We hypothesized that insulin stimulates phosphorylation of CEACAM1 which in turn leads to upregulation of receptor-mediated insulin endocytosis and degradation in the hepatocyte. We have generated transgenic mice over-expressing in liver a dominant-negative, phosphorylation-defective S503A-CEACAM1 mutant. Supporting our hypothesis, we found that S503A-CEACAM1 transgenic mice developed hyperinsulinemia resulting from impaired insulin clearance. The hyperinsulinemia caused secondary insulin resistance with impaired glucose tolerance and random, but not fasting, hyperglycemia. Transgenic mice developed visceral adiposity with increased amounts of plasma free fatty acids and plasma and hepatic triglycerides. These findings suggest a mechanism through which insulin signaling regulates insulin sensitivity by modulating hepatic insulin clearance.

In skeletal muscle, glucose transport is stimulated by insulin, contractions and hypoxia. In this study, we used the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin to examine whether (i) PI 3-kinase activity is necessary for stimulation of glucose transport by insulin in muscle, and (ii) PI 3-kinase mediates a step in the pathway by which contractions/ hypoxia stimulate glucose transport. Wortmannin completely blocked insulin-and insulin-like growth factor-l-stimulated glucose transport in muscle. In contrast, wortmannin had no effect on the stimulation of glucose transport by contractions or hypoxia, providing evidence that PI 3-kinase activity is not involved in the activation of glucose transport by these stimuli.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates insulin sensitivity by promoting hepatic insulin clearance. Liver-specific inactivation or global null-mutation of Ceacam1 impairs hepatic insulin extraction to cause chronic hyperinsulinemia, resulting in insulin resistance and visceral obesity. In this study we investigated whether diet-induced insulin resistance implicates changes in hepatic CEACAM1. We report that feeding C57/BL6J mice a high-fat diet reduced hepatic CEACAM1 levels by >50% beginning at 21 days, causing hyperinsulinemia, insulin resistance, and elevation in hepatic triacylglycerol content. Conversely, liver-specific inducible CEACAM1 expression prevented hyperinsulinemia and markedly limited insulin resistance and hepatic lipid accumulation that were induced by prolonged high-fat intake. This was partly mediated by increased hepatic β-fatty acid oxidation and energy expenditure. The data demonstrate that the high-fat diet reduced hepatic CEACAM1 expression and that overexpressing CEACAM1 in liver curtailed diet-induced metabolic abnormalities by protecting hepatic insulin clearance.

Background & Aims: The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) exhibits pleotropic functions, including promoting hepatic insulin clearance. The current studies investigate the functions of its close relative, CEACAM2, with more limited tissue-specific distribution. Methods: A global Ceacam2 (Cc2−/−) null mouse (on 129/Sv × C57BL/6J) was generated. Females were subjected to hyperinsulinemic-euglycemic clamp, indirect calorimetry, body fat composition, and pair-feeding followed by insulin tolerance test for phenotypic characterization. Results: Female, but not male Cc2−/− mice exhibit obesity, which results from hyperphagia and reduced energy expenditure. Hyperphagia leads to peripheral insulin resistance, as demonstrated by pair-feeding experiments. Whereas insulin action is normal in liver, it is compromised in skeletal muscle, which exhibits incomplete fatty acid oxidation and impaired glucose uptake and disposal. The mechanism of hyperphagia in Cc2−/− mice is not well delineated, but appears to result partly from hyperinsulinemia-induced hypothalamic fatty acid synthase level and activity. Hyperinsulinemia is, in turn, caused by increased insulin secretion. Conclusions: Consistent with the absence of CEACAM2 from peripheral insulin target tissues and its localization to the hypothalamus, the phenotype of Cc2−/− mice identifies a novel role for CEACAM2 in the central regulation of energy balance and insulin sensitivity.

Rats selectively bred for low aerobic running capacity exhibit the metabolic syndrome, including hyperinsulinemia, insulin resistance, visceral obesity, and dyslipidemia. They also exhibit features of nonalcoholic steatohepatitis, including chicken-wire fibrosis, inflammation, and oxidative stress. Hyperinsulinemia in these rats is associated with impaired hepatic insulin clearance. The current studies aimed to determine whether these metabolic abnormalities could be reversed by caloric restriction (CR). CR by 30% over a period of 2-3 months improved insulin clearance in parallel to inducing the protein content and activation of the carcinoembryonic antigen-related cell adhesion molecule 1, a main player in hepatic insulin extraction. It also reduced glucose and insulin intolerance and serum and tissue (liver and muscle) triglyceride levels. Additionally, CR reversed inflammation, oxidative stress, and fibrosis in liver. The data support a significant role of CR in the normalization of insulin and lipid metabolism in liver.