Leptin responsiveness of mice deficient in corticotrophin-releasing hormone receptor type 2

Abstract

Leptin acts centrally to inhibit food intake and increase energy expenditure. Corticotrophin-releasing hormone (CRH) is one of the neuropeptides that may contribute to leptin-induced hypophagia and thermogenesis. Acute leptin administration increases CRH mRNA expression in the paraventricular nucleus of the hypothalamus and CRH receptor type 2 (CRHR2) expression in the ventromedial nucleus of the hypothalamus. Studies described here used male and female CRHR2 knockout (KO) mice and wild-type (WT) controls to test the importance of CRHR2 in mediating the effects of leptin on food intake, weight gain and body composition. Peripheral injections of 0.5 mg/kg leptin for 3 days inhibited food intake in female WT and male KO mice, but inhibited weight gain in female KO and male WT mice suggesting an important role for thermogenesis in mediating weight loss. A single third ventricle injection of 1 μg leptin inhibited 12 h food intake of all mice, 36 h cumulative intake of KO mice and weight loss in WT and KO female and WT male mice. A 12-day peripheral infusion of 10 μg leptin/day had no effect on food intake of any group, but significantly reduced carcass fat and protein content of all mice. These results indicate that CRHR2 are not essential for the effects of leptin on food intake, body weight or body composition. Leptin response seems to be determined by a combination of mouse gender and genotype, but CRHR2 KO mice may have an extended response to central leptin injections compared with their WT controls.

Fig. 1

Body weight expressed as a percentage of baseline weight (line graphs) and 60 h food intake (bar graph) of mice that received intraperitoneal injections of 0.5 mg/kg leptin or an equivalent volume of saline each day for 3 days in Experiment 1. Data are means ± SEM for groups of 8 mice. * Differences in weight gain of saline- and leptin-treated mice of a specific sex and genotype. Bars in the graph of food intake that do not share a common superscript are significantly different at p < 0.05.

Fig. 2

Body weight expressed as a percentage of baseline weight (line graphs) and 12 or 36 h food intake (bar graphs) of mice that received a single third ventricle injection of 1 μg of leptin in Experiment 2. Data are means ± SEM for groups of 8–11 mice. * Significant differences in weight gain of leptin-injected and PBS-injected mice of a specific sex and genotype. Values for food intake that do not share a common superscript are significantly different at p < 0.05.

Fig. 3

Daily body weights of female (a) and male mice (b) and total food intake of all of the groups of mice (c) that received continuous intraperitoneal infusions of leptin or PBS for 12 days in Experiment 3. Data are means ± SEM for groups of 6 or 8 mice. * Significant differences between PBS and leptin infused groups for both WT and KO mice. ^$ Significant difference between leptin-treated KO mice and their PBS controls. ^# Significant difference between leptin-treated KO mice and both groups of WT mice as well as PBS-treated KO mice.