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Title: The glucose sensor ChREBP links de-novo lipogenesis to PPARgamma activity and adipocyte differentiation

Author
item WITTE, NICOLE - Charite' University Hospital Berlin
item MUENZNER, MATTHIAS - Charite' University Hospital Berlin
item RIETSCHER, JANITA - Charite' University Hospital Berlin
item KNAUER, MIRIAM - Charite' University Hospital Berlin
item HEIDENREICH, STEFFI - Charite' University Hospital Berlin
item NUOTIO-ANTAR, ALLI - Children'S Nutrition Research Center (CNRC)
item GRAEF, FRANZISKA - Charite' University Hospital Berlin
item FEDDERS, RONJA - Charite' University Hospital Berlin
item TOKACHOV, ALEXANDER - Charite' University Hospital Berlin
item GOEHRING, ISABEL - Charite' University Hospital Berlin
item SCHUPP, MICHAEL - Charite' University Hospital Berlin

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/14/2015
Publication Date: 7/16/2015
Citation: Witte, N., Muenzner, M., Rietscher, J., Knauer, M., Heidenreich, S., Nuotio-Antar, A.M., Graef, F.A., Fedders, R., Tokachov, A., Goehring, I., Schupp, M. 2015. The glucose sensor ChREBP links de-novo lipogenesis to PPARgamma activity and adipocyte differentiation. Endocrinology. http://dx.doi.org/10.1210/EN.2015-1209.

Interpretive Summary: In obese individuals, the production of fatty acids from excess glucose has been shown to be reduced in fat cells, and this has been associated with reduced expression of carbohydrate response element binding protein (ChREBP), a protein that regulates the expression of enzymes that are involved in this process. However, not much is known about the physiological role of ChREBP in fat cells. We found that ChREBP promotes the maturation of fat cells and increases their ability to produce heat. Conversely, deficiency of ChREBP activity prevented normal maturation of fat cells. These results suggest that the reduced activity of ChREBP observed in fat tissue of obese individuals may have negative consequences on their health and indicate that ChREBP may protect against type 2 diabetes, in part by promoting further maturation of fat cells.

Technical Abstract: Reduced de-novo lipogenesis DNL)in adipose tissue, often observed in obese individuals, is thought to contribute to insulin resistance. Besides trapping excess glucose and providing for triglycerides and energy storage, endogenously synthesized lipids can function as potent signaling molecules. Indeed, several specific lipids and their molecular targets that mediate insulin sensitivity have been recently identified. Here we report that carbohydrate response element binding protein (ChREBP), a transcriptional inducer of glucose utilization and DNL, controls the activity of the adipogenic master regulator peroxisome proliferator-activated receptor (PPAR)gamma. Expression of constitutive-active ChREBP (CA) in precursor cells activated endogenous PPARgamma and promoted adipocyte differentiation. Intriguingly, ChREBP-CA expression induced PPAR' activity in a fatty acid synthase-dependent manner and by trans-activating the PPAR' ligand binding domain. Reducing endogenous ChREBP activity by either siRNA-mediated depletion, exposure to low glucose concentrations, or expressing a dominant-negative ChREBP impaired differentiation. In adipocytes, ChREBP regulated the expression of PPARgamma target genes, in particular those involved in thermogenesis, similar to synthetic PPARgamma ligands. In summary, our data suggest that ChREBP controls the generation of endogenous fatty acid species that activate PPARgamma. Thus, increasing ChREBP activity in adipose tissue by therapeutic interventions may promote insulin sensitivity through PPARgamma.