Decreased Transcription of ChREBP-α/β Isoforms in Abdominal Subcutaneous Adipose Tissue of Obese Adolescents With Prediabetes or Early Type 2 Diabetes

Abstract

Insulin resistance associated with altered fat partitioning in liver and adipose tissues is a prediabetic condition in obese adolescents. We investigated interactions between glucose tolerance, insulin sensitivity, and the expression of lipogenic genes in abdominal subcutaneous adipose and liver tissue in 53 obese adolescents. Based on their 2-h glucose tests they were stratified in the following groups: group 1, 2-h glucose level <120 mg/dL; group 2, 2-h glucose level between 120 and 140 mg/dL; and group 3, 2-h glucose level >140 mg/dL. Liver and adipose tissue insulin sensitivity were greater in group 1 than in group 2 and group 3, and muscle insulin sensitivity progressively decreased from group 1 to group 3. The expression of the carbohydrate-responsive element-binding protein (ChREBP) was decreased in adipose tissue but increased in the liver (eight subjects) in adolescents with impaired glucose tolerance or type 2 diabetes. The expression of adipose ChREBPα and ChREBPβ was inversely related to 2-h glucose level and positively correlated to insulin sensitivity. Improvement of glucose tolerance in four subjects was associated with an increase of ChREBP/GLUT4 expression in the adipose tissue. In conclusion, early in the development of prediabetes/type 2 diabetes in youth, ChREBPβ expression in adipose tissue predicts insulin resistance and, therefore, might play a role in the regulation of glucose tolerance.

ChREBP regulates fructose-induced glucose production independently of insulin signaling

“…By induce G6pc and overcome insulin's ability to suppress it? These questions are motivated by reports that ChREBP-β expression as a marker of ChREBP activity is increased in livers from obese, insulin-resistant humans (57,58). Here we show that fructose feeding induces G6PC activity and HGP and this is dominant over insulin's effect of reducing G6pc expression via regulation of FOXO1A.…”

Recent progress on the role of ChREBP in glucose and lipid metabolism [Review]

“…In addition, Chrebp mRNA expression decreases during the development of non-alcoholic steatohepatitis [70]. A couple of groups have reported that in adolescents with impaired glucose tolerance or T2DM (type 2 diabetes mellitus), the expression of ChREBP was increased in the liver [75,76]. Similarly, hepatic Chrebp mRNA levels in obese subjects were much higher than in lean subjects [77].…”

“…Similarly, ChREBP is increased during differentiation of human omental and subcutaneous preadipocytes [77]. In adolescents with impaired glucose tolerance or T2DM, the expression of Chrebp is decreased in adipose tissue but increased in the liver [75]. It has been reported that decreased expression of Chrebp causes a decrease in peripheral glucose uptake and worsens insulin resistance through decreased expression of glucose transporter type 4 (Glut4) mRNA [25,76].…”

Le facteur de transcription ChREBP

“…Cette étude ayant été publiée avant l'identification de ChREBPβ, les auteurs ne font donc pas la distinction entre les deux isoformes et n'établissent pas non plus de corrélation entre l'expression de ChREBP et la sensibilité à l'insuline [29]. Dans une autre cohorte de sujets obèses (BMI = 38) et insulino-résistants (classés selon trois groupes : 1-glycémie < 120 mg/dl ; 2-glycémie comprise entre 120 et 140 mg/dl ; 3-glycémie > 140 mg/dl), une corrélation positive entre l'expression de ChREBPα (mais pas de ChREBPβ) et la sévérité de la résistance à l'insuline a pu être mise en évidence [30]. L'étude de Eissing et collaborateurs [31], quant à elle, rapporte une corrélation positive entre la résistance à l'insuline et l'expression de ChREBPβ dans le foie de sujets obèses et résistants à l'insuline (BMI = 54).…”

“…Des études de cohortes ont pu mettre en évidence un lien entre l'expression de ChREBPβ dans le tissu adipeux blanc et la sensibilité à l'insuline chez l'Homme. En effet, une corrélation négative entre l'expression de ChREBPβ dans le tissu adipeux sous-cutané et l'indice de résistance à l'insuline a été observée pour des individus de corpulence identique (37,4 < BMI < 38,5) dans une cohorte d'adolescents pré-diabétiques [30]. De la même façon, une corrélation inverse entre l'expression de ChREBPβ dans le tissu adipeux viscéral de patients obèses (BMI = 51,4) et la résistance à l'insuline a pu être également mise en évidence [31].…”