Developmental programming of brown adipose tissue sympathetic tone

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The proposed studies will use brown adipose tissue (BAT) as a platform to elucidate how postnatal developmental influences control the neuroanatomical structure of sympathetic nervous system (SNS) inputs and how these changes impart lasting and specific effects on whole body physiology and susceptibility to disease risk. A wide range of developmental exposures influence SNS tone onto metabolically-relevant organs, including pancreas, kidney, adipose tissue and heart. To date, evidence for a relationship between developmental influences on SNS tone and organ function is purely correlational. An obstacle to direct investigations of the contributions of SNS programming to adult physiology is that experimental manipulations of their activity during development would likely have impacts on organ function that affect the overall health of the animal, which would confound interpretation of the results. We identified two early postnatal exposures that specifically reduce the number of sympathetic neurons in the stellate ganglion that project to BAT (SGBAT), but program disparate responses to physiological challenges in healthy adults. Housing at 30°C leads to lasting effects on responsiveness to cold but not high fat diet, while lactation in a small litter (SL) programs susceptibility to diet-induced obesity but not cold. Studies outlined here will establish novel systems to test whether changes in SGBAT number impact innervation and SNS tone onto BAT (Aim 1), and whether they are necessary and sufficient to program lasting effects on organ function and physiological responses to cold and diet challenges (Aim 2). We will leverage our discovery of molecularly distinct subpopulations of SGBAT neurons and differentially expressed genes in BAT from mice raised at 30°C vs. 22°C to uncover molecular mediators of programming in SNS circuits (Aim 3). We will perform parallel transcriptomic analyses in BAT and SG to identify sources of specificity in the functional responses to manipulations of litter size or temperature during a critical period of development. Because transcriptional signatures of SGBAT subclasses are shared by all SG neurons, lessons from these studies can be applied to other postnatal exposures and organ systems that have been implicated in developmental programming of disease risk.