Human obesity and type 2 diabetes are associated with alterations in SREBP1 isoform expression that are reproduced ex vivo by tumor necrosis factor-α

Ciaran Sewter, Dirk Berger, Robert Considine, Gema Medina, Justin Rochford, Theodore Ciaraldi, Robert Henry, Lynis Dohm, Jeffrey S. Flier, Stephen O'Rahilly, Antonio J. Vidal-Puig

Research output: Contribution to journalArticle

113 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1035-1041
Number of pages7
JournalDiabetes
Volume51
Issue number4
StatePublished - 2002

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Type 2 Diabetes Mellitus
Protein Isoforms
Tumor Necrosis Factor-alpha
Obesity
Sterol Regulatory Element Binding Protein 1
Hyperinsulinism
Insulin
Adipocytes
Adipose Tissue
Skeletal Muscle
Gene Expression
Adipogenesis
Subcutaneous Fat
Transcription Factors
Fatty Acids
Messenger RNA
Health

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Sewter, C., Berger, D., Considine, R., Medina, G., Rochford, J., Ciaraldi, T., ... Vidal-Puig, A. J. (2002). Human obesity and type 2 diabetes are associated with alterations in SREBP1 isoform expression that are reproduced ex vivo by tumor necrosis factor-α. Diabetes, 51(4), 1035-1041.

Human obesity and type 2 diabetes are associated with alterations in SREBP1 isoform expression that are reproduced ex vivo by tumor necrosis factor-α. / Sewter, Ciaran; Berger, Dirk; Considine, Robert; Medina, Gema; Rochford, Justin; Ciaraldi, Theodore; Henry, Robert; Dohm, Lynis; Flier, Jeffrey S.; O'Rahilly, Stephen; Vidal-Puig, Antonio J.

In: Diabetes, Vol. 51, No. 4, 2002, p. 1035-1041.

Research output: Contribution to journalArticle

Sewter, C, Berger, D, Considine, R, Medina, G, Rochford, J, Ciaraldi, T, Henry, R, Dohm, L, Flier, JS, O'Rahilly, S & Vidal-Puig, AJ 2002, 'Human obesity and type 2 diabetes are associated with alterations in SREBP1 isoform expression that are reproduced ex vivo by tumor necrosis factor-α', Diabetes, vol. 51, no. 4, pp. 1035-1041.
Sewter, Ciaran ; Berger, Dirk ; Considine, Robert ; Medina, Gema ; Rochford, Justin ; Ciaraldi, Theodore ; Henry, Robert ; Dohm, Lynis ; Flier, Jeffrey S. ; O'Rahilly, Stephen ; Vidal-Puig, Antonio J. / Human obesity and type 2 diabetes are associated with alterations in SREBP1 isoform expression that are reproduced ex vivo by tumor necrosis factor-α. In: Diabetes. 2002 ; Vol. 51, No. 4. pp. 1035-1041.
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