The elegance of energy balance: Insight from circuit-level manipulations

Mechanisms of energy balance were first examined using very powerful neuroscience techniques such as lesions and electrical stimulation. This early work identified the hypothalamus as a key structure involved in hunger and feeding; however, neural resolution of cell-defined populations contributing to appetite regulation remained elusive. Recent innovations in neuroscience have produced constructs that allow for a high degree of specificity in loss- and gain-of-function manipulations in molecularly circumscribed neural subsets as well as monosynaptic circuit mapping and in vivo neurophysiology. These complimentary techniques have provided researchers an unprecedented amount of empirical agility. As a result, cell populations in two subregions of the hypothalamus have emerged as key players in the physiological control of feeding behavior. The arcuate nucleus of the hypothalamus and the paraventricular nucleus of the hypothalamus contain neural populations that have a direct role in the promotion of hunger and satiety. These include neurons that express agouti-related peptide, pro-opiomelanocortin, single-minded homolog 1 protein, and the melanocortin-4 receptor. This review focuses on how these neural subsets communicate with one another, link up to build elaborate networks, and ultimately contribute to alterations in food intake. The continuing advancement of neuroscience tools, as well as a multimodal integration of findings, will be critical in illuminating an exhaustive and clinically relevant hunger circuit.