Adipocyte-specific glucocorticoid inactivation protects against diet-induced obesity

Abstract

Local glucocorticoid (GC) action depends on intracellular GC metabolism by 11beta-hydroxysteroid dehydrogenases (11betaHSDs). 11betaHSD1 activates GCs, while 11betaHSD2 inactivates GCs. Adipocyte-specific amplification of GCs through transgenic overexpression of 11betaHSD1 produces visceral obesity and the metabolic syndrome in mice. To determine whether adipocyte-specific inactivation of GCs protects against this phenotype, we created a transgenic model in which human 11betaHSD2 is expressed under the control of the murine adipocyte fatty acid binding protein (aP2) promoter (aP2-h11betaHSD2). Transgenic mice have increased 11betaHSD2 expression and activity exclusively in adipose tissue, with the highest levels in subcutaneous adipose tissue, while systemic indexes of GC exposure are unchanged. Transgenic mice resist weight gain on high-fat diet due to reduced fat mass accumulation. This improved energy balance is associated with decreased food intake, increased energy expenditure, and improved glucose tolerance and insulin sensitivity. Adipose tissue gene expression in transgenic mice is characterized by decreased expression of leptin and resistin and increased expression of adiponectin, peroxisome proliferator-activated receptor gamma, and uncoupling protein 2. These data suggest that reduction of active GCs exclusively in adipose tissue is an important determinant of a favorable metabolic phenotype with respect to energy homeostasis and the metabolic syndrome.

FIG. 1

11βHSD2 and 11βHSD1 expression and activity. A: h11βHSD2 expression relative to 18S RNA in various adipose tissue depots of 24-week-old transgenic and WT mice (n = 10 per group) using quantitative real-time PCR with human kidney standard curve and a primer-probe set that detects only human and not murine 11βHSD2. B: 11βHSD2 activity (% conversion Cort→11DHC) in the above adipose tissue depots and kidney of 24-week-old transgenic mice (n = 10 per group). 11βHSD2 (C) and 11βHSD1 (D) activity (% conversion 11DHC→Cort) in SCAT of 24-week-old transgenic and WT mice on chow and HFD (n = 10 per group). Data are expressed as means ± SE. ***P < 0.001 between genotypes on a given diet; ###P < 0.001 between diet groups for a given genotype.

FIG. 2

Body weight. Body weight in transgenic and WT mice fed chow or HFD from 3 to 24 weeks of age (n = 18–22 per group). □, WT-chow; ○, transgenic-chow; ■, WT-HFD; ●, transgenic-HFD. Data are expressed as means ± SE. ****P < 0.0001 between genotypes on a given diet; ####P < 0.0001 between diet groups for a given genotype by repeated-measures ANOVA.

FIG. 3

Fat mass. A: Percent fat mass by DEXA in 24-week-old transgenic and WT mice fed chow or HFD (n = 18–22 per group). Total (B) and individual (C) fat pad weights in 24-week-old transgenic and WT mice fed chow or HFD (n = 10 per group). For individual fat pad weights, significant differences between diet groups for a given genotype are omitted for clarity. Data are expressed as means ± SE. *P < 0.05 and **P < 0.01 between genotypes on a given diet; ###P < 0.001 between diet groups for a given genotype.

FIG. 4

Food intake and energy expenditure. Daily food intake (A), cumulative food intake (B), oxygen consumption (Vo₂) (C), and diurnal oxygen consumption profile (D) of 24-week-old transgenic and WT mice fed HFD (n = 8 per group) measured for 12 days in a comprehensive laboratory animal monitoring system. Data are expressed as means ± SE. ■, WT-HFD; ●, transgenic-HFD. For food intake, *P < 0.05 between genotypes. For oxygen consumption, ****P < 0.0001 between genotypes by mixed model analysis.

FIG. 5

Glucose tolerance and insulin sensitivity. Plasma glucose (A) and serum insulin (B) after an overnight fast in 20-week-old transgenic and WT mice (n = 18–22 per group). Data are expressed as means ± SE. C: Glucose tolerance test. Glucose (1 g/kg) was administered intraperitoneally after an overnight fast to 16-week-old transgenic and WT mice fed chow or HFD (n = 10 per group). Data are expressed as means ± SE. D: Insulin tolerance test. Insulin (1.125 units/kg) was administered intraperitoneally after a 6-h fast to 21-week-old transgenic and WT mice fed chow or HFD (n = 18–22 per group). Values are expressed as means ± SE of percent initial value. The initial decrement from 0 to 15 min after insulin injection for WT-HFD and transgenic-HFD groups are indicated (inset). □, WT-chow; ○, transgenic-chow; ■, WT-HFD; ●, transgenic-HFD. *P < 0.05, **P < 0.01, and ***P < 0.001 between genotypes on a given diet; #P < 0.05, ##P < 0.01, and ###P < 0.001 between diet groups for a given genotype.