Glucocorticoid metabolism; a hidden link between obesity and its consequences

Obesity confers major risk of diabetes and cardiovascular disease, but not all obese people/animals develop these complications. Identifying those most at risk remains a challenge. Although the genetic drivers of obesity are known to exert effects predominantly on central appetitive regulatory circuitry, the peripheral determinants of downstream complications such as insulin resistance (IR), remain poorly defined. Glucocorticoids have long been associated with obesity, but recent human genetic data suggest they drive co-morbidities rather than obesity per se. Obesity is associated with complex tissue-specific glucocorticoid dysregulation, but the direction of causality, and the direct consequences of this dysregulation, are unknown. Using a porcine model of obesity, I will address the hypothesis that obesity-induced glucocorticoid dysregulation is a key mediator of obesity-related IR. Regulation of glucocorticoids is conserved between humans and pigs, unlike rodents. Risk of metabolic disease varies in pigs, as in humans, and my preliminary data implicate altered glucocorticoid regulation as the cause. By comparing the glucocorticoid response to obesity of pigs divergent for metabolic risk, manipulating tissue glucocorticoid action and quantifying glucocorticoid receptor activation I will determine the contribution of tissue glucocorticoids to IR in obesity and identify genetic mechanisms driving metabolic risk in pigs and then humans.

Over 650 million people worldwide are obese and 18 million die annually from complications including diabetes and cardiovascular disease. How obesity results in these serious complications in some, but not all people, is unclear. I will investigate how glucocorticoids (stress hormones) change in response to obesity and how they contribute to the development of complications. I will use pigs fed a high-calorie diet to study the effect of obesity on glucocorticoids. Pigs have very similar stress hormones to humans and like humans, they become obese and develop complications on a high-calorie diet. Importantly, also like humans, some pigs are more at risk of these complications than others. In this study, I will compare the stress hormones and genetics of high and low risk pigs to understand what makes their complications different. Understanding how stress hormones contribute to obesity complications can help identify people most at risk and target treatment appropriately.