Cortisol responsivity to ACTH marks innate predisposition to obesity, changes in energy homeostasis in response to stress & coping behaviours
thesisposted on 01.03.2017, 05:38 by Lee, Tao-Kwang Kevin
Overcoming the innate determinants of body weight in the overweight and obese person is not easy in today’s obesogenic environment. Despite strong public awareness of what a healthy lifestyle entails, the obesity epidemic continues to worsen. The difficulty lies in an individual not being able to sustain the effort required to maintain a lower body weight leading to a return to a higher natural setpoint. In this Thesis, I present a novel way of viewing this growing epidemic by evaluating stress responsiveness as a way to mark the innate determinants of weight gain. Stress plays an instrumental part in regulating our desire for food and sex, or in physiological terms, energy homeostasis and reproduction. Stress responsiveness can be determined by measuring the stress hormone, cortisol. In the animal model used in the present studies, I have identified high stress responders (HR) and low stress responders (LR) from a population of outbred sheep by injecting Synacthen (synthetic adrenocorticotropin –ACTH) and selecting those animals at either extreme in terms of cortisol response. In the first study, it was shown that HR have a greater tendency to become obese when exposed to a high energy diet compared with LR and this was found to be due to a greater positive energy balance in HR. This greater positive energy balance was not a result of increased food intake but rather a lower thermogenic output from muscle. The characterstics of these animals in terms of leptin sensitivity, insulin sensitivity were also detailed showing no difference between HR and LR groups. Finally, the study included measures of muscle thermogenesis in terms of mitochondrial respiration and futile calcium cycling, demonstrating that though increased futile calcium cycling and mitochondrial respiration can explain the mechanism of postprandial thermogenesis, neither of the mechanisms adequately explained the difference observed between HR and LR groups. In the second study, it was shown that energy homeostasis can be marked by cortisol responsiveness to stress in HR and LR. In other words, the greater the difference in cortisol response to particular stressors, the greater the difference in the metabolic response to stress in the HR and LR in terms of food intake and thermogenic output. Three stressors were used to demonstrate this relationship, namely metabolic stress in the form of insulin induced hypoglycaemia, psychosocial stress in the form of a barking dog and immune stress in the form of lipopolysaccharide (LPS) infusion. Of the three stressors, the greatest divergence in cortisol response between HR and LR was seen with LPS immune stress where LPS treatment reduced (P<0.01) food intake in both groups, but LR showed a greater (P<0.05) reduction in food intake and a more substantial (P<0.05) rise in muscle temperature. Introduction of the barking dog demonstrated differences in peak cortisol and reduced (P<0.05) food intake in LR only; there was no significant difference in thermogenic output. In metabolic stress, no difference was seen in cortisol response between HR and LR and there was also no difference in food intake and thermogenic output between the two groups. Thus, LR animals typically displayed a greater catabolic response to stress than HR. Finally, I characterized behavioural differences in HR and LR animals. Cortisol responsiveness was also shown to mark an innate difference in coping styles to stress. By using three different behavioural tests, it was shown that LR have greater activity as well as more initiative and less fearfulness in response to stress than HR. Thus, LR may be considered to have a proactive coping style, whereas HR exhibit a relatively reactive series of coping strategies. In conclusion, cortisol responsiveness can predict the susceptibility for obesity in sheep fed a high energy diet, predict changes to energy balance in relation to stressors and also predict coping behavioural strategies. The teleological implication and potential of these findings is to provide novel insight into mechanisms underlying propensity for obesity and there is an indication that Synacthen testing may be useful as a predictor of subsequent metabolic outcome.