Location: Children's Nutrition Research Center
Project Number: 3092-10700-069-010-S
Project Type: Non-Assistance Cooperative Agreement
Start Date: Apr 1, 2019
End Date: Mar 31, 2024
Objective:
Objective 1: Determine if potassium channels (SK3) expressed by serotonin neurons are required to regulate feeding behavior and body weight balance using a Cre-loxP strategy to generate mouse models that either lack SK3 selectively in serotonin neurons. Test whether these manipulations in mice alter animals’ food intake and body weight.
Objective 2: Identify downstream neural circuits that mediate serotonin neuron actions to regulate feeding behavior and body weight balance. Selectively stimulate specific downstream neural circuits that originate from brain serotonin neurons in mice, and measure effects on animals’ feeding behavior and body weight.
Objective 3: Identify upstream and downstream signaling molecules of glycogen synthase kinase 3 beta that controls suppressor of cytokine signaling 3 levels and cellular insulin and leptin actions in the hypothalamus by using an ex vivo brain slice model.
Objective 4: Determine if each component of the glycogen synthase kinase 3 beta -related pathway determines hypothalamic levels of suppressor of cytokine signaling 3 and hypothalamic leptin and insulin actions in vivo by using genetically engineered mouse models.
Objective 5: Determine the physiological roles of genetically defined Agouti-related protein/proopiomelanocortin-parabrachial nucleus circuit in differential control of feeding behavior and energy metabolism.
Objective 6: Determine the physiological roles of key gamma amino butyric acid and N-methyl-D-aspartic acid glutamate receptor subunits expressed in the Agouti-related protein/proopiomelanocortin-parabrachial nucleus circuit for the regulation of appetite, energy balance, and development of obesity.
Approach:
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, research scientists will tackle this concern from multiple angles. Based on the previous observations that brain serotonin (5-HT) neurons regulate feeding, body weight and glucose balance, we 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. Additionally we will identify a previously unrecognized neural signaling pathway that controls leptin and insulin actions in the hypothalamus and mediates whole-body energy balance. Scientists will also 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.
