Death and disease from obesity largely result from insulin resistance and diabetes. Weight-loss strategies are too often ineffective. Targeting pathways to improve insulin sensitivity with obesit may reduce risk of diabetes and cardiovascular disease;but such pathways have been elusive. We discovered a novel pathway mediated by cholesteryl ester transfer protein (CETP) that prevents insulin resistance, even with obesity. CETP shuttles triglycerides and cholesteryl esters between serum lipoproteins (VLDL and HDL), and tissues including liver. Pharmacological CETP inhibition raises HDL cholesterol but does not protect against cardiovascular disease. This failure may suggest non-HDL functions of CETP. Mice naturally lack CETP expression, so our lab used CETP transgenic mice to define how obesity impacts HDL protein composition. Our studies led to the surprising finding that constitutive CETP expression protected mice from high-fat diet (HFD)-induced insulin resistance -by insulin clamp techniques. This protection was despite becoming obese. We used an innovative approach where we integrated in vivo metabolism techniques with systems-based tools in order to define the mechanism for CETP-mediated protection from insulin resistance. CETP promotes bile secretion, so we profiled metabolites from CETP mice and found that increased liver and serum bile acids associated with insulin sensitivity. We also found increased gut bile acids that recirculate to the liver and led to activation of the hepatic bile-sensor FXR and small heterodimer partner (SHP). With transcriptional profiling we found CETP augments bile signaling, and enhances insulin-suppression of gluconeogenic genes in the liver. Female CETP mice had a greater improvement in insulin sensitivity than males, which was linked to an altered network of genes that increase estradiol levels and promote estrogen signaling in the liver. We hypothesize that CETP expression promotes insulin sensitivity by increasing bile acid secretion and bile acid signaling in the liver. We propose that CETP also promotes estrogen signaling, which is required for the full protective effects of CETP. We will explore these novel metabolic effects of CETP in 3 aims:
In AIM1 we will use transgenic mice expressing CETP driven by the human gene promoter to test the hypothesis that induction of CETP with obesity protects from HFD-induced insulin resistance by activating bile signaling pathways.
In AIM2 we will define if hepatic estrogen signaling is required for CETP-mediated insulin sensitivity using mice with knock-out of the estrogen receptor alpha. We expect to define important pathways that contribute to sex-differences in glucose and lipid metabolism.
In AIM3 we will focus on the bile signaling pathway, and how CETP activates SHP. Using intergrated metabolite and transcriptional network models, we expect to discover pathways that can be targeted to generate a """"""""metabolically healthy"""""""" obese phenotype. These innovative studies will be an important step towards preventing insulin resistance and diabetes associated with obesity, which are a major health burden to the US Veteran population.

Public Health Relevance

Death and disease from obesity are largely due to the development of insulin resistance and diabetes. Mechanisms by which some individuals are susceptible to insulin resistance - while others are protected - are not well defined. While studying a model with humanized lipoprotein profiles, mice expressing cholesteryl ester transfer protein (CETP);we discovered a novel mechanism to prevent insulin resistance, even with obesity. We will define the mechanisms by which CETP may prevent insulin resistance and complications of obesity. The VA healthcare system is one of the largest healthcare providers in the United States, enrolling over 8 million individuals. In studies of VA patients in ambulatory clinic, over 75% were overweight or obese. There is a particularly high prevalence of obesity in young Veterans, who have a longer exposure risk to the cardiovascular complications of obesity. These studies will define therapeutic targets to limit diabetes and cardiovascular disease with obesity, and are poised reduce a health burden to the US Veteran population.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Endocriniology A (ENDA)
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Veterans Health Administration
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Palmisano, Brian T; Zhu, Lin; Eckel, Robert H et al. (2018) Sex differences in lipid and lipoprotein metabolism. Mol Metab 15:45-55
Mueller, Paul A; Zhu, Lin; Tavori, Hagai et al. (2018) Deletion of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Accelerates Atherosclerosis Regression and Increases C-C Chemokine Receptor Type 7 (CCR7) Expression in Plaque Macrophages. Circulation 138:1850-1863
Zhu, Lin; Shi, Jeanne; Luu, Thao N et al. (2018) Hepatocyte estrogen receptor alpha mediates estrogen action to promote reverse cholesterol transport during Western-type diet feeding. Mol Metab 8:106-116
Zhu, Lin; Luu, Thao; Emfinger, Christopher H et al. (2018) CETP Inhibition Improves HDL Function but Leads to Fatty Liver and Insulin Resistance in CETP-Expressing Transgenic Mice on a High-Fat Diet. Diabetes 67:2494-2506
Palmisano, Brian T; Zhu, Lin; Stafford, John M (2017) Role of Estrogens in the Regulation of Liver Lipid Metabolism. Adv Exp Med Biol 1043:227-256
Dai, Chunhua; Kayton, Nora S; Shostak, Alena et al. (2016) Stress-impaired transcription factor expression and insulin secretion in transplanted human islets. J Clin Invest 126:1857-70
Palmisano, Brian T; Le, Thao D; Zhu, Lin et al. (2016) Cholesteryl ester transfer protein alters liver and plasma triglyceride metabolism through two liver networks in female mice. J Lipid Res 57:1541-51
Zhu, Lin; Giunzioni, Ilaria; Tavori, Hagai et al. (2016) Loss of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 Confers Resistance to the Antiatherogenic Effects of Tumor Necrosis Factor-? Inhibition. Arterioscler Thromb Vasc Biol 36:1483-95
Saunders, Diane; Powers, Alvin C (2016) Replicative capacity of ?-cells and type 1 diabetes. J Autoimmun 71:59-68
Cappel, David A; Lantier, Louise; Palmisano, Brian T et al. (2015) CETP Expression Protects Female Mice from Obesity-Induced Decline in Exercise Capacity. PLoS One 10:e0136915

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