Major gaps exist in our knowledge of the molecular mechanisms underlying insulin resistance and type 2 diabetes. Dysregulation of both glucose and lipid metabolism play a role. This proposal investigates the mechanistic links between these pathways. Fatty acid synthesis (de novo lipogenesis, DNL) is elevated in liver in obesity and type 2 diabetes and is usually associated with insulin resistance. In contrast, our new data indicate DNL in adipose tissue is metabolically beneficial since it promotes insulin sensitivity an protects against high fat diet-induced insulin resistance. Furthermore, in humans, increased lipogenic enzyme expression in adipose tissue is associated with enhanced insulin sensitivity. One of the major transcriptional regulators of DNL is Carbohydrate responsive-element binding protein (ChREBP), a glucose-responsive transcription factor. ChREBP has been studied mainly in liver and pancreatic cells where it regulates fatty acid synthesis and glycolysis. ChREBP knockout mice have mild diet-related insulin resistance. However, knocking down the elevated ChREBP expression in liver of obese mice improves insulin sensitivity and metabolic syndrome. The effects of selective ChREBP knockdown in adipose tissue have not been studied. Our recent paper demonstrates that adipose tissue ChREBP is a key determinant of systemic insulin sensitivity and glucose homeostasis in humans and rodents. The goal of this application is to integrate whole animal and cellular studies to define the physiological, cellular and molecular mechanisms underlying the effects of ChREBP in adipose tissue to promote insulin sensitivity. We will create mice that overexpress or lack ChREBP selectively in adipocytes.
Aim 1 is to determine whether increased expression of ChREBP selectively in adipocytes is sufficient to enhance systemic insulin sensitivity and improve glucose homeostasis.
Aim 2 is to determine whether absence of ChREBP selectively in adipocytes causes systemic insulin resistance. In addition to physiological and metabolic characterization, in both aims we will perform genomic and lipidomic analyses of adipose tissue and serum to identify pathways associated with insulin sensitivity and insulin resistance.
Aim 3 is to determine the cellular mechanisms by which ChREBP regulates de novo lipogenesis in adipocytes. Molecular, cell biological, biochemical and quantitative microscopy methods will be used to determine the mechanisms for regulation of ChREBP nuclear-cytoplasmic shuttling and activation in adipocytes, and the potential role of insulin signaling in regulation of adipose-ChREBP activity. Overall, this project will provide physiological, molecular, and cellular insights into ChREBP regulation. Because reduced ChREBP expression in adipose tissue of obese humans correlates highly with insulin resistance, understanding the mechanisms that regulate ChREBP in adipocytes could lead to novel therapeutic approaches to prevent and treat type 2 diabetes.

Public Health Relevance

We are in the midst of a growing epidemic of obesity, insulin resistance and type 2 diabetes. There are few sustainable prevention strategies and not enough fully effective treatments for these serious disorders. Major gaps exist in our knowledge of the molecular mechanisms underlying insulin resistance and type 2 diabetes, limiting our ability to develop highly effective and safe therapies. Significant attention has focused on understanding the problems with glucose or lipid metabolism separately but the mechanistic links between these pathways are poorly understood. This proposal addresses this critical interface through studies in adipose tissue of a glucose-controlled protein, ChREBP, that regulates lipid synthesis. Our recently published work demonstrates that ChREBP in fat tissue has an essential role in regulation of insulin-sensitivity and glucose homeostasis. Understanding the physiologic, cellular and molecular mechanisms for regulation of ChREBP in fat cells could provide new insights into the pathogenesis of obesity and type 2 diabetes and new treatment opportunities

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Laughlin, Maren R
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Beth Israel Deaconess Medical Center
United States
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Vijayakumar, Archana; Aryal, Pratik; Wen, Jennifer et al. (2017) Absence of Carbohydrate Response Element Binding Protein in Adipocytes Causes Systemic Insulin Resistance and Impairs Glucose Transport. Cell Rep 21:1021-1035
Gr├╝nberg, John R; Hoffmann, Jenny M; Hedjazifar, Shahram et al. (2017) Overexpressing the novel autocrine/endocrine adipokine WISP2 induces hyperplasia of the heart, white and brown adipose tissues and prevents insulin resistance. Sci Rep 7:43515
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Zhang, Tejia; Chen, Shili; Syed, Ismail et al. (2016) A LC-MS-based workflow for measurement of branched fatty acid esters of hydroxy fatty acids. Nat Protoc 11:747-63
Kolar, Matthew J; Kamat, Siddhesh S; Parsons, William H et al. (2016) Branched Fatty Acid Esters of Hydroxy Fatty Acids Are Preferred Substrates of the MODY8 Protein Carboxyl Ester Lipase. Biochemistry 55:4636-41
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