The metabolic syndrome is a cluster of disorders that includes obesity, hypertriglyceridemia, hypertension, non-alcoholic fatty liver disease and insulin resistance which predispose to the development of diabetes and cardiovascular disease. Excessive sugar consumption, predominantly in the form of sugar- sweetened beverages, can contribute to the development of the metabolic syndrome. The mechanisms by which excessive fructose consumption contributes to metabolic disease remain uncertain. Carbohydrate Responsive- Element Binding Protein (ChREBP) is a transcription factor which is activated by products of carbohydrate metabolism and regulates metabolic gene programs and systemic glucose and lipid homeostasis. SNPs in the ChREBP locus identified in genome-wide association studies predict features of the metabolic syndrome in human populations. Hepatic and intestinal ChREBP are highly responsive to fructose ingestion. Loss of intestinal ChREBP results in fructose-intolerance due to fructose malabsorption. In contrast, loss of hepatic ChREBP is well-tolerated and protects against fructose-induced metabolic disease. Some mouse strains are highly sensitive to fructose-induced disease whereas others are highly resistant. Preliminary data suggests that this susceptibility may be mediated by relative differences in intestinal fructose absorption and metabolism, which may affect delivery of fructose to the liver where it is deleterious. Understanding the molecular determinants of intestinal versus hepatic fructose metabolism may have important implications for the susceptibility to diet-induced disease. Through a combination of genetic and dietary models, we will investigate physiological, molecular, and genetic mechanisms by which ChREBP-mediated intestinal and hepatic fructose metabolism protect against or contribute to fructose-induced disease.
In Aim 1, using an intestine-specific, loss-of-function mouse model, we will explore the importance of intestinal fructose metabolism in regulating endogenous glucose production and mediating fructose-induced disease.
In Aim 2, we will determine whether the net beneficial versus adverse effects of hepatic ChREBP activation may be dependent on the metabolic hormone FGF21.
In Aim 3, using fructose sensitive and fructose resistant mice in combination with an intestinal organoid model, we will explore the molecular mechanisms giving rise to differences in intestinal fructose absorption, metabolism, and susceptibility to fructose-induced 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.

Public Health Relevance

Increased sugar consumption contributes to the obesity and diabetes epidemics, and the fructose component of sugar appears to be particularly harmful. We have demonstrated that a key cellular factor called ChREBP plays an important role in intestinal and liver fructose metabolism and participates in fructose-induced disease. Using animal models, we will explore the mechanisms by which this factor and additional genetic factors participate in fructose-induced disease, which will provide the basic knowledge needed to develop rational strategies to prevent and treat obesity, diabetes, and associated metabolic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK100425-08
Application #
10117227
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Laughlin, Maren R
Project Start
2014-01-15
Project End
2024-02-29
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
8
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Kumar, Anil; Katz, Liora S; Schulz, Anna M et al. (2018) Activation of Nrf2 Is Required for Normal and ChREBP?-Augmented Glucose-Stimulated ?-Cell Proliferation. Diabetes 67:1561-1575
Hannou, Sarah A; Haslam, Danielle E; McKeown, Nicola M et al. (2018) Fructose metabolism and metabolic disease. J Clin Invest 128:545-555
McKeown, Nicola M; Dashti, Hassan S; Ma, Jiantao et al. (2018) Sugar-sweetened beverage intake associations with fasting glucose and insulin concentrations are not modified by selected genetic variants in a ChREBP-FGF21 pathway: a meta-analysis. Diabetologia 61:317-330
White, Phillip J; McGarrah, Robert W; Grimsrud, Paul A et al. (2018) The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase. Cell Metab 27:1281-1293.e7
Haslam, Danielle E; McKeown, Nicola M; Herman, Mark A et al. (2017) Interactions between Genetics and Sugar-Sweetened Beverage Consumption on Health Outcomes: A Review of Gene-Diet Interaction Studies. Front Endocrinol (Lausanne) 8:368
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
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
Kim, MiSung; Astapova, Inna I; Flier, Sarah N et al. (2017) Intestinal, but not hepatic, ChREBP is required for fructose tolerance. JCI Insight 2:
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
Herman, Mark A; Samuel, Varman T (2016) The Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis. Trends Endocrinol Metab 27:719-730

Showing the most recent 10 out of 13 publications