Endocrine Abstracts

Glucocorticoids (GC) are critical to stress adaptation but in excess (Cushing’s syndrome) drive metabolic dysfunction. 11β-hydroxysteroid dehydrogenase type 1(11β-HSD1) amplifies intracellular GC signaling with 11β-HSD1KO mice protected from the side-effects of GC excess. Brown adipose tissue (BAT) function is impaired by GC’s, which repress UCP1 and beta-adrenergic stimulated thermogenesis. Identifying mechanisms regulating BAT function is important as humans have metabolically useful BAT, with more active BAT associated with enhanced energy dissipation. We postulated 11β-HSD1 plays a novel role in controlling BAT GC exposure, moderating thermogenic capacity. To test this 11β-HSD1KO mice were administered corticosterone over 4-weeks mimicking GC excess and BAT function assessed. Cultured BAT adipocyte energy metabolism was assessed measuring Oxygen consumption rates (OCR)±GC±beta-adrenergic stimulation. Profiling by qPCR and immunoblot for metabolic and mitochondrial function was conducted. GC excess increases 11β-HSD1 and impairs BAT in WT mice which display decreased UCP1 protein, expression of BAT-specific markers (PGC1a, PPARg, TFAM), and reduced OxPhos complexes content. Conversely, 11β-HSD1KO mice retained UCP1 to untreated control levels, resisted suppression of BAT expression markers and maintained expression of OxPhos complexes. GC exposed primary brown adipocytes from 11β-HSD1KO resisted suppression of UCP1 and of BAT genes. KO cells also demonstrated enhanced adaptation to cold stress at 30°C. Also KO cells have 30% higher basal OCR, which is not supressed by GC. Finally, beta-3 adrenergic stimulation of the BAT thermogenic program was enhanced in 11β-HSD1KO by 20%, and again was not supressed by GCs. We show that 11β-HSD1 regulates BAT energy metabolism and cell autonomous control of the thermogenic program in response to cold stress and beta-adrenergic stimulation. BAT may contribute to the metabolic derangements seen in GC excess through suppression of its capacity to dissipate energy, suggesting inhibition of 11β-HSD1 in BAT in the context of Cushing’s syndrome may be beneficial.