Multiple neural systems controlling food intake and body weight.

Discovery of the leptin receptor and its downstream peptidergic pathways has reconfirmed the crucial role of the hypothalamus in the regulation of food intake and energy balance. Strategically located in the midst of the mammalian neuraxis, the hypothalamus receives at least three distinct types of relevant information via direct or indirect neural connections as well as hormone receptors and substrate sensors bestowed on hypothalamic neurons. First, the medial and to a lesser extent the lateral hypothalamus receive a rich mix of information pertaining to the internal state of relative energy repletion/depletion. Second, specific hypothalamic nuclei receive information about the behavioral state, such as diurnal clock, physical activity-level, reproductive cycle, developmental stage, as well as imminent (e.g. fight and flight) and chronic (e.g. infection) stressors, that can potentially impact on short-term availability of fuels and long-term energy balance. Third, the hypothalamus, particularly its lateral aspects, receives information from areas in the forebrain involved in the acquisition, storage, and retrieval of sensory representations of the external food space and internal food experience, as well as from the executive forebrain involved in behavior selection and initiation. In addition, rich intrahypothalamic connections facilitate further distribution of incoming information to various hypothalamic nuclei. On the other hand, the hypothalamus has widespread neural projections to the same cortical areas it receives inputs, and many hypothalamic neurons are one synapse away from most endocrine systems and from both sympathetic and parasympathetic effector organs involved in the flux, storage, mobilization, and utilization of fuels. It is argued that processing within cortico-limbic areas and communication with hypothalamic areas are particularly important in human food intake control that is more and more guided by cognitive rather than metabolic aspects in the obesigenic environment of affluent societies. A distributed neural network for the control of food intake and energy balance consisting of a central processor and several parallel processing loops is hypothesized. Detailed neurochemical, anatomical, and functional analysis of reciprocal connections of the numerous peptidergic neuron populations in the hypothalamus with extrahypothalamic brain areas will be necessary to better understand what hypothalamus, forebrain, and brainstem tell each other and who is in charge under specific conditions of internal and external nutrient availability.