Inhibition of 11β-hydroxysteroid dehydrogenase type 1 reduces food intake and weight gain but maintains energy expenditure in diet-induced obese mice

Abstract

Aims/hypothesis: The 11β-hydroxysteroid dehydrogenase type-1 inhibitor BVT.2733 lowers blood glucose and insulin in mutant mouse models of obesity and diabetes. Its effects on energy balance and body composition, and their contribution to improved glucose homeostasis have received little attention. Materials and methods: BVT.2733 (100 mg/kg, orally) was given twice daily to lean and diet-induced obese mice for 16 or 17 days. A group of obese mice was pair-fed to the amounts consumed by BVT.2733-treated mice. Results: In both obese and lean mice, BVT.2733 reduced food intake and weight gain, but increased water intake. Pair-feeding caused almost as great a decrease in body weight as BVT.2733. Energy expenditure was 38±8% higher in the BVT.2733-treated obese mice than in the pair-fed mice. Terminal plasma corticosterone was raised, lean body weight reduced and percentage fat unchanged in the pairfed mice (control, 47.8±2.6%; pair-fed, 47.1±1.9%), whereas BVT.2733 did not reduce lean mass, but did reduce percentage fat (40.9±2.0%). BVT.2733 but not pairfeeding reduced both the glucose tolerance AUC and the plasma insulin concentration 30 min after giving glucose. Conclusions/interpretation: BVT.2733 reduced food intake but prevented a concomitant reduction in lean body mass and energy expenditure. The latter effects may have contributed to improved glucose tolerance.

Obesity and corticosteroids: 11β-Hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease

“…Clarification of the potentially beneficial effects on (adipose and myocardial) angiogenesis will be needed. Central effects of 11 -HSD1 on appetite (Densmore et al, 2006) have been observed and some (Hermanowski-Vosatka 2005, Gu et al, 2005, Wang et al, 2006, but not all inhibitor studies report an effect on food intake. Since this appears to be weight loss, this could be a positive therapeutic effect.…”

Additive action of 11β-HSD1 inhibition and PPAR-γ agonism on hepatic steatosis and triglyceridemia in diet-induced obese rats

“…It is noteworthy that ingestive behavior, a major confounding factor with regard to lipid metabolism, was not affected by low-dose CA as is the case in 11b-HSD1 -/-mice 9 or with higher doses of various inhibitors reported earlier. 10,11 This allowed assessment in this study of the direct, food intake-independent effects of 11b-HSD1 inhibition in the context of diet-induced obesity.…”

11β-Hydroxysteroid Dehydrogenase Type 1 and the Metabolic Syndrome

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