Principal Investigator/Program Director (Last, first, middle): Najjar, Sonia, MInsulin resistance is the common factor among metabolic diseases that include obesity, type 2 diabetes andsteatohepatitis. Hyperinsulinemia is an early indicator of insulin resistance. Although in many instanceshyperinsulinemia reflects impaired insulin response, considerable data support the alternative view thathyperinsulinemia causes insulin resistance. Studies supported by this grant have pioneered the biochemical,physiological, and genetic identification of a CEACAM1-dependent signaling pathway that regulates hepaticinsulin clearance. We have shown that CEACAM1 regulates peripheral insulin action by promoting hepaticinsulin clearance. Using mice with liver-specific inactivation or global null mutation of Ceacam1, we haveshown that impairment of insulin extraction causes chronic hyperinsulinemia and leads to insulin resistance bydown-regulating insulin receptors and promoting de novo lipogenesis in liver. Based on preliminary data thatunderscore the central role of CEACAM1 in pathways regulating insulin action, lipid synthesis, andinflammation, we now expand our work to investigate the cause-effect relationship between hyperinsulinemiaand insulin resistance in the context of diet-induced obesity. We show that loss of hepatic CEACAM1 isassociated with human and rodent obesity, and is an early correlate of diet-induced obesity in mice. Thus,feeding mice a high-fat diet reduces hepatic CEACAM1 levels by > 50% to cause hyperinsulinemia and insulinresistance. Conversely, Ceacam1 overexpression in liver protects mice against insulin resistance and visceralobesity. This suggests that hyperinsulinemia plays a detrimental role in the pathogenesis of diet-inducedobesity and insulin resistance. We now propose to test the hypothesis that reduction in hepatic CEACAM1underlies the causative role of hyperinsulinemia in diet-induced insulin resistance. To this end, we willin Aim 1, investigate whether preventing hyperinsulinemia curbs diet-induced insulin resistance in a model ofhepatic Ceacam1 gain-of-function, and we will systematically dissect which aspect of the metabolic syndrome(insulin resistance, dyslipidemia, hepatosteatosis, and inflammation) is prevented by the sustained expressionof CEACAM1.
In Aim 2, we will investigate the mechanism by which free fatty acids acting throughPPAR??cause transcriptional repression of Ceacam1.
In Aim 3, we will investigate whether abolishingCeacam1 regulation by PPAR? preserves CEACAM1 expression, and protects against diet-induced insulinresistance. We will generate knock-in mice in which the PPAR? response element in the Ceacam1 promoterhas been mutated, and test whether this genetic manipulation confers protection against insulin resistanceinduced by high-fat diet. This should provide a critical test of the causative effect of hyperinsulinemia on insulinresistance, and identify CEACAM1 as a tractable drug target for the development of medications to combataltered metabolic conditions.Project Description Page 6
; first; middle): Najjar; Sonia; MMetabolic diseases; including type 2 diabetes; steatohepatitis; and obesity are a growing public health concernin the US and worldwide. Insulin resistance is a key factor in the etiology of these diseases; and it is commonlyheralded by a rise in plasma insulin levels; or hyperinsulinemia. This proposal seeks to determine the cause-effect relationship between insulin resistance and hyperinsulinemia. In the current funding period; we havepioneered the biochemical; physiological; and genetic identification of CEACAM1 as a key regulator of hepaticinsulin clearance and plasma insulin levels. We have shown that disturbance of this pathway causeshyperinsulinemia and insulin resistance. We now aim to test the hypothesis that reduction in hepaticCEACAM1 constitutes an early; and fully preventable mechanism of diet-induced insulin resistance. To thisend; we will use cellular and transgenic animal studies. The combined results of these experiments shouldprovide a critical test of the idea that hyperinsulinemia can be a cause of insulin resistance; as opposed to anearly consequence thereof; and identify CEACAM1 as a tractable drug target for the development ofmedications to combat this metabolic condition.Public Health Relevance Statement Page 7
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