We will continue studies of the role of CEACAM1 in insulin metabolism. CEACAM1 is a substrate of the insulin receptor kinase in the liver. In the first four years of funding, we have demonstrated that hepatic CEACAM1 plays a pivotal role in the formation of the insulin-receptor endocytosis complex to promote insulin uptake and degradation, an event that constitutes the basic mechanism of insulin clearance in liver. Using transgenic mice expressing a dominant-negative mutant CEACAM1, we have shown that functional inactivation of CEACAM1 in liver impairs insulin clearance and results in hyperinsulinemia, altered lipid metabolism and increased visceral adiposity. We propose to investigate the pathogenesis of the metabolic syndrome caused by altered CEACAM1 function using Ceacam1-deficient (Cc1-/-) mice. In contrast to the human genome, which harbors a single Ceacam gene, the mouse genome harbors two genes (Cc1 and Cc2), differing in the tissue distribution of their protein products, with CEACAM1 being the predominant liver isoform and CEACAM2 being the predominant isoform in kidney and pancreatic b-cells. We present preliminary data showing that individual Cc1/- and Cc2-/- knockouts develop metabolic abnormalities with apparently different mechanisms. Cc1-/- null mice develop impaired insulin clearance and insulin resistance without diabetes, while Cc2-/- develop diabetes with impaired insulin secretion. We also show decreased hepatic CEACAM1 expression in other models of obesity and diabetes in rodents and in mice on a high-fat diet. Based on these observations, in Aim 1 we will investigate whether the mechanism of insulin resistance in Cc1-/- mice is due to impaired insulin clearance.
In Aim 2, we will determine whether restoring CEACAM1 expression reverses the metabolic abnormalities of obese rodents.
In Aim 3, we will investigate the mechanism of b-cells dysfunction in Cc2-/- knockouts, and whether restoring CEACAM2 expression in pancreatic b-cells rescues the diabetic phenotype of Cc2-/- mice.
In Aim 4, we will study whether the two genes play overlapping or distinct functions by generating mice lacking both isoforms (Cc1-/-/Cc2-/-). The proposed studies should delineate a novel mechanism of insulin-resistant diabetes, one that highlights the role of insulin metabolism in regulating insulin sensitivity distinctly from insulin signaling.
|Ghadieh, Hilda E; Muturi, Harrison T; Russo, Lucia et al. (2018) Exenatide induces carcinoembryonic antigen-related cell adhesion molecule 1 expression to prevent hepatic steatosis. Hepatol Commun 2:35-47|
|Villa-Pérez, Pablo; Merino, Beatriz; Fernández-Díaz, Cristina M et al. (2018) Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice. Metabolism 88:1-11|
|Huang, Lei; Liu, Jehnan; Zhang, Xiao-Ou et al. (2018) Inhibition of protein arginine methyltransferase 5 enhances hepatic mitochondrial biogenesis. J Biol Chem 293:10884-10894|
|Ghanem, Simona S; Muturi, Harrison T; DeAngelis, Anthony M et al. (2017) Age-dependent insulin resistance in male mice with null deletion of the carcinoembryonic antigen-related cell adhesion molecule 2 gene. Diabetologia 60:1751-1760|
|Ghadieh, Hilda E; Muturi, Harrison T; Najjar, Sonia M (2017) Exenatide Prevents Diet-induced Hepatocellular Injury in A CEACAM1-Dependent Mechanism. J Diabetes Treat 2017:|
|Russo, Lucia; Muturi, Harrison T; Ghadieh, Hilda E et al. (2017) Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice. Diabetologia 60:2463-2474|
|Heinrich, Garrett; Russo, Lucia; Castaneda, Tamara R et al. (2016) Leptin Resistance Contributes to Obesity in Mice with Null Mutation of Carcinoembryonic Antigen-related Cell Adhesion Molecule 1. J Biol Chem 291:11124-32|
|Ghanem, Simona S; Heinrich, Garrett; Lester, Sumona G et al. (2016) Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcinoembryonic Antigen-related Cell Adhesion Molecule 2 (CEACAM2). J Biol Chem 291:980-8|
|Ramakrishnan, Sadeesh K; Russo, Lucia; Ghanem, Simona S et al. (2016) Fenofibrate Decreases Insulin Clearance and Insulin Secretion to Maintain Insulin Sensitivity. J Biol Chem 291:23915-23924|
|Stechschulte, Lance A; Qiu, Bin; Warrier, Manya et al. (2016) FKBP51 Null Mice Are Resistant to Diet-Induced Obesity and the PPAR? Agonist Rosiglitazone. Endocrinology 157:3888-3900|
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