Molecular mechanisms for dysfunction of obese adipose tissue focusing on the network of NADPH producing enzymes and intracellular glucocorticoid reactivating enzyme

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Elevated expression and activity of the intracellular glucocorticoid reactivating enzyme, 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1), contribute to dysfunction of obese adipose tissue. Although the pathophysiologic role of 11β-HSD1 in obese adipose tissue has long been investigated, the mechanism whereby 11β-HSD1 is augmented in obese adipose tissue still remains obscure. In this context, in the present study, we investigated the possible involvement of chronic inflammation, oxidative stress, ceramide signals and NADPH provision from enzymes comprising of pentose pathways. In cultured adipocytes and SVF cells from obese adipose tissue from mice, enzyme activity and expression of 11β-HSD1 was augmented by TNFα, IL-1β, LPS and ceramide. Pharmacological inhibition of 11β-HSD1 and RNA interference against 11β-HSD1 reduced a line of pro-inflammatory molecules as well as substantially attenuated NF-kβ and MAPK inflammatory signaling in cultured adipocytes. Expression of enzymes comprising of pentose pathways was elevated in obese adipose tissue in proportion to the degree of obesity in both humans and mice. Forced expression of glucose-6-phosphate dehydrogenase (G6PD), a member of pentose pathways, in adipocytes augmented intracellular glucocorticoid reamplification and resultant secretion of cortisol into the media, indicating a functional link between 11β-HSD1 and NADPH provision in obese adipose tissue. Our data highlight an unexpected role of reamplified glucocorticoids and molecular basis for augmented 11β-HSD1 in obese adipose tissue.