The metabolic syndrome is a cluster of disorders that includes obesity, dyslipidemia, hypertension, non- alcoholic fatty liver disease and insulin resistance, all of which predispose to the development of diabetes and cardiovascular disease. Epidemiological and clinical data indicate that increased sugar, and particularly fructose, ingestion is a major contributor to the development of the metabolic syndrome and progression to diabetes. The mechanisms by which fructose consumption causes metabolic dysfunction remain elusive. Carbohydrate Responsive-Element Binding Protein (ChREBP) is a master transcriptional regulator of glycolytic and lipogenic gene programs which is activated by products of carbohydrate metabolism. SNPs in the ChREBP locus identified in genome-wide association studies predict features of the metabolic syndrome in human populations. We recently discovered a novel, potent constitutively active isoform of ChREBP, ChREBP-beta. In vivo, ChREBP-beta expression is acutely and robustly increased by fructose ingestion, but only modestly by glucose ingestion. Mice with whole-body genetic deletion of ChREBP die within several days of high-fructose feeding. In this proposal, we will pursue an integrative physiological approach to determine the role of ChREBP in fructose-induced metabolic disturbances. We hypothesize that ChREBP, and particularly ChREBP-beta, is a key regulatory element that is required for the normal adaptive metabolic response to fructose ingestion and also contributes to the development of metabolic disease and diabetes when sugar is consumed in excess. Using a combination of genetic and dietary interventions in mouse models, we will evaluate the role of ChREBP in integrated fuel homeostasis by pursuing the following three aims.
In Aim 1, using tissue-specific, loss-of-function mouse models, we will explore the physiologic and cellular mechanisms by which the absence of ChREBP impairs integrated fuel homeostasis and causes fructose intolerance.
In Aim 2, using a ChREBP gain-of-function mouse model combined with diets of different carbohydrate content and composition, we will explore a novel concept that the effects of ChREBP activity on integrated fuel homeostasis and insulin sensitivity depend on the nutritional context.
In Aim 3, we will develop a novel, ChREBP-beta isoform specific conditional loss-of-function mouse model to begin to determine the physiological significance of the distinct ChREBP isoforms in relation to integrated fuel metabolism and fructose induced metabolic disease. We anticipate that these studies will provide fundamental insight into mechanisms of fructose-induced metabolic disease and lay the groundwork for novel strategies for the prevention and treatment of obesity and diabetes.
Increased sugar consumption is a major contributor to the obesity and diabetes epidemics, and the fructose component of table sugar appears to be particularly harmful. We have identified a key cellular factor called ChREBP that appears to play an important role in the biological response to fructose consumption. Using animal models, we will explore the function of this factor in fructose metabolism which will provide the crucial insiht needed to develop rational strategies to prevent and treat diabetes and obesity.
|Fisher, Ffolliott M; Kim, MiSung; Doridot, Ludivine et al. (2017) A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism. Mol Metab 6:14-21|
|Ter Horst, Kasper W; Gilijamse, Pim W; Demirkiran, Ahmet et al. (2017) The FGF21 response to fructose predicts metabolic health and persists after bariatric surgery in obese humans. Mol Metab 6:1493-1502|
|Kim, MiSung; Astapova, Inna I; Flier, Sarah N et al. (2017) Intestinal, but not hepatic, ChREBP is required for fructose tolerance. JCI Insight 2:|
|Herman, Mark A; Samuel, Varman T (2016) The Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis. Trends Endocrinol Metab 27:719-730|
|Kim, Mi-Sung; Krawczyk, Sarah A; Doridot, Ludivine et al. (2016) ChREBP regulates fructose-induced glucose production independently of insulin signaling. J Clin Invest 126:4372-4386|
|Jiang, Zhenghui G; Tapper, Elliot B; Connelly, Margery A et al. (2016) Steatohepatitis and liver fibrosis are predicted by the characteristics of very low density lipoprotein in nonalcoholic fatty liver disease. Liver Int 36:1213-20|
|Zhang, Pili; Kumar, Anil; Katz, Liora S et al. (2015) Induction of the ChREBP? Isoform Is Essential for Glucose-Stimulated ?-Cell Proliferation. Diabetes 64:4158-70|
|Dushay, Jody R; Toschi, Elena; Mitten, Emilie K et al. (2015) Fructose ingestion acutely stimulates circulating FGF21 levels in humans. Mol Metab 4:51-7|