Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice

Lucia Russo, Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA.
Harrison T. Muturi, Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA.
Hilda E. Ghadieh, Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA.
Simona S. Ghanem, Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA.
Thomas A. Bowman, Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA.
Hye Lim Noh, Division of Endocrinology, Metabolism and Diabetes, University of Massachusetts Medical School, Worcester, MA, USA.
Sezin Dagdeviren, Division of Endocrinology, Metabolism and Diabetes, University of Massachusetts Medical School, Worcester, MA, USA.
G Y. Dogbey, Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Irvine Hall 229, 1 Ohio University, Athens, OH, 45701-2979, USA.
Jason K. Kim, Division of Endocrinology, Metabolism and Diabetes, University of Massachusetts Medical School, Worcester, MA, USA.
Garrett Heinrich, Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Irvine Hall 229, 1 Ohio University, Athens, OH, 45701-2979, USA.
Sonia M. Najjar, Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA. najjar@ohio.edu.

Document Type

Article

Date of Publication

12-1-2017

Publication Title

Diabetologia

First Page

2463

Last Page

2474

Abstract

AIMS/HYPOTHESIS: The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes insulin clearance. Mice with global null mutation (Cc1 ) or with liver-specific inactivation (L-SACC1) of Cc1 (also known as Ceacam1) gene display hyperinsulinaemia resulting from impaired insulin clearance, insulin resistance, steatohepatitis and obesity. Because increased lipolysis contributes to the metabolic phenotype caused by transgenic inactivation of CEACAM1 in the liver, we aimed to further investigate the primary role of hepatic CEACAM1-dependent insulin clearance in insulin and lipid homeostasis. To this end, we examined whether transgenic reconstitution of CEACAM1 in the liver of global Cc1 mutant mice reverses their abnormal metabolic phenotype. METHODS: Insulin response was assessed by hyperinsulinaemic-euglycaemic clamp analysis and energy balance was analysed by indirect calorimetry. Mice were overnight-fasted and refed for 7 h to assess fatty acid synthase activity in the liver and the hypothalamus in response to insulin release during refeeding. RESULTS: Liver-based rescuing of CEACAM1 restored insulin clearance, plasma insulin level, insulin sensitivity and steatohepatitis caused by global deletion of Cc1. It also reversed the gain in body weight and total fat mass observed with Cc1 deletion, in parallel to normalising energy balance. Mechanistically, reversal of hyperphagia appeared to result from reducing fatty acid synthase activity and restoring insulin signalling in the hypothalamus. CONCLUSIONS/INTERPRETATION: Despite the potential confounding effects of deleting Cc1 from extrahepatic tissues, liver-based rescuing of CEACAM1 resulted in full normalisation of the metabolic phenotype, underscoring the key role that CEACAM1-dependent hepatic insulin clearance pathways play in regulating systemic insulin sensitivity, lipid homeostasis and energy balance.

DOI

10.1007/s00125-017-4432-y

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