Neurons of the arcuate nucleus of the hypothalamus (ARH) appear to be sites of convergence of central and peripheral signals of energy stores, and profoundly modulate the activity of the
melanocortin circuits, providing a strong rationale for pursuing these circuits as therapeutic targets for disorders of energy homeostasis. Recently, tremendous advances have been made in identifying genes and pathways important to regulating energy homeostasis, particularly the
hormone leptin and its receptor. This
hormone/receptor pair is expressed at high levels in the so-called satiety centers in the hypothalamus, and at lower levels elsewhere in the body. Recent studies in our lab and those of our collaborators have shown that
leptin modulates different populations of hypothalamic cells in different ways, rapidly activating
POMC neurons and inhibiting NPY/AgRP neurons. In this report, we outline an integrated model of
leptin's action in the arcuate nucleus of the hypothalamus, derived from our electrophysiological studies of brain slice preparations taken from transgenic mice that have been bred to express a variety of fluorescent
proteins in specific cell types. We also discuss the recently withdrawn
obesity drug
fenfluramine, which appears to act on
POMC neurons via the
serotonin 2C receptor. Nutrient-sensing
serotonin neurons may project from the raphe nuclei in the brainstem to the hypothalamus; within the arcuate nucleus,
serotonin signals are integrated with others such as
leptin,
ghrelin, and
peptide YY(3-36) from the gut, to produce a coordinated response to nutrient state. Finally, we review the current inquiries into the ability of the
hormone ghrelin to stimulate appetite by its action of NPY neurons and inhibition of
POMC neurons.