A transgenic model of visceral obesity and the metabolic syndrome

Abstract

Obesity is often associated with the metabolic syndrome, which includes insulin resistance, glucose intolerance and dyslipidemia. The best predictor of these morbidities is not the total body adipose mass, but the specific quantity of visceral fat, with ‘apple-shaped’ people who carry excess weight around their waists being more susceptible to these illnesses than people who are equally overweight but with the weight around their hips. The role of glucocorticoids in this process remained elusive for many years, because in most obese patients plasma glucocorticoid levels are normal. However, the activity of 11β hydroxysteroid dehydrogenase type 1 enzyme (11β HSD-1), which regenerates active cortisol from inactive cortisone, was recently shown to be greater in abdominal fat than in subcutaneous abdominal tissue, suggesting a role for increased local cortisol activity in human obesity.To test the role of 11β HSD-1 and local glucocorticoid production in the development of visceral obesity and the metabolic syndrome, Masuzaki et al. [1xA transgenic model of visceral obesity and the metabolic syndrome. Masuzaki, H. et al. Science. 2001; 294: 2166–2170Crossref | PubMed | Scopus (1268)See all References][1] created transgenic mice selectively overexpressing 11β HSD-1 in the adipose tissue. The overexpression caused a 2.4-fold increase in 11β HSD-1 activity in the adipose tissue of these mice, a magnitude similar to that found in obese humans. Corticosterone levels in the adipose tissue were significantly elevated (by 15–30%), but the serum levels of the hormone were normal, as were several other parameters, including thymic weight, bone mineral density, lean body mass weight and linear growth, which reflect the consequences of circulating glucocorticoids.By 15 weeks of age, the transgenic mice showed increased sensitivity to weight gain compared with normal mice, and the fat accumulation had a prominent abdominal component: even on a low-fat diet, the transgenic mice carried 37.9% of their adipose weight in the abdominal region compared with 27.5% in non-transgenic mice. Food intake was increased by at least 10%, which paralleled the increase in body weight. These data demonstrate that overexpression of 11β HSD-1 in adipose tissue produces disproportionate fat accumulation and hyperphagia.The transgenic mice also seemed to exhibit most symptoms of the metabolic syndrome, including pronounced insulin-resistant diabetes, hyperlipidemia and hyperphagia, in spite of showing hyperleptinemia. The expression of several genes that could influence systemic metabolic pathways was also studied in these mice: mRNA encoding resistin and Acrp30-AdipoQ decreased, whereas angiotensinogen expression in the mesenteric fat increased; mitochondrial uncoupling protein-1 mRNA was significantly decreased in brown adipose tissue.This provides evidence that a modest increase in the activity of 11β HSD-1 in the adipose tissue of mice, similar to that found in obese humans, can cause hyperphagia, visceral obesity and most symptoms of the metabolic syndrome. The authors suggest that this enzyme could be a potential pharmaceutical target for the treatment of this prevalent problem. In fact, it has been shown that thiazolidinedione antidiabetic agents markedly reduce 11β HSD-1 mRNA and activity in adipose tissue. Based on the data of Masuzaki et al., this could be a mechanism for their visceral fat-reducing action in humans, and might play a role in their antidiabetic effects.