SAT-151 Hyperinsulinemia-Driven Progressive Metabolic Dysfunction in Male Mice with Liver-Specific CEACAM1 Deletion

Abstract

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates insulin sensitivity by promoting hepatic insulin clearance. Mice with global null mutation (Cc1-/-) or with liver-specific inactivation (L-SACC1) of Ceacam1 gene display hyperinsulinemia due to impaired insulin clearance, insulin resistance, steatohepatitis, and obesity. To further investigate the primary role of hepatic CEACAM1 in insulin and lipid homeostasis independent of its potential effect in extra-hepatic tissues or without the confounding effect of the dominant-negative transgene, we examined whether hepatic-specific Ceacam1 deletion causes metabolic abnormalities starting with impairment of insulin clearance. To this end, we generated liver-specific Ceacam1 null mice (AlbCre+Cc1fl/fl) on C57BL/6 genetic background. Steady-state C-peptide to insulin molar ratio showed impairment of insulin clearance and hyperinsulinemia at 2 months, followed by hepatic insulin resistance (as measured by hyperinsulinemic-euglycemic clamp analysis) and steatohepatitis starting at 7 months of age. Relative to Cre and Flox control groups, AlbCre+Cc1fl/fl mutants developed visceral obesity and hyperphagia at 6-7 months of age, in parallel to hyperleptinemia and blunted hypothalamic STAT3 phosphorylation in response to an intraperitoneal injection of leptin. Together with hyperinsulinemia-driven rise in hypothalamic fatty acid synthase level and activity, this could contribute to hyperphagia and reduced physical activity. Pair-feeding experiment showed that hyperphagia caused systemic insulin resistance at 7-8 months of age, including blunted insulin signaling in white adipose tissue and lipolysis. Interestingly, hypothalamic Ceacam1 mRNA levels progressively decreased in controls and AlbCre+Cc1fl/fl mutants but to a higher extent in the nulls reaching more than 60% loss at ≥7 months of age, as a result of insulin resistance. Because Ceacam1 is expressed in POMC1 neurons, its significant reduction in this neuronal population could contribute to energy imbalance in AlbCre+Cc1fl/fl mutants. Collectively, these data validate the AlbCre+Cc1fl/fl mutant as an in vivo model to demonstrate the key role that impairment of hepatic insulin clearance plays in the pathogenesis of energy imbalance followed by systemic insulin resistance and lipolysis. This underscores the importance of the liver-hypothalamic axis in metabolic derangement.