Impact of early overnutrition on leptin signaling in hypothalamic neuropeptide Y neurons

Almost half the children in the U.S. are overweight and are likely to become obese adults, suffer from increased rates of type 2 diabetes, stroke, cardiovascular disease, and premature death. Unfortunately, there are very few non-invasive interventions available. Obesity has consequential effects in the brain and periphery, including on time-of-day dependent processes, which are present in nearly all cells and organ systems. A major gap in our knowledge is how early life overnutrition impacts neural circuits that regulate energy balance, particularly at the level of function cell physiology. Our project aims to investigate these effects using an integrated combination of neurophysiological approaches. The arcuate nucleus of the hypothalamus (ARH) is critical for the homeostatic control of food intake and metabolism, that also shows dynamic changes in gene expression over the day. ARH neuropeptide Y (NPY) "hunger" neurons are essential for metabolic function, but it is unknown how chronic postnatal overnutrition (CPO) impacts this critical population of cells. Aim 1 will investigate how CPO affects the physiology of ARH-NPY neurons. This will include brain slice electrophysiology to understand how time-of-day impacts the neurophysiology of these neurons and their synaptic inputs. The hormone leptin is essential for energy balance and CPO induces leptin resistance at the behavior level. In addition, diet-induced obesity alters diurnal fluctuations in endocrine signaling, including leptin. How CPO impacts the response of ARH-NPY neurons to leptin is unknown. We will employ electrophysiological approaches in Aim 2 to determine the mechanism(s) by which CPO alters leptin signaling in ARH-NPY neurons, with particular attention to time of day. There is robust foundational evidence supporting the investigation of both ARH-NPY neurons and leptin signaling to these neurons. Successful completion of these experiments will significantly contribute to our functional and mechanistic understanding of the impacts early life metabolic challenges have on the brain, and provide new avenues (including on the temporal domain) to confront long-term outcomes of childhood obesity.