Neural Circuits and Obesity Mechanisms
Obesity and its associated metabolic disorders (e.g., diabetes) represent a serious health problem to our society. The central nervous system (CNS) senses multiple hormonal/nutritional cues and coordinates homeostatic controls of body weight and glucose balance. However, the mechanisms for CNS control of metabolism remain to be fully understood. Primarily using genetic mouse models, supplemented by optogenetic and chemogenetic approaches, three research scientists seek to tackle this general problem from different angles. Based on the previous observations that brain serotonin (5-HT) neurons regulate feeding, body weight and glucose balance, our lab will continue to identify the ionic mechanisms that regulate 5-HT neuron activity and the downstream neural circuits that mediate the metabolic effects of 5-HT. We will identify a previously unrecognized neural signaling pathway that controls leptin and insulin actions in the hypothalamus and mediates whole-body energy balance. Researchers will identify a novel neural circuit with converged GABAergic and glutamatergic projections from hypothalamus to the brainstem in control of feeding, metabolism and body weight. Collectively, these studies will demonstrate the potential roles of metabolic cues (hormones/nutrients), CNS circuits, and the intra-neuronal signals in the control of energy and glucose homeostasis. Our research results should identify rational targets for the treatment or prevention of obesity and diabetes. Findings will provide evidence to support new guidelines in hormonal/chemical diet supplementation to prevent these diseases. Finally, numerous novel genetic mouse lines will be generated, which will benefit a broader research community.
Dissecting Roles for Basal Forebrain and Sensory Processing Circuits in Feeding Behavior
Healthy eating habits are guided by a balanced drive to seek or to avoid food. Abnormal eating habits manifest as a spectrum of behaviors that span uncontrolled hyperphagia to overt food aversion, leading to potential life-threatening metabolic consequences. Properly processing food cues and food related stimuli is essential to govern healthy eating behaviors, and the failure to process such sensory information can lead to spectrum of eating-associated disorders ranging from increased food seeking and excessive food consumption associated with obesity, to severe hypophagia, food aversion, and starvation that is typical of anorexia. Appetite regulation, while canonically regulated by hypothalamic integration of internal cues such as nutrient status and hormones, is also potently controlled by environmental stimuli and external sensory cues. However, feeding behavior is also directly impacted by environmental stimuli and external sensory cues. For example, the perception of palatable food increases appetite, while aversive cues can directly decrease food seeking. However, the neural circuit mechanisms that govern feeding through sensory perception remain largely unknown. We have recently identified circuits of the cholinergic basal forebrain as potent appetite regulators that dynamically respond to food-related stimuli. Here we aim to identify the downstream cellular components and circuit mechanisms that mediate processing of sensory stimuli to govern appetitive versus aversive feeding behaviors. We hypothesize that cholinergic basal forebrain circuits differentially respond to appetitive and aversive stimuli to drive feeding and food avoidance behaviors. Using wildtype and genetically engineered mice, in vivo electrophysiological and imaging analysis, metabolic profiling, and feeding behavior assays, we will elucidate the downstream circuit targets of the cholinergic basal forebrain that mediate feeding related actions to drive or suppress food seeking and/or consumption. Identifying such downstream circuit nodes and/or cellular substrates will provide new therapeutic avenues to bypass altered sensory processing systems to treat eating disorders.
Research Faculty: Ben Arenkiel
Adipose Tissue Biology
Our goal is to enhance the understanding of the mechanisms through which diet impacts adipose tissue during development and the understanding of the progression of obesity and related pathologies after birth. High fat-diet induced obesity is a well-recognized risk factor for a diverse array of health problems, including type II diabetes, heart diseases, and certain types of cancer. However, the mechanistic links between a high-fat diet and cellular injuries during development and after birth remain to be fully elucidated. This research will use mouse models of diet-induced obesity and will focus on three general problems associated with obesity: the developmental effects of maternal obesity on offspring adiposity, adipose tissue inflammation that may lead to medical complications, and the effects of dietary fatty acid composition on obesity. We will analyze the effects of maternal obesity on Wilms tumor 1 (Wt1) expressing white adipocyte progenitor cell development, and of the function of the intracellular glucose sensor ChREBP in macrophages and its contribution to the inflammation of fat tissues induced after long-term (months) feeding of a high fat diet. We will investigate the uptake and metabolism of dietary fatty acids of varying carbon chain lengths in different tissues, including fat tissue and their effects on progression of obesity and related disorders in wild type mice. An expected outcome of this research is an improved understanding of the relationship between diet-induced obesity and fat tissue development, inflammation, insulin resistance, and uptake and metabolism of dietary fatty acids.