Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice
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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.
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.
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.
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.
KeywordsCEACAM1 Energy balance Fatty acid synthase Hyperinsulinaemia Insulin clearance Insulin resistance Lipolysis Normoinsulinaemia Steatohepatitis
Brown adipose tissue
Carcinoembryonic antigen-related cell adhesion molecule 1
Fatty acid β-oxidation
Fatty acid synthase
Transgenic mice with liver-specific overexpression of wild-type rat Cc1 driven by ApoA-1 promoter
Transgenic mice with liver-specific overexpression of the dominant-negative serine to alanine phosphorylation-defective mutant of rat CEACAM1
α subunit of the insulin receptor
β subunit of the insulin receptor
Peroxisome proliferator-activated receptor-α
Sterol regulatory element binding protein-1c
White adipose tissue
The authors thank N. Beauchemin (McGill University, Montréal, QC, Canada) for her gift of the custom-made rabbit Ab2456 and Ab3759 polyclonal antibodies. We also thank J. Kalisz and M. Kopfman at the Najjar Laboratory at the University of Toledo College of Medicine for their technical assistance in the generation and maintenance of mice, and in carrying out routine RNA analyses.
Data are available on request from the corresponding senior author.
This work was supported by grants from the National Institutes of Health (R01-DK054254, R01-DK083850 and R01-HL112248 to SMN, and U24-DK093000 to the National Mouse Metabolic Phenotyping Center at UMass). It was also supported by fellowships from the American Heart Association (14POST20480294) to LR and the Middle-East Diabetes Research Center to HEG and SSG. The studies were also partially supported by the John J. Kopchick PhD OHF Eminent Research Chair Fund.
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
LR, HTM, HEG, SSG, TAB, H-LN and SD researched data and drafted parts of the manuscript. HTM and HEG revised the manuscript extensively. JKK carried out the hyperinsulinaemic–euglycaemic clamp experiment, and analysed and discussed data. GYD and GH carried out the statistical analysis. GYD, GH and JKK critically reviewed the manuscript. SMN was responsible for study design, conceptualisation, data analysis and interpretation, and reviewing the manuscript. All authors have given final approval of this version to be published. SMN had full access to all the data of the study and takes responsibility for the integrity and accuracy of data analysis and the decision to submit and publish the manuscript.
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