Insulin resistance is the hallmark of type 2 diabetes. CEACAM1, a substrate of insulin receptor in liver, regulates insulin action by promoting insulin clearance. Inactivation of CEACAM1 impairs insulin clearance and causes hyperinsulinemia, insulin resistance, dyslipidemia and visceral adiposity in transgenic mice. Moreover, CEACAM1 levels are significantly reduced in spontaneously obese rats. Thus, there is a strong association between visceral obesity, insulin resistance and reduced hepatic CEACAM1 level.
Free fatty acids (FFA) that are released from adipose tissue, in particular during fasting and obesity, are transported to liver to activate the transcription factor peroxisome proliferator-activated receptor α (PPARα), which regulates expression of genes involved in fatty acid transport and oxidation. Thus, we investigated whether PPARα downregulates CEACAM1 level and hence mediates insulin resistance in obese mice.
We fed normal wild-type male mice with a high-fat diet (HF) (45% of calories from fat), for 9 to 30 d. HF treatment for 9 d caused a loss of hepatic CEACAM1 mRNA and protein content by up to 35% without affecting insulin clearance and insulin action. However, treatment for 21-30 d reduced CEACAM1 mRNA and protein levels by ~≥ and led to impaired insulin clearance and insulin resistance in a reversible manner. On the other hand when we inhibited lipolysis in HF-fed mice by nicotinic acid, we observed normal hepatic CEACAM1 level and insulin action. Increased mobilization of 178 FFA from the adipose tissue, especially during fasting, increases FFA uptake by liver and their conversion into long chain fatty acids (LCFA) and LCFA-CoA. These activate the peroxisome proliferator-activated receptor α (PPARα, a nuclear transcription factor that upregulates transcription of proteins involved in fatty acid transport into mitochondria and oxidation in order to support gluconeogenesis). We have observed that at fasting, when PPARα levels are highest the level of CEACAM1 is low. Moreover, Wy14,643, a PPARα agonist, reduced hepatic CEACAM1 mRNA and protein levels significantly in mice and rat hepatoma cells (FAO). Additionally, feeding PPARα-/- mice HF 30 days reduced hepatic Ceacam1 mRNA levels by ~ 60% in wild-type PPARα+/+, but not PPARα-/- null mice, and this was associated with hyperinsulinemia and insulin resistance. Taken together, our data suggests that PPARα activation (by fasting, HF diet or Wy treatment) decreases hepatic CEACAM1 levels. In addition, our data suggest that reduction in hepatic CEACAM1 via PPARα-dependent pathway constitutes an early mechanism of diet-induced insulin resistance.