Gastroenterology
Volume 139, Issue 2 , Pages 644-652.e1, August 2010

Carcinoembryonic Antigen-Related Cell Adhesion Molecule 2 Controls Energy Balance and Peripheral Insulin Action in Mice

  • Garrett Heinrich

      Affiliations

    • The Center for Diabetes and Endocrine Research at the College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio
    • Department of Physiology & Pharmacology at the College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio
    • ,
  • Sumona Ghosh

      Affiliations

    • The Center for Diabetes and Endocrine Research at the College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio
    • Department of Physiology & Pharmacology at the College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio
    • ,
  • Anthony M. DeAngelis

      Affiliations

    • The Center for Diabetes and Endocrine Research at the College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio
    • Department of Physiology & Pharmacology at the College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio
    • ,
  • Jill M. Schroeder–Gloeckler

      Affiliations

    • The Center for Diabetes and Endocrine Research at the College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio
    • Department of Physiology & Pharmacology at the College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio
    • ,
  • Payal R. Patel

      Affiliations

    • The Center for Diabetes and Endocrine Research at the College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio
    • Department of Physiology & Pharmacology at the College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio
    • ,
  • Tamara R. Castaneda

      Affiliations

    • The Center for Diabetes and Endocrine Research at the College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio
    • Department of Physiology & Pharmacology at the College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio
    • ,
  • Shane Jeffers

      Affiliations

    • The Center for Diabetes and Endocrine Research at the College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio
    • Department of Physiology & Pharmacology at the College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio
    • ,
  • Abraham D. Lee

      Affiliations

    • The Center for Diabetes and Endocrine Research at the College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio
    • Department of Physical Therapy at the College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio
    • ,
  • Dae Young Jung

      Affiliations

    • Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
    • Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
    • ,
  • Zhiyou Zhang

      Affiliations

    • Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
    • ,
  • Darren M. Opland

      Affiliations

    • Department of Medicine, University of Michigan, Ann Arbor, Michigan
    • ,
  • Martin G. Myers Jr

      Affiliations

    • Department of Medicine, University of Michigan, Ann Arbor, Michigan
    • ,
  • Jason K. Kim

      Affiliations

    • Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
    • Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
    • ,
  • Sonia M. Najjar

      Affiliations

    • The Center for Diabetes and Endocrine Research at the College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio
    • Department of Physiology & Pharmacology at the College of Medicine at the University of Toledo, Health Science Campus, Toledo, Ohio
    • Corresponding Author InformationReprint requests Address requests for reprints to: Sonia M. Najjar, PhD, College of Medicine, University of Toledo, Health Science Campus, 3000 Arlington Avenue, Mail Stop 1008, Toledo, Ohio 43614. fax: (419) 383-2871

Received 20 January 2010; accepted 25 March 2010. published online 09 April 2010.

Background & Aims

The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a transmembrane glycoprotein with pleotropic functions, including clearance of hepatic insulin. We investigated the functions of the related protein CEACAM2, which has tissue-specific distribution (kidney, uterus, and crypt epithelia of intestinal tissues), in genetically modified mice.

Methods

Ceacam2-null mice (Cc2−/−) were generated from a 129/Sv × C57BL/6J background. Female mice were assessed by hyperinsulinemic-euglycemic clamp analysis and indirect calorimetry and body fat composition was measured. Cc2−/− mice and controls were fed as pairs, given insulin tolerance tests, and phenotypically characterized.

Results

Female, but not male Cc2−/− mice exhibited obesity that resulted from hyperphagia and reduced energy expenditure. Pair feeding experiments showed that hyperphagia led to peripheral insulin resistance. Insulin action was normal in liver but compromised in skeletal muscle of female Cc2−/− mice; the mice had incomplete fatty acid oxidation and impaired glucose uptake and disposal. The mechanism of hyperphagia in Cc2−/− mice is not clear, but appears to result partly from increased hyperinsulinemia-induced hypothalamic fatty acid synthase levels and activity. Hyperinsulinemia was caused by increased insulin secretion.

Conclusions

In mice, CEACAM2 is expressed by the hypothalamus. Cc2−/− mice develop obesity from hyperphagia and reduced energy expenditure, indicating its role in regulating energy balance and insulin sensitivity.

Keywords: Ventromedial Hypothalamus, Substrate Switching, Fasting-Refeeding Paradigm, Leptin Resistance

Abbreviations used in this paper: Cc2, Ceacam2 gene, Cc2+/+, wild-type mouse, Cc2−/−, Ceacam2 null mutant mouse, CEACAM2, the carcinoembryonic antigen-related cell adhesion molecule 2, FAS, fatty acid synthase, PCR, polymerase chain reaction, STAT3, the signal transducer and activator of transcription 3, Vco2, carbon dioxide production per unit time, Vo2, oxygen consumption per unit time, VMH, ventromedial nucleus of the hypothalamus

To access this article, please choose from the options below

Login to an existing account or Register a new account.

  • Purchase this article for 30.00 USD (You must login/register to purchase this article)

    Online access for 24 hours. The PDF version can be downloaded as your permanent record.

  • Subscribe to this title

    Get unlimited online access to this article and all other articles in this title 24/7 for one year.

  • Claim access now

    For current subscribers with Society Membership or Account Number.

  • Visit SciVerse ScienceDirect to see if you have access via your institution.
 

 Conflicts of interest The authors disclose no conflicts.

 Funding This work was supported by grants from the National Institutes of Health (R01DK054254 and R01DK083850 to S.M.N., R37DK56731 to M.G.M., and R01-DK80756 and 5-P30-DK32520 [UMass Diabetes Endocrinology Research Center] to J.K.K.), United States Department of Agriculture (USDA 38903-19826 to S.M.N.), the American Diabetes Association (to J.K.K. and M.G.M.), and the American Heart Association (to M.G.M. and G.H.).

PII: S0016-5085(10)00513-5

doi:10.1053/j.gastro.2010.03.056

Gastroenterology
Volume 139, Issue 2 , Pages 644-652.e1, August 2010

Article Tools

* Image Usage & Resolution