Location: Children's Nutrition Research Center
Project Number: 3092-10700-069-002-S
Project Type: Non-Assistance Cooperative Agreement
Start Date: Apr 1, 2024
End Date: Mar 31, 2029
Objective:
Objective 1: Determine whether the lateral habenula to serotonin circuit inhibits food intake.
Objective 2: Determine the physiological roles of genetically defined parabrachial nucleus-originated neural circuit in differential control of feeding behavior and energy metabolism.
Objective 3: Determine whether cholinergic basal forebrain circuits differentially respond to appetitive and aversive stimuli to drive feeding and food avoidance behaviors.
Objective 4: Determine the role of brain AMPK in glycemic control during overnutrition.
Objective 5: Determine the impact of digenic heterozygous ciliary gene loss on ciliary structure, function, and weight regulation.
Approach:
Obesity-associated health complications, such as diabetes, account for one of the leading causes of death in the United States, and obesity-related health costs pose a financial burden of nearly 150 billion dollars annually. Neural circuits in the brain coordinate proper energy and glucose homeostasis. Disruptions in these networks dramatically affect eating behaviors, resulting in nutritional imbalances with adverse impacts on human health. Thus, identification of key neurons, their circuits, and the intra-neuronal signaling mechanisms that regulate feeding behavior and glucose balance represents a needed step towards developing new and effective therapeutic strategies to treat obesity and diabetes. Previous work demonstrated critical roles for neural circuits in coordinating various neurotransmitters, e.g. serotonin, GABA, dopamine, and acetylcholine, to regulate feeding behavior. We will continue to unravel the complex synaptic connectivity, modes of neurotransmission, and/or plasticity within these neurocircuits for feeding regulation. Our team discovered that central administration of a small dose of the antidiabetic drug metformin can correct high blood glucose levels in mouse models of type 2 diabetes. Since AMPK is potently activated by metformin and is considered to mediate at least some of the effects of metformin, we will test the new hypothesis that AMPK in the brain responds to metformin as well as to distinct nutritional conditions to control whole-body glucose metabolism. Researchers observed that some children with severe, early-onset obesity and dysregulated satiety had heterozygous loss of 2 different ciliary genes (digenic heterozygous), which involved the loss of ALMS1 with different BBS genes. We will test the hypothesis that digenic heterozygous loss of ciliary genes causes a fundamental defect in ciliary function and results in obesity.
