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Title: FABP4-Cre mediated expression of constitutively active ChREBP protects against obesity

Author
item NUOTIO-ANTAR, ALLI - Children'S Nutrition Research Center (CNRC)
item POUNGVARIN, NARAVAT - Baylor College Of Medicine
item LI, MING - Baylor College Of Medicine
item SCHUPP, MICHAEL - Charite' University Hospital Berlin
item MOHAMMAD, MAHMOUD - Children'S Nutrition Research Center (CNRC)
item GERARD, SARAH - Children'S Nutrition Research Center (CNRC)
item ZOU, FANG - Children'S Nutrition Research Center (CNRC)
item CHAN, LAWRENCE - Baylor College Of Medicine

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/3/2015
Publication Date: 11/20/2015
Citation: Nuotio-Antar, A.M., Poungvarin, N., Li, M., Schupp, M., Mohammad, M., Gerard, S., Zou, F., Chan, L. 2015. FABP4-Cre mediated expression of constitutively active ChREBP protects against obesity. Endocrinology. 11:4020-4032.

Interpretive Summary: Carbohydrate response element binding protein (ChREBP) is a glucose sensing protein whose activity in fat cells has been inversely associated with obesity in humans. However, not much is known about the physiological role of ChREBP in fat cells. Using mice in which ChREBP activity is increased in fat cells, we found that ChREBP promotes the maturation of fat cells, increases the energy-burning capacity of fat cells, alters the way that fat cells handle fatty acids, and reduces fat tissue inflammation. When these mice were placed on a high fat, high sucrose, and high cholesterol Western-type diet, fat-specific ChREBP-overexpressing mice exhibited blunted weight gain and improved insulin sensitivity in comparison with control mice. These results suggest that future drug therapies that increase the activity of ChREBP in fat tissue of obese individuals may promote weight loss and protect against type 2 diabetes.

Technical Abstract: Carbohydrate response element binding protein (ChREBP) regulates cellular glucose and lipid homeostasis. Although ChREBP is highly expressed in many key metabolic tissues, the role of ChREBP in most of those tissues and consequent effects on whole-body glucose and lipid metabolism are not well understood. Therefore, we generated a transgenic mouse that overexpresses a constitutively active ChREBP isoform under the control of the Fabp4-Cre-driven promoter (FaChOX). Weight gain was blunted in male, but not female, FaChOX mice when placed on either normal chow diet or obesogenic Western diet. Respiratory exchange ratios were increased in Western diet-fed FaChOX mice, indicating a shift in whole-body substrate utilization favoring carbohydrate metabolism. Western diet-fed FaChOX mice showed improved insulin sensitivity and glucose tolerance in comparison with controls. Hepatic triglyceride content was reduced in Western diet-fed FaChOX mice in comparison with controls, suggesting protection from fatty liver. Epididymal adipose tissue exhibited differential expression of genes involved in differentiation, "browning," metabolism, lipid homeostasis, and inflammation between Western diet-fed FaChOX mice and controls. Our findings support a role for ChREBP in modulating adipocyte differentiation and adipose tissue metabolism and inflammation, as well as consequent risk for obesity and insulin resistance.