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Stanford BIO 230 - Study Notes

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Divergence of Melanocortin Pathways in the Control of Food Intake and Energy ExpenditureIntroductionResultsGeneration and Validation of loxTB Mc4r MiceReactivation of the loxTB Mc4r AlleleNeuronal Reactivation of Mc4rs in loxTB Mc4r MiceStereotaxic Injections of AAV-Cre in the PVH of loxTB Mc4r MiceGeneration of Sim1-Cre Transgenic MiceAnatomic Assessments of Mc4R mRNA ReexpressionBody-Weight Homeostasis in Sim1-Cre, loxTB Mc4r MiceFood Intake versus Energy Expenditure in Sim1-Cre, loxTB Mc4r MiceMTII Effects in Sim1-Cre, loxTB Mc4r MiceDiscussionGenetically Dissecting Central Melanocortin PathwaysThe Physiological Role of MC4Rs on PVH/Amygdala NeuronsPVH Neurons versus Amygdala NeuronsPresynaptic MC4Rs versus Postsynaptic MC4RsDivergence in Melanocortin Pathways Regulating Food Intake versus Energy ExpenditureExperimental ProceduresGeneration of loxTB Mc4r MiceIn Situ HybridizationImmunohistochemistryBody and Blood CompositionOxygen ConsumptionAAV InjectionsGeneration of Sim1-Cre BAC Transgenic MiceMTII InjectionsStatistical MethodsSupplemental DataAcknowledgmentsReferencesCell, Vol. 123, 493–505, November 4, 2005, Copyright ©2005 by Elsevier Inc. DOI 10.1016/j.cell.2005.08.035Divergence of Melanocortin Pathwaysin the Control of Food Intakeand Energy ExpenditureNina Balthasar,1Louise T. Dalgaard,1Charlotte E. Lee,1Jia Yu,1Hisayuki Funahashi,1Todd Williams,1Manuel Ferreira,1Vinsee Tang,1Robert A. McGovern,1Christopher D. Kenny,1Lauryn M. Christiansen,1Elizabeth Edelstein,1Brian Choi,1Olivier Boss,1Carl Aschkenasi,1Chen-yu Zhang,1Kathleen Mountjoy,4Toshiro Kishi,1,3Joel K. Elmquist,1,2,5,*and Bradford B. Lowell1,5,*1Department of MedicineDivision of Endocrinology2Department of NeurologyProgram in NeuroscienceBeth Israel Deaconess Medical CenterHarvard Medical School99 Brookline AvenueBoston, Massachusetts 022153Department of Anatomy and MorphologicalNeuroscienceShimane University School of MedicineIzumo 693-8501Japan4Department of PhysiologyFaculty of Medical and Health ScienceUniversity of AucklandAuckland 1New ZealandSummaryActivation of melanocortin-4-receptors (MC4Rs) re-duces body fat stores by decreasing food intake andincreasing energy expenditure. MC4Rs are expressedin multiple CNS sites, any number of which could me-diate these effects. To identify the functionally rele-vant sites of MC4R expression, we generated a loxP-modified, null Mc4r allele (loxTB Mc4r) that can bereactivated by Cre-recombinase. Mice homozygousfor the loxTB Mc4r allele do not express MC4Rs andare markedly obese. Restoration of MC4R expressionin the paraventricular hypothalamus (PVH) and a sub-population of amygdala neurons, using Sim1-Cretransgenic mice, prevented 60% of the obesity. Ofnote, increased food intake, typical of Mc4r null mice,was completely rescued while reduced energy expen-diture was unaffected. These findings demonstratethat MC4Rs in the PVH and/or the amygdala controlfood intake but that MC4Rs elsewhere control energyexpenditure. Disassociation of food intake and en-ergy expenditure reveals unexpected divergence inmelanocortin pathways controlling energy balance.*Correspondence: [email protected] (J.K.E.); [email protected] (B.B.L.)5These authors contributed equally to this work.IntroductionThe brain controls fat storage (i.e., energy homeostasis)by regulating food intake and energy expenditure. Sen-sory input is received from the body in the form of cir-culating hormones (leptin, ghrelin, etc.), fuels (glucose,fatty acids, etc.), and vagal afferents from the gut (forreview Saper et al. [2002]). This information is integ-rated with cues from the outside world as well as theemotional state of the organism. The brain then initiatesappropriate alterations in food intake and energy ex-penditure with the ultimate goal of maintaining energybalance. Obesity develops when this system malfunc-tions. Because obesity is linked with serious comorbidi-ties (type 2 diabetes, cardiovascular disease, etc.),there is tremendous interest in understanding the neu-ronal mechanisms by which the brain maintains en-ergy balance.The last decade has seen the identification of a num-ber of proteins that are critical components of this sys-tem. One such protein is the melanocortin-4-receptor(MC4R), a G protein-coupled receptor expressed by anumber of neurons in the brain (Kishi et al., 2003;Mountjoy et al., 1994). The essential role of MC4Rs isevident from the presence of severe obesity in bothgene knockout mice (Huszar et al., 1997) and in humanswith naturally occurring mutations (Vaisse et al., 1998;Yeo et al., 1998). In the case of Mc4r null mice, in whichenergy balance has been studied in great detail, obe-sity has been found to be caused by the combined ef-fects of increased food intake (hyperphagia) and de-creased energy expenditure (Chen et al., 2000; Huszaret al., 1997; Ste Marie et al., 2000). While the impor-tance of MC4R signaling is clear, the neural substrateresponsible for MC4R-mediated regulation of food in-take and energy expenditure is presently unknown.MC4Rs are expressed widely in the central nervoussystem (CNS), including a number of sites that couldplausibly contribute to coordinated control of body-weight homeostasis (Kishi et al., 2003; Liu et al., 2003;Mountjoy et al., 1994).One site of dense MC4R expression is the paraventri-cular nucleus of the hypothalamus (PVH) (Harris et al.,2001; Kishi et al., 2003; Liu et al., 2003; Mountjoy et al.,1994). The PVH is a microcosm of hypothalamic controlas it regulates a variety of neuroendocrine, behavioral,and autonomic functions. The following findings sug-gest an important role for these MC4R-bearing neu-rons. First, the PVH receives strong input from proopio-melanocortin (POMC) and agouti-related peptide (AgRP)neurons, which release the MC4R agonist and antago-nist, α-MSH and AgRP, respectively (Bagnol et al., 1999;Cowley et al., 1999). Second, stereotaxic microinjectionof MC4R ligands into the PVH alters food intake andenergy expenditure (Cowley et al., 1999; Giraudo et al.,1998; Kask and Schioth, 2000). Third, obesity developsin mice and humans heterozygous for a null allele ofSim1 (single-minded 1), a transcription factor that con-trols development of the PVH (Holder et al., 2000;Michaud et al., 1998, 2001). Fourth, the PVH has beenCell494linked with regulation of food intake and energy expen-diture. The link with food intake comes from obser-vations of marked hyperphagia in animals with PVHlesions (Gold, 1973;


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