Insulin resistance is the common factor among metabolic diseases that include obesity, type 2 diabetes and steatohepatitis. Hyperinsulinemia is an early indicator of insulin resistance. Although in many instances hyperinsulinemia reflects impaired insulin response, considerable data support the alternative view that hyperinsulinemia causes insulin resistance. Studies supported by this grant have pioneered the biochemical, physiological, and genetic identification of a CEACAM1-dependent signaling pathway that regulates hepatic insulin clearance. We have shown that CEACAM1 regulates peripheral insulin action by promoting hepatic insulin clearance. Using mice with liver-specific inactivation or global null mutation of Ceacam1, we have shown that impairment of insulin extraction causes chronic hyperinsulinemia and leads to insulin resistance by down-regulating insulin receptors and promoting de novo lipogenesis in liver. Based on preliminary data that underscore the central role of CEACAM1 in pathways regulating insulin action, lipid synthesis, and inflammation, we now expand our work to investigate the cause-effect relationship between hyperinsulinemia and insulin resistance in the context of diet-induced obesity. We show that loss of hepatic CEACAM1 is associated 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 insulin resistance. Conversely, Ceacam1 overexpression in liver protects mice against insulin resistance and visceral obesity. This suggests that hyperinsulinemia plays a detrimental role in the pathogenesis of diet-induced obesity and insulin resistance. We now propose to test the hypothesis that reduction in hepatic CEACAM1 underlies the causative role of hyperinsulinemia in diet-induced insulin resistance. To this end, we will in Aim 1, investigate whether preventing hyperinsulinemia curbs diet-induced insulin resistance in a model of hepatic 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 expression of CEACAM1.
In Aim 2, we will investigate the mechanism by which free fatty acids acting through PPARa cause transcriptional repression of Ceacam1.
In Aim 3, we will investigate whether abolishing Ceacam1 regulation by PPARa preserves CEACAM1 expression, and protects against diet-induced insulin resistance. We will generate knock-in mice in which the PPARa response element in the Ceacam1 promoter has been mutated, and test whether this genetic manipulation confers protection against insulin resistance induced by high-fat diet. This should provide a critical test of the causative effect of hyperinsulinemia on insulin resistance, and identify CEACAM1 as a tractable drug target for the development of medications to combat altered metabolic conditions.

Public Health Relevance

Metabolic diseases, including type 2 diabetes, steatohepatitis, and obesity are a growing public health concern in the US and worldwide. Insulin resistance is a key factor in the etiology of these diseases, and it is commonly heralded 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 have pioneered the biochemical, physiological, and genetic identification of CEACAM1 as a key regulator of hepatic insulin clearance and plasma insulin levels. We have shown that disturbance of this pathway causes hyperinsulinemia and insulin resistance. We now aim to test the hypothesis that reduction in hepatic CEACAM1 constitutes an early, and fully preventable mechanism of diet-induced insulin resistance. To this end, we will use cellular and transgenic animal studies. The combined results of these experiments should provide a critical test of the idea that hyperinsulinemia can be a cause of insulin resistance, as opposed to an early consequence thereof, and identify CEACAM1 as a tractable drug target for the development of medications to combat this metabolic condition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054254-13
Application #
8661749
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Silva, Corinne M
Project Start
2000-03-01
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Toledo
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Toledo
State
OH
Country
United States
Zip Code
43614
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 PPARγ Agonist Rosiglitazone. Endocrinology 157:3888-3900
Ramakrishnan, Sadeesh K; Khuder, Saja S; Al-Share, Qusai Y et al. (2016) PPARα (Peroxisome Proliferator-activated Receptor α) Activation Reduces Hepatic CEACAM1 Protein Expression to Regulate Fatty Acid Oxidation during Fasting-refeeding Transition. J Biol Chem 291:8121-9
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
Li, Caixia; Culver, Silas A; Quadri, Syed et al. (2015) High-fat diet amplifies renal renin angiotensin system expression, blood pressure elevation, and renal dysfunction caused by Ceacam1 null deletion. Am J Physiol Endocrinol Metab 309:E802-10
Balasubramanian, Priya; Varde, Pratibha A; Abdallah, Simon Labib et al. (2015) Differential effects of prenatal stress on metabolic programming in diet-induced obese and dietary-resistant rats. Am J Physiol Endocrinol Metab 309:E582-8
Al-Share, Qusai Y; DeAngelis, Anthony M; Lester, Sumona Ghosh et al. (2015) Forced Hepatic Overexpression of CEACAM1 Curtails Diet-Induced Insulin Resistance. Diabetes 64:2780-90
Liu, Jehnan; Ramakrishnan, Sadeesh K; Khuder, Saja S et al. (2015) High-calorie diet exacerbates prostate neoplasia in mice with haploinsufficiency of Pten tumor suppressor gene. Mol Metab 4:186-98
Alshahrani, Musaed M; Yang, Eunice; Yip, Jana et al. (2014) CEACAM2 negatively regulates hemi (ITAM-bearing) GPVI and CLEC-2 pathways and thrombus growth in vitro and in vivo. Blood 124:2431-41

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