| Impaired hepatic insulin clearance causes hyperinsulinemia and secondary insulin resistance, which may progress to involve various components of metabolic syndrome. The carcinoembryonic-related cell adhesion molecule 1 (CEACAM1) has been shown to promote insulin clearance, downregulate the mitogenic action of insulin, and limit lipogenesis in the early hours of refeeding. Mice with liver-specific Ceacam1 inactivation (L-SACC1) or with global null mutation (Cc1--/--), exhibit impairment of insulin clearance and hyperinsulinemia, which causes insulin resistance. Since the lack of CEACAM1 correlates with insulin resistance, and regulates insulin action in liver, an important diet-responsive organ, we proposed that reduction of CEACAM1 is implicated in the pathogenesis of diet-induced insulin resistance; and that increasing hepatic levels of CEACAM1 would be protective against metabolic abnormalities associated with metabolic syndrome. Therefore we examined CEACAM1 levels in an animal model of metabolic syndrome and non-alcoholic steatohepatitis (NASH), the low aerobic capacity runner (LCR) rats, in comparison to high aerobic capacity runner (HCR) rats. We found that in response to caloric restriction by 30% over a period of 2-3 months profound improvements in insulin sensitivity and reversal of hepatic inflammation, oxidative stress and fibrosis. Caloric restriction exerts these effects along with increases in fasting levels of CEACAM1 in liver. Additionally we examined the effect of high-fat diet on wild-type mice and on a transgenic mouse with liver-specific overexpression of rat CEACAM1 (L-CC1). We found that an early event associated with high-fat feeding is repression of CEACAM1 by a PPARalpha-mediated mechanism, and that this leads to impaired insulin clearance prior to the development of a pro-inflammatory state. Transgenic overexpression of CEACAM1 in liver prevents hyperinsulinemia and insulin resistance, and limits visceral obesity and the metabolic response to high-fat intake. |
