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Stanford BIO 230 - Diet-Induced Obesity Causes Severe but Reversible Leptin Resistance in Arcuate Melanocortin Neurons

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Diet-Induced Obesity Causes Severe but Reversible Leptin Resistance in Arcuate Melanocortin NeuronsIntroductionResultsEffects of HFD on Body Composition: Body Weight, Fat Tissue, and Leptin LevelsEffects of HFD on Food IntakePeripheral Leptin Effect on Food Intake and Body Weight after 20 weeks on HFDCentral Leptin Effect after 20 Weeks on HFDHypothalamic Secretion Experiment after 20 or 37 Weeks on HFDPeripheral Leptin Effect on ARH mRNA Expression after 20 Weeks on HFDSynthesis of POMC-Derived Peptides in ARHPeripheral Leptin Effect on ARH Signal Transduction after 20 Weeks on HFDIntegrity of the Melanocortin PathwayRestoration of Leptin Sensitivity after Changing from HFD to Regular ChowDiscussionExperimental ProceduresAnimals: Diet and Experimental ProceduresRadioimmunoassayIntraperitoneal Leptin in Mice before and after 20 or 37 Weeks on HFDIntraperitoneal Melanotan-II in Mice after 20 or 37 Weeks on HFDIntracerebroventricular Leptin/MTII in Mice after 20 Weeks on HFDStatic Incubation of Hypothalamic Explants after 20 or 37 Weeks on HFDImmunohistochemical Studies after 20 Weeks on HFDIn Situ Hybridization after 20 Weeks on HFDMicrodissection and Real-Time PCR after 20 Weeks on HFDGlucose/Insulin Tolerance Tests after 20 or 37 Weeks on HFDHPLC Fractionation and RIAStatistical AnalysisSupplemental DataAcknowledgmentsReferencesCell MetabolismArticleDiet-Induced Obesity Causes Severebut Reversible Leptin Resistancein Arcuate Melanocortin NeuronsPablo J. Enriori,1Anne E. Evans,1Puspha Sinnayah,1Erin E. Jobst,1,4Luciana Tonelli-Lemos,1Sonja K. Billes,1Maria M. Glavas,1Bernadette E. Grayson,1Mario Perello,2Eduardo A. Nillni,2,3Kevin L. Grove,1and Michael A. Cowley1,*1Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton,OR 97006, USA2Division of Endocrinology, Department of Medicine, Brown Medical School/Rhode Island Hospital, Providence, RI 02903, USA3Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02903, USA4School of Physical Therapy, Pacific University, Hillsboro, OR 97123, USA*Correspondence: [email protected] 10.1016/j.cmet.2007.02.004SUMMARYDespite high leptin levels, most obese humansand rodents lack responsiven ess to its appe-tite-suppressing effects. We demonstrate thatleptin modulates NPY/AgRP and a-MSH secre-tion from the ARH of lean mice. High-fat diet-induced obese (DIO) mice have normal ObRblevels and increased SOCS-3 levels, but leptinfails to modulate peptide secretion and any ele-ment of the leptin signaling cascade. Despitethis leptin resistance, the melanocortin systemdownstream of the ARH in DIO mice is over-responsive to melanocortin agonists, probablydue to upregulation of MC4R. Lastly, we showthat by decreasing the fat content of themouse’s diet, leptin responsiveness of NPY/AgRP and POMC neurons recovered simulta-neously, with mice regaining normal leptin sen-sitivity and glycemic control. These resultshighlight the physiological importance of leptinsensing in the melanocortin circuits and showthat their loss of leptin sensing likely contrib-utes to the pathology of leptin resistance.INTRODUCTIONObesity is defined as an excessive amount of body fat inrelation to lean mass of sufficient magnitude to produceadverse health consequenc es. More than 60% of Ameri-can adults are now overweight or obese, and the obesityprevalence in adults and children is growing dramatically(Zamboni et al., 2005). In most adults, body weight is rel-atively constant despite large variations in daily food in-take and energy expenditure. Energy balance is regulatedby neural and hormonal signals that are integrated in thebrain (Seeley and Woods, 2003). Leptin, a hormone se-creted primarily by adipocytes, is present in serum con-centrations directly proportional to the amount of adiposetissue (Considine et al., 1996), signaling to the central ner-vous system (CNS) the relative extent of energy (adipose)stores in the body (Spiegelman and Flier, 2001).Leptin regulates food intake by binding to CNS recep-tors and modulating the activity of neurons in appetitecontrol centers in the brain (de Luca et al., 2005). In obeseleptin-deficient mice, administration of leptin reduces hy-perphagia and obesity. In contrast, obese mice that aredeficient in the leptin receptor (ObRb) do not respond toleptin (Chen et al., 1996; Halaas et al., 1995). Leptin alsoaffects energy expenditure in rodents and humans (Halaaset al., 1995; Rosenbaum et al., 2005). Activation of centralObRb increases sympathetic nervous system activity,which stimulates energy expenditure in adipose tissue(Commins et al., 1999).The arcuate nucleus in the hypothalamus (ARH) is amajor site of leptin sensing (Balthasar et al., 2004; Coppariet al., 2005; Cowley et al., 2001; van den Top et al., 2004).ObRb is highly expressed in the ARH (Elmquist et al.,1998; Schwartz et al., 1996). To access these receptors,peripheral leptin is transported across the blood-brainbarrier to reach areas distal to circumventricular organs(Banks, 2003).The ARH contains at least two key populations of leptin-responsive neurons that have opposite actions on food in-take. One population expresses the anorexigenic peptidea-melanocyte-stimulating hormone (a-MSH), derived fromthe proopiomelanocortin (POMC) precursor. The otherpopulation expresses the orexigenic peptides, neuropep-tide Y (NPY) and agouti-related peptide (AgRP) (Cone,2005). Arcuate neurons subsequently innervate varioussecond-order hypothalamic targets that express melano-cortin-4 receptors (MC4R) and NPY receptors (Liu et al.,2003). Leptin can modulate both POMC and AgRP neu-rons and can promote the release of a-MSH, a potent ano-rexigen at central MC4Rs (Cowley et al., 2001; Elias et al.,1999; Schwartz et al., 1997).Although most obese humans and rodents have veryhigh amounts of circulating leptin, this hyperleptinemianeither reduces appetite nor increases energy expendi-ture. This state has been termed ‘‘leptin resistance.’’ ThereCell Metabolism 5, 181–194, March 2007 ª2007 Elsevier Inc. 181are only rare examples of single-gene mutations responsi-ble for obesity in humans, and the majority of ‘‘normal’’obesity is thought to be a consequence of polygenic inter-action with the environment (Tschop and Heiman, 2001).Two hypotheses proposing mechanistic explanations forleptin resistance have received considerable attention:(1) failure of circulating leptin to reach


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Stanford BIO 230 - Diet-Induced Obesity Causes Severe but Reversible Leptin Resistance in Arcuate Melanocortin Neurons

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