Interaction of diet and adipose glucocorticoid action in metabolic syndrome
Man, Tak Yung
Metabolic syndrome, a combination of co-associated features including visceral obesity, dyslipidemia, hypertension, insulin resistance and increased risk of cardiovascular disease, has reached epidemic levels. Recent evidence has indicated a pathogenic role for elevated glucocorticoid (GC) levels within adipose tissue specifically, in obesity. Levels of the glucocorticoid regenerating enzyme 11β- hydroxysteroid dehydrogenase type 1 (11β-HSD-1), which converts inactive GC into active forms within cells, are elevated in adipose tissues of obese humans. Transgenic overexpression of 11β-HSD1 in adipose tissue recapitulates metabolic syndrome in mice, including visceral obesity, perhaps because glucocorticoid receptor (GR) levels are higher in visceral than subcutaneous adipose tissue. Therefore, increased adipose GC action, especially in visceral adipose tissue, might explain the striking similarities between idiopathic metabolic syndrome and rare Cushing’s syndrome of plasma GC excess. One of the major contributors to obesity and metabolic syndrome is consumption of excessive amounts of dietary fat. Specifically, saturated fats are associated with obesity and insulin resistance whereas unsaturated fats are reported to ameliorate some aspects of metabolic disease. Interestingly, chronic high fat feeding in mice decreases adipose 11β-HSD1 expression, usually without changing expression in liver. The reduced glucocorticoid regeneration in adipose tissue may ameliorate metabolic disease. This study investigated the effect of diets enriched in saturated or unsaturated fats on adipose tissue glucocorticoid action, focusing on 11β-HSD1 and glucocorticoid receptor expression. Two studies were carried out, one with pair-feeding (to control low-fat diet) and one with ab libitum feeding. In both studies, a diet high in saturated fat (stearate) resulted in significant weight loss whereas a diet consisting of 58% mixed fats resulted in significant weight gain. In the ab libitium study (but not in pair-fed animals) both mono-unsaturated (oleic) and poly-unsaturated (safflower) fat-enriched diets induced weight gain and hyperinsulinaemia and lowered levels of adipose11β-HSD1 when compared to control diet. These data suggest that diets high in saturated fats elevate adipose tissue and liver 11β-HSD1 levels which might contribute detrimentally to, or offset, any improvements in the systemic metabolic profile. Conversely, unsaturated fats cause an adipose-specific down-regulation of 11β-HSD1. In addition, genetic evidence from human and animal studies has shown that regulation of glucocorticoid production and receptor density may be an important factor determining visceral adiposity. The role of adipocyte GR levels in determining visceral adiposity was investigated. Two types of transgenic mice were generated with altered GR levels in adipocytes using the adipocyte-specific aP2 promoter; one with a “sense” rat GR cDNA (2 independent lines; D- and B-FSG) and one with an “anti-sense” rat GR-cDNA (GR-5). Initial characterisation of D- and B-FSG mice showed expression of rat GR mRNA in both female and male transgenic mice with D-FSG showing a higher copy number than B-FSG. In D-FSG transgenic mice, female mice of the F1 generation had greater adipose tissue mass than non-transgenic littermates. A 6-month high fat study was then carried out on line D-FSG. However, no differences in body weight, food intake, adipose tissue weight or blood pressure were found in either males or females. Further investigations of the levels of rat GR mRNA expression within various adipose tissues showed variable transgene expression between different generations of B- and D-FSG lines and even between adipose tissues within the same mouse. In contrast, following 6-months high fat diet, female mice under-expressing GR within adipose tissues (GR-5) showed a significant reduction in body weight and subcutaneous adipose tissue weight compared to their non-transgenic littermates. These data suggest that adipose GR density is an important determinant of visceral adiposity, in a sex-specific manner. Collectively, the data in this thesis support a role for GR density and GC metabolism in adipose tissue as important determinants of adiposity in mice. Drugs that manipulate these targets are of therapeutic interest.