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

Lucia Russo, Harrison T. Muturi, Hilda E. Ghadieh, Simona Ghanem, Thomas A. Bowman, Hye Lim Noh, Sezin Dagdeviren, Godwin Y. Dogbey, Jason K. Kim, Garrett Heinrich, Sonia M. Najjar

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2463-2474
Number of pages12
JournalDiabetologia
Volume60
Issue number12
DOIs
Publication statusPublished - 1 Dec 2017
Externally publishedYes

Fingerprint

Carcinoembryonic Antigen
Cell Adhesion Molecules
Insulin
Liver
Insulin Resistance
Fatty Acid Synthases
Fatty Liver
Phenotype
Hypothalamus
Homeostasis
Lipids
Hyperphagia
Indirect Calorimetry
Lipolysis
Hyperinsulinism
Obesity
Fats
Body Weight
Mutation

Keywords

  • CEACAM1
  • Energy balance
  • Fatty acid synthase
  • Hyperinsulinaemia
  • Insulin clearance
  • Insulin resistance
  • Lipolysis
  • Normoinsulinaemia
  • Steatohepatitis

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice. / Russo, Lucia; Muturi, Harrison T.; Ghadieh, Hilda E.; Ghanem, Simona; Bowman, Thomas A.; Noh, Hye Lim; Dagdeviren, Sezin; Dogbey, Godwin Y.; Kim, Jason K.; Heinrich, Garrett; Najjar, Sonia M.

In: Diabetologia, Vol. 60, No. 12, 01.12.2017, p. 2463-2474.

Research output: Contribution to journalArticle

Russo, L, Muturi, HT, Ghadieh, HE, Ghanem, S, Bowman, TA, Noh, HL, Dagdeviren, S, Dogbey, GY, Kim, JK, Heinrich, G & Najjar, SM 2017, 'Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice', Diabetologia, vol. 60, no. 12, pp. 2463-2474. https://doi.org/10.1007/s00125-017-4432-y
Russo, Lucia ; Muturi, Harrison T. ; Ghadieh, Hilda E. ; Ghanem, Simona ; Bowman, Thomas A. ; Noh, Hye Lim ; Dagdeviren, Sezin ; Dogbey, Godwin Y. ; Kim, Jason K. ; Heinrich, Garrett ; Najjar, Sonia M. / Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice. In: Diabetologia. 2017 ; Vol. 60, No. 12. pp. 2463-2474.
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AU - Muturi, Harrison T.

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AU - Ghanem, Simona

AU - Bowman, Thomas A.

AU - Noh, Hye Lim

AU - Dagdeviren, Sezin

AU - Dogbey, Godwin Y.

AU - Kim, Jason K.

AU - Heinrich, Garrett

AU - Najjar, Sonia M.

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