Novel CNS mechanisms to combat obesity

About This Grant

Summary Obesity is characterized by visceral fat accrual and lipid spillover to liver and heart, driven largely by systemic insulin resistance. Key drivers of obesity are excessive feeding and reduced energy expenditure. Consequently, understanding the mechanisms that control feeding and/or energy expenditure will help develop strategies to combat obesity and metabolic diseases. At the whole organismal level, the central nervous system (CNS), in particular the hypothalamus and hindbrain, sense signals of nutrient availability and coordinate energy metabolism. While cell-types in the arcuate and their functions are well-characterized, how different cell-types and neuronal populations in the paraventricular nucleus of the hypothalamus (PVH), a deep-seated region in the hypothalamus, coordinate peripheral energy metabolism remains poorly studied. In particular, it is unclear how the PVH integrates physiological nutrient-related cues to control peripheral energy and lipid metabolism, and how these processes are disrupted to cause obesity and insulin resistance. My studies using brain-wide imaging of c-Fos, a defined neuron activation marker, revealed that dietary triglycerides administered via an oral gavage activates diverse regions across the brain, with greatest activation in discrete regions of the hypothalamus, including the PVH. Comparative bulk-RNA sequencing of multiple regions with the greatest response to lipids revealed Zinc Finger and BTB Domain Containing 16, a transcription factor required for stem cell maintenance and cell differentiation, as a key ubiquitously upregulated gene in response to corn oil gavage, including the PVH. Based on hypothalamic single-nuclei RNA sequencing, and PVH spatial transcriptomics, we reveal that this lipid-driven induction of ZBTB16 expression occurs in a small cluster of a poorly-characterized PVH neurons. On this basis, I hypothesize that these lipid-responsive PVH neurons play a role in regulating systemic lipid metabolism. Consistently, my preliminary studies in a small group of mice revealed that deletion of ZBTB16 in these PVH neurons leads to weight gain and adiposity when compared to controls. Taken together, in this K01 Mentored Research Scientist Career Development Award, I will test the hypothesis that lipid-driven induction of ZBTB16 in these novel PVH neurons facilitates energy expenditure in peripheral fat depots and maintains energy balance; and that sustained high fat diet feeding alters the activity of these neurons to cause obesity. I will test this hypothesis via three specific aims: Aim 1 will characterize the changes that occur in these poorly studied PVH neurons as mice transition from lean to obesity states; Aim 2 will determine the role of ZBTB16 in PVH neurons in the pathophysiology of obesity; while Aim 3 will evaluate the effect of stimulation of these PVH neurons on the reversal of obesity phenotypes. I expect that the completion of these studies will not only reveal novel roles of an uncharacterized neuronal population in combating obesity, but this K01 grant will also serve as a critical mechanism for my career development into an independent neuroscience-focused obesity researcher.