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: Garrett Heinrich, Lucia Russo, Tamara R Castaneda, Verena Pfeiffer, Hilda E Ghadieh, Simona S Ghanem, Jieshen Wu, Latrice D Faulkner, Süleyman Ergün, Marcia F McInerney, Jennifer W Hill, Sonia M Najjar
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 291 Issue 21 Pg. 11124-32 (May 20 2016) ISSN: 1083-351X [Electronic] United States
• PMID: 27002145 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Carcinoembryonic Antigen
• Ceacam1 protein, mouse
• Cell Adhesion Molecules
• Fatty Acids
• Leptin
• Triglycerides
• Pro-Opiomelanocortin

Topics

• Animals
• Arcuate Nucleus of Hypothalamus (metabolism)
• Carcinoembryonic Antigen (genetics, metabolism)
• Cell Adhesion Molecules (deficiency, genetics, metabolism)
• Energy Metabolism
• Fatty Acids (metabolism)
• Gene Deletion
• Hyperphagia (etiology, genetics, metabolism)
• Hypothalamus (metabolism)
• Insulin Resistance
• Leptin (metabolism)
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle, Skeletal (metabolism)
• Mutation
• Obesity (etiology, genetics, metabolism)
• Pro-Opiomelanocortin (metabolism)
• Signal Transduction
• Triglycerides (metabolism)