Kevin W. Williams, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): There remains intense interest in new therapies that safely and effectively lower blood glucose in diabetic subjects. The naturally occurring regulatory peptide glucagon-like peptide 1 (GLP-1) exhibits multiple desirable actions for a potential anti-diabetic agent, and protease-resistant long-acting GLP-1 analogs are currently available for the treatment of Type 2 diabetes. GLP-1 is also an endogenous neuropeptide that exerts actions in the central nervous system (CNS) that are less well understood. Given the increasing likelihood that one or more GLP-1 analogues will be used to treat diabetic patients, understanding the central role of GLP-1 is increasingly relevant for predicting the biological consequences of sustained GLP-1 administration. The CNS expression of GLP-1 is primarily in a subpopulation of cells within the caudal nucleus tractus solitaries (NTS). Caudal NTS subnuclei receive and process viscerosensory information from thoracic and abdominal viscera and the NTS is reciprocally connected with various brain areas, including hypothalamic areas such as the arcuate that regulate appetitive functions. Additionally, the NTS is located adjacent to a circumventricular organ, the area postrema (AP), and contains fenestrated capillaries, potentially allowing circulating peptides access to the nucleus. The NTS (including GLP-1 cells) is therefore in a prime position to process information arising from a variety of neural and humoral sources. Understanding which peptides, involved in energy balance, modulate neuronal activity of brainstem GLP-1 neurons will aid in the understanding of central GLP-1 regulation. We propose a model that predicts: 1) GLP-1 neurons in the NTS co-express the leptin receptor (Ob-R), and that leptin administration induces the activation of SOCS-3 and STAT-3 in these neurons, 2) leptin induces a membrane depolarization and/or increases excitatory synaptic activity within GLP-1 NTS neurons, and 3) deletion of leptin receptors specifically in GLP-1 neurons will result in hyperphagia and obesity. The studies offered in this application are designed to directly test the different components of this model. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Obesity has become one of the most pressing public health issues of the current century. Unfortunately, tackling the high incidence of obesity is proving to be extremely difficult. The initial discovery of leptin, an adipocyte-derived hormone that acts on hypothalamic neurons to suppress appetite and regulate energy expenditure, raised hope for an obesity therapy. However, its therapeutic use is hampered by the development of leptin resistance in obese humans, a phenomenon for which the precise molecular mechanisms are not fully understood. Interestingly, endoplasmic reticulum (ER) stress is associated with obesity and implicated in leptin and insulin resistance in peripheral tissues and in the brain. Recent evidence suggests that a key site involved this stress response is the hypothalamus. Arcuate POMC neurons are key targets of leptin and insulin action, and normal melanocortin signaling is required for normal food intake, body weight, and euglycemia. Thus we hypothesize arcuate POMC neurons are involved in this hypothalamic stress response. The proposed experiments make use of mouse models unique to the Elmquist laboratory and our collaborators to investigate the role of metabolic and cellular stress in the development of central leptin and insulin resistance. In Aim 1A, we will extend our preliminary observations and examine the effects of free fatty acids and other chemical stimulators on leptin and insulin signaling in POMC neurons. In aim 1B, mice which selectively overexpress XBP1s in POMC neurons (POMC-XBP1s) will be used to investigate the role of the unfolded protein response in leptin and insulin signaling following stimulation by these metabolic and cellular stressors. In Aim 2, POMC-XBP1s mice will be used to determine if enhanced XBP1s signaling can defend against diet-induced obesity and accompanying co-morbidities. In summary, the proposed studies will comprehensively test the action of metabolic and cellular stress in POMC neurons and their subsequent effect on the development of obesity and central leptin and insulin resistance. PUBLIC HEALTH RELEVANCE: The proposed studies will greatly increase our understanding of the mechanisms underlying leptin and insulin resistance and obesity. The study findings will provide valuble information with which to develop treatment strategies for the prevention of obesity and diabetes.

DESCRIPTION (provided by applicant): Obesity has become one of the most pressing public health issues of the current century. Unfortunately, tackling the high incidence of obesity is proving to be extremely difficult. The initial discovery of leptin, an adipocyte-derived hormone that acts on hypothalamic neurons to suppress appetite and regulate energy expenditure, raised hope for an obesity therapy. However, its therapeutic use is hampered by the development of leptin resistance in obese humans, a phenomenon for which the precise molecular mechanisms are not fully understood. Similarly, diabetes mellitus is characterized by insulin deficiency or resistance. Interestingly, endoplasmic reticulum (ER) stress is associated with obesity and implicated in leptin and insulin resistance in peripheral tissues and in the brain. Recent evidence suggests that a key site involved this stress response is the hypothalamus. Notably, arcuate POMC and NPY/AgRP neurons are key targets of leptin and insulin action. Moreover, normal melanocortin signaling is required for normal food intake, body weight, and euglycemia. Thus we hypothesize arcuate POMC and NPY/AgRP neurons are involved in this hypothalamic stress response. In the current proposal, we will extend prior observations. We will identify cellular mechanisms through which ER stress induces acute leptin and insulin resistance. We will also determine a role for ER stress in identified hypothalamic neurons to regulate metabolism.

The incidence of obesity and diabetes continues to rise. Alarmingly this is a trend that is not limited to the United States; rather obesity and its co-morbidities such as type II diabetes mellitus are on the rise and pose a serious threat to public health around the world. Thus, identifying effective strategies for body weight and blood glucose control is a priority. Exercise provides multiple metabolic benefits, including improved insulin sensitivity and body composition. Within the brain, the melanocortin system is an interface between signals of metabolic state and neural pathways governing energy balance and glucose metabolism. In the current proposal, we will identify cellular mechanisms through which exercise alters the synaptic and cellular properties of hypothalamic melanocortin neurons. We will also determine a role for these acute/chronic cellular mechanisms to regulate metabolism.

Physical activity provides multiple metabolic benefits, including improved insulin sensitivity and body composition. Within the brain, less is known about the effects of exercise to acutely alter synaptic/cellular properties and how these effects contribute to altered metabolism. In the current proposal, we have found that CNS derived GLP-1 neurons are activated in response to exercise. Moreover, GLP-1 and GLP-1 mimetics mimic the effects of exercise on arcuate melanocortin neurons. Collectively, these data support the hypothesis that an NTS GLP-1 to arcuate POMC circuit is activated in response to exercise. We will identify cellular mechanisms through which exercise activates GLP-1 and melanocortin neurons. We will also determine a role for these acute/chronic cellular mechanisms to regulate metabolism.