title: Leptin Resistance Contributes to Obesity in Mice with Null Mutation of Carcinoembryonic Antigen-related Cell Adhesion Molecule 1.
abstract: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes hepatic insulin clearance. Consistently, mice with null mutation of Ceacam1 (Cc1(-/-)) exhibit impaired insulin clearance with increased lipid production in liver and redistribution to white adipose tissue, leading to visceral obesity at 2 months of age. When the mutation is propagated on the C57/BL6J genetic background, total fat mass rises significantly with age, and glucose intolerance and systemic insulin resistance develop at 6 months of age. This study was carried out to determine the mechanisms underlying the marked increase in total fat mass in 6-month-old mutants. Indirect calorimetry analysis showed that Cc1(-/-) mice develop hyperphagia and a significant reduction in physical activity, in particular in the early hours of the dark cycle, during which energy expenditure is only slightly lower than in wild-type mice. They also exhibit increased triglyceride accumulation in skeletal muscle, due in part to incomplete fatty acid β-oxidation. Mechanistically, hypothalamic leptin signaling is reduced, as demonstrated by blunted STAT3 phosphorylation in coronal sections in response to an intracerebral ventricular injection of leptin. Hypothalamic fatty-acid synthase activity is also elevated in the mutants. Together, the data show that the increase in total fat mass in Cc1(-/-) mice is mainly attributed to hyperphagia and reduced spontaneous physical activity. Although the contribution of the loss of CEACAM1 from anorexigenic proopiomelanocortin neurons in the arcuate nucleus is unclear, leptin resistance and elevated hypothalamic fatty-acid synthase activity could underlie altered energy balance in these mice.
authors.affiliation: From the Center for Diabetes and Endocrine Research and.
authors.forename: Garrett
authors.initials: G
authors.lastname: Heinrich
authors.affiliation: From the Center for Diabetes and Endocrine Research and.
authors.forename: Lucia
authors.initials: L
authors.lastname: Russo
authors.affiliation: From the Center for Diabetes and Endocrine Research and Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, Toledo, Ohio 43614.
authors.forename: Tamara R
authors.initials: TR
authors.lastname: Castaneda
authors.affiliation: the Institut für Anatomie und Zellbiologie, Universität Würzburg, 97070 Würzburg, Germany, and.
authors.forename: Verena
authors.initials: V
authors.lastname: Pfeiffer
authors.affiliation: From the Center for Diabetes and Endocrine Research and.
authors.forename: Hilda E
authors.initials: HE
authors.lastname: Ghadieh
authors.affiliation: From the Center for Diabetes and Endocrine Research and.
authors.forename: Simona S
authors.initials: SS
authors.lastname: Ghanem
authors.affiliation: From the Center for Diabetes and Endocrine Research and.
authors.forename: Jieshen
authors.initials: J
authors.lastname: Wu
authors.affiliation: From the Center for Diabetes and Endocrine Research and.
authors.forename: Latrice D
authors.initials: LD
authors.lastname: Faulkner
authors.affiliation: the Institut für Anatomie und Zellbiologie, Universität Würzburg, 97070 Würzburg, Germany, and.
authors.forename: Süleyman
authors.initials: S
authors.lastname: Ergün
authors.affiliation: From the Center for Diabetes and Endocrine Research and Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, Toledo, Ohio 43614.
authors.forename: Marcia F
authors.initials: MF
authors.lastname: McInerney
authors.affiliation: From the Center for Diabetes and Endocrine Research and.
authors.forename: Jennifer W
authors.initials: JW
authors.lastname: Hill
authors.affiliation: From the Center for Diabetes and Endocrine Research and the Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701 najjar@ohio.edu.
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Najjar
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D002272:Carcinoembryonic Antigen / Q000235:genetics* / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D017353:Gene Deletion; D006963:Hyperphagia / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D009765:Obesity / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D015398:Signal Transduction; D014280:Triglycerides / Q000378:metabolism
chemical_list: D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D015815:Cell Adhesion Molecules; D005227:Fatty Acids; D020738:Leptin; D014280:Triglycerides; D011333:Pro-Opiomelanocortin
keywords: CEACAM1; Energy homeostasis; fatty acid oxidation; fatty-acid synthase (FAS); hyperleptinemia; hyperphagia; insulin resistance; leptin; leptin resistance NIH [, and (to S.M. Najjar), (to J.W. Hill) and; nuclear magnetic resonance (NMR)