Complex interactions between diet, exercise, and the HPA axis on the development of obesity, insulin resistance, and type 2 diabetes

Chronic elevations in glucocorticoids (GCs), resulting from hyperactivation of the hypothalamic-Pituitary-Adrenal (HPA) axis, can induce insulin resistance, hyperglycaemia, and dyslipidemia and consequently has been proposed to result in the development of Type 2 Diabetes Mellitus (T2DM). Exercise, on the other hand, improves insulin resistance and is crucial in the prevention/treatment ofT2DM. However, exercise is also a potent stimulator of the HPA axis. Therefore, we investigated the effects of exercise training on both central (HPA axis) and peripheral aspects of GC biology. First, we demonstrated that 2 weeks of regular exercise in healthy Sprague-Dawley rats induces hyperactivation of the HPA axis, but that by 8 weeks of training, HPA activity is restored to control levels. We found that the transient hyperactivity of the HPA axis with short term exercise is mediated through changes in the adrenal gland sensitivity to adrenocorticotropic hormone (ACTH) that are ameliorated with sustained training. Next, to determine the interaction of exercise and GCs in T2DM, we exercise trained Zucker Diabetic Fatty (ZDF) rats, a rodent model of T2DM. We found that sedentary ZDF rats developed elevated HPA activity prior to hyperglycaemia, also due to altered adrenal sensitivity to ACTH. Exercised ZDF rats maintained normal GC levels, remained euglycaemic, and displayed normal adrenal sensitivity. These studies demonstrate that sustained exercise training maintains normal circulating GCs, which may help prevent/delays the development of T2DM. We next explored the adaptive changes in peripheral GC biology caused by exercise. In ZDF rats, exercise training did not change GC exposure in skeletal muscle or liver tissue, however, did increase exposure in adipose tissue. In fructose-fed hamsters, another rodent model of insulin resistance, exercise training also had modest effects in skeletal muscle and liver tissue, but again increased GC exposure in adipose tissue. The role of GCs in adipose tissue is poorly defined, making it difficult to understand why exercise increases the action of GCs in adipose tissue. Thus, we next determined the effects of GCs on adipose tissue metabolism both in vitro and in vivo. We found that GCs work on two distinct cell populations in adipose tissue to simultaneously stimulate differentiation in preadipocytes and lipolysis in mature adipocytes. The net balance of these opposing actions appears dependent upon the diet and activity of the animal. Overall, these findings show that sustained exercise training induces positive changes in both central and peripheral aspects of GC biology that help prevent the development of insulin resistance, obesity, and T2DM.