Leptin resistance contributes to obesity in mice with null mutation of carcinoembryonic antigen-related cell adhesion molecule 1

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

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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.

Original languageEnglish
Pages (from-to)11124-11132
Number of pages9
JournalJournal of Biological Chemistry
Volume291
Issue number21
DOIs
Publication statusPublished - 20 May 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Heinrich, G., Russo, L., Castaneda, T. R., Pfeiffer, V., Ghadieh, H. E., Ghanem, S. S., Wu, J., Faulkner, L. D., Ergün, S., McInerney, M. F., Hill, J. W., & Najjar, S. M. (2016). Leptin resistance contributes to obesity in mice with null mutation of carcinoembryonic antigen-related cell adhesion molecule 1. Journal of Biological Chemistry, 291(21), 11124-11132. https://doi.org/10.1074/jbc.M116.716431