4 research outputs found
Human obesity and type 2 diabetes are associated with alterations in SREBP1 isoform expression that are reproduced ex vivo by tumor necrosis factor-α
Sterol regulatory element binding protein (SREBP)-1 is a transcription factor with important roles in the control of fatty acid metabolism and adipogenesis. Little information is available regarding the expression of this molecule in human health or disease. Exposure of isolated human adipocytes to insulin enhanced SREBP1 gene expression and promoted its proteolytic cleavage to the active form. Furthermore, 3 h of in vivo hyperinsulinemia also significantly increased SREBP1 gene expression in human skeletal muscle. Transcript levels of SREBP1c, the most abundant isoform in adipose tissue, were significantly decreased in the subcutaneous adipose tissue of obese normoglycemic and type 2 diabetic subjects compared with that of nonobese normoglycemic control subjects. In skeletal muscle, SREBP1 expression was significantly reduced in type 2 diabetic subjects but not in obese subjects. Within the diabetic group, the extent of SREBP1 suppression was inversely related to metabolic control and was normalized by 3 h of in vivo hyperinsulinemia. Exposure of isolated human adipocytes to tumor necrosis factor-α (TNF-α) produced a marked and specific decrease in the mRNA encoding the SREBPlc isoform and completely blocked the insulin-induced cleavage of SREBP1 protein. Thus, both the expression and proteolytic maturation of human SREBP1 are positively modulated by insulin. The specific reduction in the SREBPlc isoform seen in the adipose tissue of obese and type 2 diabetic subjects can be recapitulated ex vivo by TNF-α, suggesting a possible mechanism for this association.A.J.V.P. and S.O.R. are funded by Wellcome Trust, G.M. is funded by a fellowship from the Spanish Ministry of Education, D.B. is funded by Deutsche Forschunsgemeinschaft (DFG), and T.C. and R.H. are supported by a grant from Medical Research Services, Department of Veterans Affairs and VA San Diego Healthcare System, a grant from Chiron, and Grant M01 RR-00827 in support of the General Clinical Research center from the General Clinical Research Branch Division of Research Sources.Peer Reviewe