose deficiency, produced similar suppression of the counterregulatory hormonal response to systemic...

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“…The original Ucp2 −/− mouse, established on a mixed 129/SVJ × C57BL/6 background [11], exhibited increased glucose tolerance and increased GSIS. Part of this phenotype may have been caused by improved glucose responsiveness, as UCP2 is also involved in the response to glucose in pro-opiomelanocortin (POMC) neurons [25], but the main mechanism behind the improved glucose tolerance phenotype in these UCP2-deficient mice was proposed to occur in the β-cells. In contrast, when this global Ucp2 −/− strain was recently backcrossed onto three different genetic backgrounds, GSIS was not stimulated [26].…”

Section: Uncoupling Proteins and Gsis In Micementioning

confidence: 99%

Mitochondrial uncoupling protein 2 in pancreatic β‐cells

Brand

Parker

Affourtit

et al. 2010

Diabetes Obesity Metabolism

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Pancreatic β-cells have remarkable bioenergetics in which increased glucose supply upregulates the cytosolic ATP/ADP ratio and increases insulin secretion. This arrangement allows glucose-stimulated insulin secretion (GSIS) to be regulated by the coupling efficiency of oxidative phosphorylation. Uncoupling protein 2 (UCP2) modulates coupling efficiency and may regulate GSIS. Initial measurements of GSIS and glucose tolerance in Ucp2 −/− mice supported this model, but recent studies show confounding effects of genetic background. Importantly, however, the enhancement of GSIS is robustly recapitulated with acute UCP2 knockdown in INS-1E insulinoma cells. UCP2 protein level in these cells is dynamically regulated, over at least a fourfold concentration range, by rapid proteolysis (half-life less than 1 h) opposing regulated gene transcription and mRNA translation. Degradation is catalysed by the cytosolic proteasome in an unprecedented pathway that is currently known to act only on UCP2 and UCP3. Evidence for proteasomal turnover of UCP2 includes sensitivity of degradation to classic proteasome inhibitors in cells, and reconstitution of degradation in vitro in mitochondria incubated with ubiquitin and the cytosolic 26S proteasome. These dynamic changes in UCP2 content may provide a fine level of control over GSIS in β-cells. Keywords: glucose-stimulated insulin secretion, INS-1E cells, mitochondria, proteasome, protein degradation, turnover, UCP2, UCP3 Date submitted 25 March 2010; date of final acceptance 24 April 2010 IntroductionThe energy metabolism of pancreatic β-cells is extraordinary. Nearly all other mammalian cells rigorously regulate their bioenergetics using internal cues, and only take up fuels when they need them for oxidation and energy release or for storage. Pancreatic β-cells work the other way round, and use fuel supply to regulate their ATP production and cytosolic ATP/ADP ratio.A skeletal muscle cell, for example, will take up glucose from the bloodstream through a plasma membrane glucose transporter, glucose transporter type 4 (GLUT4), when insulin is high and glucose is abundant, otherwise it will use fatty acids as fuel [1]. It will store glucose as glycogen when insulin and ATP are high and calcium (the trigger for muscle contraction and energy demand) is low. Even after glucose enters the cytoplasm, a muscle cell will allow it to enter glycolysis only when that cell requires energy. Glucose 6-phosphate is a non-competitive inhibitor of muscle hexokinase, so when ATP is sufficiently high, glycolysis stalls, glucose 6-phosphate builds up, hexokinase activity is inhibited and glucose metabolism slows. When more ATP is needed because of internal ATP demand, phosphofructokinase and pyruvate kinase are activated, glucose 6-phosphate levels fall and hexokinase channels glucose into glycolysis and to the mitochondria. The mitochondrial electron transport chain pumps protons across the mitochondrial inner membrane, restoring a high protonmotive force and ATP production, until ATP rises and oxidativ...

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Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity

Cited by 624 publications

References 30 publications

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

Evidence for Central Regulation of Glucose Metabolism

Mitochondrial uncoupling protein 2 in pancreatic β‐cells

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