Mitofusin 2 in POMC Neurons Connects ER Stress with Leptin Resistance and Energy Imbalance

Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain.
Cell (Impact Factor: 32.24). 09/2013; 155(1):172-87. DOI: 10.1016/j.cell.2013.09.003
Source: PubMed


Mitofusin 2 (MFN2) plays critical roles in both mitochondrial fusion and the establishment of mitochondria-endoplasmic reticulum (ER) interactions. Hypothalamic ER stress has emerged as a causative factor for the development of leptin resistance, but the underlying mechanisms are largely unknown. Here, we show that mitochondria-ER contacts in anorexigenic pro-opiomelanocortin (POMC) neurons in the hypothalamus are decreased in diet-induced obesity. POMC-specific ablation of Mfn2 resulted in loss of mitochondria-ER contacts, defective POMC processing, ER stress-induced leptin resistance, hyperphagia, reduced energy expenditure, and obesity. Pharmacological relieve of hypothalamic ER stress reversed these metabolic alterations. Our data establish MFN2 in POMC neurons as an essential regulator of systemic energy balance by fine-tuning the mitochondrial-ER axis homeostasis and function. This previously unrecognized role for MFN2 argues for a crucial involvement in mediating ER stress-induced leptin resistance.

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    • "Mice and Diets C57BL/6J mice were purchased from Harlan Europe. The generation of POMCMfn2KO mice has been previously reported (Schneeberger et al., 2013). Mice were maintained on a 12:12 hr light-dark cycle with free access to water and NCD (Harlan Research Laboratories) or HFD (45% kcal fat; Research Diets) for 4 days (starting at 6 weeks of age). "
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    ABSTRACT: Alterations in ER homeostasis have been implicated in the pathophysiology of obesity and type-2 diabetes (T2D). Acute ER stress induction in the hypothalamus produces glucose metabolism perturbations. However, the neurobiological basis linking hypothalamic ER stress with abnormal glucose metabolism remains unknown. Here, we report that genetic and induced models of hypothalamic ER stress are associated with alterations in systemic glucose homeostasis due to increased gluconeogenesis (GNG) independent of body weight changes. Defective alpha melanocyte-stimulating hormone (α-MSH) production underlies this metabolic phenotype, as pharmacological strategies aimed at rescuing hypothalamic α-MSH content reversed this phenotype at metabolic and molecular level. Collectively, our results posit defective α-MSH processing as a fundamental mediator of enhanced GNG in the context of hypothalamic ER stress and establish α-MSH deficiency in proopiomelanocortin (POMC) neurons as a potential contributor to the pathophysiology of T2D. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 07/2015; 12(3). DOI:10.1016/j.celrep.2015.06.041 · 8.36 Impact Factor
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    • "We also considered the temporal recovery of cellular ATP during refeeding post-fasting, since ATP-derived adenosine reduces synaptic strength and the firing rate of neurons (Chen and van den Pol, 1997; Liu and Gao, 2007; Obrietan et al., 1995; Thompson et al., 1992). The neuronal electrical activities are crucial for orchestrating feeding (Aponte et al., 2011; Atasoy et al., 2012; Kong et al., 2012; Schneeberger et al., 2013). "
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    ABSTRACT: It is well recognized that feeding behavior in mammals is orchestrated by neurons within the medial basal hypothalamus. However, it remains unclear whether food intake is also under the control of glial cells. Here, we combine chemical genetics, cell-type-specific electrophysiology, pharmacology, and feeding assays to show that stimulation of astrocytes within the medial basal hypothalamus reduces both basal- and ghrelin-evoked food intake. This occurs by a mechanism of adenosine-mediated inactivation of the orexigenic agouti-related peptide (AGRP) neurons in the hypothalamic arcuate nucleus (ARC) via adenosine A1 receptors. Our data suggest that glial cells participate in regulating food intake by modulating extracellular levels of adenosine. These findings reveal the existence of a glial relay circuit that controls feeding behavior, one that might serve as a target for therapeutic intervention in the treatment of appetite disorders. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 116(5). DOI:10.1016/j.celrep.2015.04.002 · 8.36 Impact Factor
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    • "bealsosuggestedthatsparingmitochondriamaybeusefulto permitthemtoserveasanautophagosomemembranesourcein nutrientdepletionconditions. Ontheotherhand,inastudyperformedtoevaluatedynamic mitochondrialbehaviorinananimalmodelofCR(micesubmit- tedto40%CRfor6months),proteinsrelatedtomitochondrial fission(Fis1andmitochondrialDrp1)increased,butnochanges weredetectedinproteinsinvolvedinmitochondrialfusion (Mfn1/Mfn2,andOpa1)(Khraiweshetal.,2013)(Figure1E).A significantincreaseinthenumberofmitochondriapercellsas wellasinparametersrelatedtomitochondrialbiogenesiswasalso foundinCRconditions(Nisolietal.,2005;López-Lluchetal., 2006).Giventhatfissionisthepostulatedmechanismformito- chondrialproliferation(Scheffler,2007),theincreaseinFis1and Drp1proteinssupporttheideaofincreasedmitochondrialbio- genesisinCR.Moreover,inamodelofinvitroCR,thegreater numberofmitochondriawaslinkedtoreducedoxygenconsumptionandmembranepotential(López-Lluchetal .,2006).Asit hasbeendemonstratedthatROSproductionbyelectronleak- ageincreasesathighmembranepotential(LambertandMerry, 2004),thedecreasedmembranepotentialfoundinCRconditions isinagreementwiththelowerROSproductionassociatedwith CR.Noteworthy,thelevelsofATPproductionwerenodifferent inCRconditionsvs.control(Khraiweshetal.,2013).Ineffect, CRinducedanincreaseinthenumberofmitochondriacapable tomaintaincriticalATPlevelsinconditionsofdecreasedoxidativestress .ItiswellknownthatCRattenuatesage-dependent oxidativedamageanditiscorrelatedwithanextensionoflife- spaninanimalsaswellaswithpreventionofcanceranddiabetes (SohalandWeindruch,1996;Colmanetal.,2009).Ithasbeen suggestedthattheincreaseinfissionproteinsfoundinCRmay beusefulinremovingdamagedmitochondriaandtosupportthe prolongevityeffectofCR(López-Lluchetal.,2008;Khraiwesh etal.,2013).Thissuggestionseemstobeincontrastwiththe reportthatunopposedmitochondrialfissioninabsenceofmito- chondrialfusioninthemgm1mutantsofS.cerevisiae(yeast "
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