The Influence of Central Insulin Signals on Stress Response in Mice

The Influence of Central Insulin Signals on Stress Response in Mice Chi Nok Chong Stress is an anticipatory or actual disruption of homeostasis which triggers physiological responses to prepare for the threat or to reestablish the system’s internal equilibrium. Other than physical stress (e.g. blood loss, infection, pain, and cold) and psychogenic stress (e.g. novel environment (rodent) and immobilization (rodent)), nutrient (metabolic) stress such as high fat diet and fasting can also trigger stress responses. Central to the activation and regulation of the stress response in mammals is the hypothalamus, where signals from the periphery and other regions of the brain are integrated and processed. Insulin and leptin are two important hormones that provide information about the energy status of the body to the hypothalamus. The hypothalamic insulinand leptinsensing circuits integrate these signals to coordinate metabolic outcomes such as food intake, energy expenditure, fuel partitioning, etc. Given the tight correlation between stress axis activity and nutrient status, it raises the possibility that hypothalamic insulinand leptinsensing circuits may also be involved in coordinating responses of the stress axis, particularly during stress pertaining changes in energy homeostasis. My thesis research focused on understanding the roles and the interactions of hypothalamic insulin and leptin signals in regulating and coordinating metabolic and hypothalamic-pituitary-adrenal (HPA) axis functions. My first project involved understanding the role of hypothalamic insulin signals in hypothalamic Leptin receptor deficient animals (L KO) in regulating energy metabolism (Chapter 2). We observed an increase in body weight and adiposity in D KO mice that lack both hypothalamic insulin receptor (InsR) and leptin receptor (LepRb) signals. These changes were accompanied by reduced energy expenditure, rather than an increase in food intake. Unexpectedly, there was a drastic loss in body temperature in D KO during fasting that was significantly exacerbated by single-housing. These results suggest that interactions between hypothalamic insulin and leptin signals are important for regulating energy expenditure and body temperature. Furthermore, this study also highlights the influence of housing conditions on the evaluation of thermogenic defects in mice. My second project involved the study of hypothalamic insulin signals in regulating stress-related functions by using the non-obese hypothalamic InsRdeficient mice (I KO)(Chapter 3). We showed that I KOs have elevated baseline hypothalamic Avp synthesis, increased activity of the HPA axis after restraint, as well as increased anxiety-like behaviors. This study demonstrated that hypothalamic InsR signals suppress the stress response to restraint, possibly by influencing AVP release to the median eminence and decreasing hypothalamic glucocorticoid receptor (GR) signals, and may also modulate anxiety-like behaviors. My current research focuses are: to remove InsR signals by using more restrictedly expressed Cre lines in order to identify brain nuclei mediating insulin’s effect on stress response and/or anxiety-like behaviors; to identify the hypothalamic AVP neuronal population affected by the loss of InsR and potential extra-hypothalamic downstream targets of these neurons; to pinpoint the hypothalamic nuclei where GR signaling is altered in I KO. By identifying the critical anatomical and functional components mediating insulin’s effects, we hope to provide more understanding of the contribution of central insulin resistance to the development of HPA axis dsyregulation and anxiety disorders in humans.