Effects of metyrapone on food intake, body weight and leptin signaling in the brain in diet-induced obesity (DIO)

Metyrapone, a 11-beta steroid hydroxylase inhibitor, may both act to inhibit adrenal steroid genesis and to enhance hypothalamic-pituitary axis activity as a stressor. Moreover, there are reports in the literature that it affects food intake and body weight regulation. We thus decided to study the effects of metyrapone on physiological parameters such as body weight and leptin signalling in control and DIO mice.

C57BL/6J mice fed either normal chow or high-fat-diet for 20 weeks and received metyrapone for another 4 weeks via the intraperitoneal (ip) route. As endpoints we compared body weight changes, food intake, endocrine parameters and the ability of STAT3 (signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) to be phosphorylated. Under metyrapone treatment control and DIO mice lost a substantial amount of body weight, had lower plasma leptin levels, increased plasma ACTH and increased plasma corticosterone levels. The STAT3 phosphorylation in the hypothalamus of the control and DIO mice was two fold higher in the Metyrapone treatment group when compared to the saline control, but the MAPK activity was only increased in the DIO mice. The STAT3 activity in cortex, cerebellum and hippocampus was significantly increased in the DIO only. These results suggest a direct effect of metyrapone on body weight, despite elevated plasma levels of corticosterone levels. These findings support the previously described dose-dependent metyrapone effects as a stressor. The increased STAT3 and MAPK activity might be explained by direct effect of metyrapone and /or indirect effects by increasing the transport capacity of leptin via the blood brain barrier into the brain.