title: Age-related onset of obesity corresponds with metabolic dysregulation and altered microglia morphology in mice deficient for Ifitm proteins.
abstract: The IfitmDel mouse lacks all five of the Ifitm genes via LoxP deletion. This animal breeds normally with no obvious defect in development. The IfitmDel animals exhibit a steady and significantly enhanced weight gain relative to wild-type controls beginning about three months of age and under normal feeding conditions. The increased weight corresponds with elevated fat mass, and in tolerance tests they are hyporesponsive to insulin but respond normally to glucose. Both young (4 mo) and older (12 mo) IfitmDel mice have enhanced levels of serum leptin suggesting a defect in leptin/leptin receptor signaling. Analysis of the gene expression profiles in the hypothalamus of IfitmDel animals, compared to WT, demonstrated an altered ratio of Pomc and Npy neuropeptide expression, which likely impairs the satiation response of the IfitmDel animal leading to an increased eating behavior. Also elevated in hypothalamus of IfitmDel mice were pro-inflammatory cytokine expression and reduced IL-10. Anatomical analysis of the hypothalamus using immunohistochemistry revealed that microglia exhibit an abnormal morphology in IfitmDel animals and respond abnormally to Poly:IC challenge. These abnormalities extend the phenotype of the IfitmDel mouse beyond abnormal responses to viral challenge to include a metabolic phenotype and weight gain. Further, this novel phenotype for the IfitmDel mouse could be related to abnormal neuropeptide production, inflammatory status and microglia status in the hypothalamus.
authors: Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors: Yin Shen
authors: YS
authors: Wee
authors: Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors: Janis J
authors: JJ
authors: Weis
authors: Geriatric Research, Education and Clinical Center (GRECC), Veterans Affairs Medical Center, Salt Lake City, Utah, United States of America; Department of Internal Medicine, Division of Geriatrics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors: Lorise C
authors: LC
authors: Gahring
authors: Geriatric Research, Education and Clinical Center (GRECC), Veterans Affairs Medical Center, Salt Lake City, Utah, United States of America; Department of Neurobiology and Anatomy, Salt Lake City, Utah, United States of America.
authors: Scott W
authors: SW
authors: Rogers
authors: Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors: John H
authors: JH
authors: Weis
mesh_terms: D017668:Age of Onset; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D007031:Hypothalamus / Q000378:metabolism*; D007150:Immunohistochemistry; D020738:Leptin / Q000097:blood; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D051379:Mice; D017628:Microglia / Q000473:pathology*; D005810:Multigene Family / Q000235:genetics; D009478:Neuropeptide Y / Q000378:metabolism; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D011333:Pro-Opiomelanocortin / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D016207:Cytokines; D020738:Leptin; D009478:Neuropeptide Y; C062010:leu-13 antigen; D011333:Pro-Opiomelanocortin