title: Postnatal ablation of POMC neurons induces an obese phenotype characterized by decreased food intake and enhanced anxiety-like behavior.
abstract: Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus are central components of systems regulating appetite and energy homeostasis. Here we report on the establishment of a mouse model in which the ribonuclease III ribonuclease Dicer-1 has been specifically deleted from POMC-expressing neurons (POMC(ΔDCR)), leading to postnatal cell death. Mice are born phenotypically normal, at the expected genetic ratio and with normal hypothalamic POMC-mRNA levels. At 6 weeks of age, no POMC neurons/cells could be detected either in the arcuate nucleus or in the pituitary of POMC(ΔDCR) mice. POMC(ΔDCR) develop progressive obesity secondary to decreased energy expenditure but unrelated to food intake, which was surprisingly lower than in control mice. Reduced expression of AgRP and ghrelin receptor in the hypothalamus and reduced uncoupling protein 1 expression in brown adipose tissue can potentially explain the decreased food intake and decreased heat production, respectively, in these mice. Fasting glucose levels were dramatically elevated in POMC(ΔDCR) mice and the glucose tolerance test revealed marked glucose intolerance in these mice. Secondary to corticotrope ablation, basal and stress-induced corticosterone levels were undetectable in POMC(ΔDCR) mice. Despite this lack of activation of the neuroendocrine stress response, POMC(ΔDCR) mice exhibited an anxiogenic phenotype, which was accompanied with elevated levels of hypothalamic corticotropin-releasing factor and arginine-vasopressin transcripts. In conclusion, postnatal ablation of POMC neurons leads to enhanced anxiety and the development of obesity despite decreased food intake and glucocorticoid deficiency.
authors.affiliation: Institute of Endocrinology, Metabolism, and Hypertension, Tel Aviv-Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Yona
authors.initials: Y
authors.lastname: Greenman
authors.forename: Yael
authors.initials: Y
authors.lastname: Kuperman
authors.forename: Yonat
authors.initials: Y
authors.lastname: Drori
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
authors.forename: Inbal
authors.initials: I
authors.lastname: Navon
authors.forename: Oren
authors.initials: O
authors.lastname: Forkosh
authors.forename: Shosh
authors.initials: S
authors.lastname: Gil
authors.forename: Naftali
authors.initials: N
authors.lastname: Stern
authors.forename: Alon
authors.initials: A
authors.lastname: Chen
mesh_terms: D050154:Adiposity; D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000378:metabolism* / Q000473:pathology*; D001481:Basal Metabolism; D001522:Behavior, Animal; D001835:Body Weight; D052680:Corticotrophs / Q000378:metabolism / Q000473:pathology; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000473:pathology; D004435:Eating; D020869:Gene Expression Profiling; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009765:Obesity / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D043244:Ribonuclease III / Q000378:metabolism
chemical_list: D011333:Pro-Opiomelanocortin; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases