Lipids act as cues in key groups of neurons that regulate energy balance and glucose homeostasis. In the past grant period, we discovered that vagal sensory neurons are highly enriched for ?lipid-sensing? genes, including nuclear receptors such as PPAR? and the LXRs. We also uncovered enrichment of putative lipid transporters including the long-chain fatty acid (FA) transporter CD36. We found that deletion of the nuclear receptors PPAR?, LXR?, and LXR? from sensory neurons protected mice from developing diet-induced obesity. However, the physiological importance of the transport of lipids into vagal neurons remains unknown. In the current application, we will directly test the hypothesis that FA uptake in vagal sensory neurons is required to regulate energy balance in the setting of high fat diet exposure. Recent and significant evidence also suggests that neuronal lipid levels in the hypothalamus control peripheral metabolism. A prevalent model that has emerged predicts that the intermediate malonyl-CoA is required for hypothalamic neurons to respond normally to hormone and nutrient signals. Hypothalamic levels of malonyl-CoA change significantly depending on energy status, but it is unknown which cell types and which neuronal populations are responsible for these effects. In the past grant period, we found that melanocortin neurons regulate the ?browning? of white adipose tissue and hepatic insulin sensitivity. In the current application, we will determine if alterations of the levels of malonyl CoA in Pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons regulate glucose and lipid homeostasis, especially in the liver and adipose tissue.

Public Health Relevance

Lipids serve as key signals in neurons that regulate metabolism. In the past grant period we found that vagal sensory neurons express key lipid sensing genes and deleting these genes affects energy balance. Evidence also suggests that lipid synthesis in the hypothalamus regulate metabolism. In the current application we will investigate the physiological importance of lipid transport into vagal neurons. We will also examine the metabolic effects of altering levels of malonly-CoA, a key lipid in hypothalamic melanocortin neurons. Our experiments will take advantage of the unique collaboration formed by the laboratories and cores of this PPG.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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University of Texas Sw Medical Center Dallas
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