Dysregulated ipid homeostasis represents a major contributing factor in obesity-related chronic diseases, but the role of the central nervous system (CNS) in lipid metabolism during obesity is still poorly defined. Serotonin 2C receptors (5-HT2CRs) found in the CNS is predicted to regulate lipid homeostasis. For example, 5-HT2CR agonists have lipid-lowering benefits in human subjects, while atypical anti-psychotic drugs that inhibit 5-HT2CRs are associated with elevated serum cholesterol and triglycerides. However, it is still unclear which populations of 5-HT2CR-expressing neurons in the CNS mediate these effects on lipid homeostasis. Recent studies have found that 5-HT2CRs expressed by pro-opiomelanocortin (POMC) neurons in the hypothalamus directly regulate glucose homeostasis and insulin sensitivity independent of weight loss. The current proposal is to test whether 5-HT2CRs expressed by POMC neurons also have physiologically important effects on lipid homeostasis dissociable from body weight. This objective will be accomplished using genetically engineered mouse models and comprehensive analysis of lipid metabolism, including serum lipid profiles, white adipose tissue homeostasis, and the development of fatty liver disease. The first experimental aim will use mice lacking 5-HT2CRs only in POMC neurons to test whether the maintenance of normal lipid homeostasis requires 5-HT2CRs expressed by POMC neurons. The second experimental aim will use 5-HT2CR-null mice with re-expression of 5-HT2CRs only in POMC neurons to test whether 5-HT2CRs expressed only by POMC neurons are sufficient to rescue lipid homeostasis. Taken together, these approaches will provide mechanistic insight into the role of serotonin signaling in POMC neurons to regulate lipid homeostasis. The mouse models are relevant to human patients treated with atypical anti-psychotic drugs or obesity drugs that inhibit or activate 5-HT2CRs, respectively. These findings will advance the basic understanding of CNS pathways that control lipid metabolism during obesity and could potentially offer new lipid-lowering therapeutic targets.

Public Health Relevance

Serotonin 2C receptors (5-HT2CRs) found in the brain are predicted to regulate lipid metabolism, based on lipid changes in human patients treated with drugs that target 5-HT2CRs, but the neurons that mediate these effects are still unknown. The objective of the current proposal is to test whether 5-HT2CR-expressing pro-opiomelanocortin (POMC) neurons directly regulate lipid metabolism independent of body weight. These findings will improve our understanding of how serotonin signaling in specific brain neurons controls lipid metabolism and could also identify novel lipid-lowering strategies in the treatment of obesity-related chronic diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1-GRB-R (M1))
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Castle, Arthur
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University of Texas Sw Medical Center Dallas
Internal Medicine/Medicine
Schools of Medicine
United States
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Lord, Caleb C; Wyler, Steven C; Wan, Rong et al. (2017) The atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2C. J Clin Invest 127:3402-3406