Development of Hypothalamic Circuits That Control Food Intake and Energy Balance

Interest in the importance of early life events in lifelong metabolic regulation has been increasing since the work by Hales and Barker (1992) in the early 1990s. Based on compelling epidemiological evidence, they found a strong association between suboptimal fetal and neonatal nutrition and a number of chronic metabolic conditions later in life, including cardiovascular diseases, hypertension, and diabetes. They proposed that poor nutrition during perinatal development causes a “thrifty phenotype” wherein the individual becomes adapted to an environment with short food supply by growing to a smaller stature, having a lower metabolic rate, and showing less behavioral activity to conserve energy. If such individuals are later exposed to a richer environment, they may instead run a higher risk of developing obesity and type 2 diabetes due to a mismatch between actual and expected nutritional environment. The concept of perinatal programming of obesity and diabetes has then been extended to other nutritional insults, including maternal and/or postnatal overnutrition. It has been suggested that changes in the perinatal environment can affect the structure and function of key metabolically relevant organs such as the pancreas, liver, and adipose tissue. There is also growing appreciation that developmental programming of neural systems involved in energy balance by the perinatal environment represents a potential cause for obesity and diabetes. An important component of this neural system involves neurons located in the hypothalamus. Classic experiments using physical lesions of specific hypothalamic loci and, more recently, studies using conditional, neuron-specific gene targeting strategies have revealed that the hypothalamic regulation of energy homeostasis involves an interconnected neural network that contains specialized neurons located in the arcuate nucleus (ARC), the ventromedial nucleus (VMH), the dorsomedial nucleus (DMH), the paraventricular nucleus (PVN), and the lateral hypothalamic area (LHA) (for review, see Gao and Horvath 2007, Williams and Elmquist 2012) (Figure 7.1). The ARC and VMH appear to be predominant sites for the integration of blood-borne molecules, such as hormones (e.g., leptin, insulin, ghrelin, etc) and nutrients (e.g., glucose, free fatty acids, etc). Within the ARC, primary importance has been given to neurons that coexpress agouti-related peptide (AgRP) and neuropeptide Y (NPY) and the neurons that contain proopiomelanocortin (POMC)-derived peptides. Both NPY/AgRP- and POMC-containing neurons project extensively to other key hypothalamic nuclei, including the PVN, DMH, and LHA, that in turn send projections to intrahypothalamic and extrahypothalamic sites to regulate feeding. Of particular importance are projections to the PVN because it is the most thoroughly characterized hypothalamic interface between the endocrine, autonomic, and somatomotor systems that influence feeding behavior and energy metabolism (Sawchenko 1998, Sawchenko and Swanson 1983, Watts 2000). The complex pattern of neuronal wiring in the adult hypothalamus depends on a series of cellular and endocrine events during development that establish a framework on which functional circuits can be built.