Acute Antiobesity Effects of Intracerebroventricular 11β-HSD1 Inhibitor Administration in Diet-induced obese mice

Abstract

Hypothalamus is the regulatory center of both appetite and energy balance, and endoplasmic reticulum (ER) stress in the hypothalamus is involved in the pathogenesis of obesity. Recently, inhibition of 11 β hydroxysteroid dehydrogenase type1 (11β-HSD1) was reported to have an anti-obesity effect by reducing fat mass. However, link between the role of 11β-HSD1 in hypothalamus and obesity has yet to be elucidated. In this study, embryonal primary hypothalamic neurons and high fat diet (HFD) fed mice were used to investigate the anorexigenic effects of 11β-HSD1 inhibitors in in vitro and in vivo. In hypothalamic neurons, carbenoxolone (a non selecitve 11β-HSD inhibitor) alleviated ER stress and ER stress-induced neuropeptide alterations. In HFD mice, intracerebroventricular (ICV) administrations of carbenoxolone or KR67500 (non-selective and selective 11β-HSD1 inhibitors, respectively) were associated with less weight gain than controls for 24 hours after the treatment, presumably by reducing food intake. Furthermore, glucose regulated protein(Grp78), spliced X-box binding protein(Xbp-1s), c/EBP homologous protein (chop), and ER DnaJ homolog protein(Erdj4) expressions were decreased in the hypothalami of mice administrated 11β-HSD1inhibitors as compared with controls. Conversely the phosphorylations of protein kinase B (PKB/Akt), signal transducers and activators transcription 3 (Stat3), mitogen activated protein kinase (MAPK/ERK), S6 kinase1 (S6K1) in hypothalamus were more induced in mice treated using the same regimes. In conclusion, acute11β-HSD1 inhibition in hypothalamus could reduce food intake by decreasing ER stress and increasing insulin, leptin, and mammalian target of rapamycin complex 1(mTORC1) signaling.

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