Description of image: A schematic of the central melanocortin system - Fan et al Nat. Neurosci. 7, 335-336 (2004)
and his associates work on the central control of energy homeostasis. His laboratory concentrates on the central melanocortin system, a complex set of neural circuits they have demonstrated to regulate a variety of physiological processes important to energy homeostasis. Expressed primarily in the pituitary and the arcuate nucleus of the hypothalamus, POMC is the precursor of at least three families of biologically active peptides: the adrenocorticotropins, the melanotropins, and the endorphins. The first two families, the melanocortins, have well-defined roles in adrenocortical function and pigmentation in addition to several identified actions in the central and peripheral nervous systems.
After cloning and characterizing a family of five receptors for ACTH and MSH peptides, the Cone laboratory focused its efforts on defining the roles of the melanocortin-3 and melanocortin-4 receptors (MC3-R and MC4-R). These receptors are involved in the etiology of the agouti obesity syndrome, one of the five original monogenic obesity syndromes in the mouse. The agouti peptide was demonstrated by Cone and colleagues to be an antagonist of the MSH and the MC4 receptors. Synthetic MC4-R antagonists, as well as deletion of the MC4-R gene in the mouse, were then used to demonstrate that the agouti obesity syndrome results from aberrant antagonism or disruption of central MC4-R signaling. These data showed that central POMC neurons exert a tonic inhibitory effect on feeding behavior and energy storage. Furthermore, neurons expressing MC4-R appear capable of integrating both orexigenic and anorexigenic signals downstream of leptin action, and thus may represent a component of the adipostat.
Current work in the laboratory is focused on:
- Identifying the normal hormonal, nutritional, and afferent signals involved in energy homeostasis that depend on the POMC circuitry
- Identifying the effector neurons and molecules downstream of POMC
- Developing zebrafish as a model system for the identification of genes involved in the regulation of energy homeostasis.