Research Interests

My primary interest is the homeostatic regulation of energy stores by the central nervous system. When we cloned the melanocortin receptors and elucidated the role of the agouti proteins as endogenous antagonists of these receptors, we identified the central melanocortin circuits as a critical component of the adipostat. These circuits appear to coordinate long-term adipostatic signals with short term hunger and satiety signals, and to coordinate energy intake with expenditure. We continue to focus on the specific physiological mechanisms involved in these homeostatic processes mediated by central melanocortin signaling. For example, even haploinsufficiency of the melanocortin-4 receptor causes profound hyperphagia in response to dietary fat, and we are studying the mechanisms involved. Our work utilizes a variety of techniques and model systems to better understand these signaling pathways. We have characterized the central melanocortin circuits in the zebrafish to be able to apply unbiased forward genetics to identification of the genes involved in this system. We have recently initiated clinical studies of melanocortin obesity syndrome in children. Finally, since MC4R haploinsufficiency is the most common cause of severe obesity known, and excessive MC4R activation appears to play a role in disease cachexia, we are using high throughput screening to identify small molecule allosteric modifiers of MC4R function. These may be used to test the hypothesis that modulation of receptor activity may be used to treat disorders of energy homeostasis.

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Primary Section

Section 42: Medical Physiology and Metabolism

Secondary Section

Section 24: Cellular and Molecular Neuroscience