Sangho Yu, Ph.D.
Project: Thermoregulatory Circuit Mapping of Preoptic Leptin Receptor Neurons
Synopsis: Obesity arises as a result of chronic positive energy balance, and stimulating brown adipose tissue (BAT) or browning of white adipose tissue (WAT) has received great attention as a potential obesity treatment by increasing energy expenditure to restore energy balance. BAT is a specialized fat tissue dedicated to heat production and its activity is regulated by sympathetic neural activity. The preoptic area (POA) of the hypothalamus orchestrates the sympathetic output to various effector organs, including BAT, to regulate the energy expenditure level and core body temperature.
Leptin receptor (LepRb) is expressed in a subpopulation of the POA (LepRbPOA neurons) and we have shown that pharmacogenetic activation of LepRbPOA neurons by DREADD dramatically decreased core body temperature and energy expenditure by suppression of sympathetic neural activity. We recently discovered that LepRbPOA neurons also modulate food intake, emphasizing the importance of LepRbPOA neurons in both arms (energy intake and expenditure) of energy homeostasis. Therefore, elucidating neural circuits mediated by LepRbPOA neurons has significant implications in better understanding how energy balance is regulated and devising new strategies for obesity treatment.
For anatomical and functional circuit mapping of LepRbPOA neurons, we will apply state-of-the-art neuronal tracing and manipulation techniques using various genetically engineered viruses. For example, we will selectively express channelrhodopsin-2 (ChR2), a light-sensitive cation channel, in LepRbPOA neurons to activate them with 473nm light. By shining light at a specific projection site, we can activate only axons innervating that target site without affecting other projection areas (Figure 1). Through a systematic dissection of downstream circuits of LepRbPOA neurons, we can identify the critical circuit(s) involved in the regulation of BAT activity. We will use retrograde viral tracers combined with optogenetics/pharmacogenetics for mapping upstream brain regions that regulate the activity of LepRbPOA neurons.
Dissecting neural circuits of LepRbPOA neurons into their components is expected to provide not only better insights into how energy homeostasis is regulated but also means to selectively activate BAT without affecting sympathetic nerve activity to other tissues. In addition, brain regions identified from this project will serve as new entry points to further study central regulation of energy balance.