Obesity, particularly abdominal (visceral) obesity, is a major risk factor for development of the metabolic syndrome. Human and animal studies have shown elevated intra-adipose glucocorticoid-action in obesity and suggest that increased glucocorticoid receptor (GR) density may be an important determinant of visceral adiposity. We have tested this hypothesis in transgenic (Tg) mice in which adipose GR levels have been increased or decreased, by expression of sense or antisense rat GR cDNA under control of the adipocyte-specific aP2 promoter.
Transgenic expression of antisense GR (AS-GR) reduced adipose GR mRNA levels by in the mesenteric, subcutaneous and gonadal depots in both males and females by 2060%. (P<0.05). On chow diet, adipose mass (all depos) was modestly reduced (3040%) in transgenic (Tg AS-GR) female mice vs. wild type (WT). Female Tg AS-GR mice had a substantially reduced body weight gain after 24 weeks on both high fat and low fat diets for 24 weeks (HF Tg AS-GR 31.8 g±1.8 g, WT 42.35g±2.2 g, P<0.05: LF Tg AS-GR 22.5 g±0.5 g, WT 25.38 g±0.8 g,) despite unaltered food intake. Further, Tg AS-GR females had a marginally elevated core body temperature, indicative of a higher basal metabolic rate, when measured by rectal probe (Tg AS-GR, 37.2 °C, ±0.15, n=6; WT 36.8±0.2 °C, n=7) and improved glucose tolerance (ANOVA of AUC Tg versus WT, P<0.02). Tg AS-GR males did not differ from WT littermates either on LF or HF diet. Conversely, transgenic expression of sense GR (S-GR) increases adipose mass only in female mice (~50% greater subcutaneous, ~50% mesenteric and ~40% gonadal mass vs non-tg littermates. Thus, these data support the hypothesis that adipose GR density influences fat deposition and metabolic state and confirm previous studies of sex-dependent differences in the development of the metabolic syndrome in rodents.