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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Available from: Rubén Nogueiras
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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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    • "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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