Abstract: Human energy homeostasis principally depends on thermal and food intake regulation mechanisms. In addition to describing the major pathways, brain centers, and their connections which control these functions, this review focuses on (i) interrelations between thermoregulation and food intake, (ii) the role of tanycytes, and (iii) the regenerative capacity of the system in mammals. In the arcuate nucleus, anorexigenic proopiomelanocortin/melanocyte-stimulating hormone neurons and orexigenic neuropeptide Y/agouti-related peptide neurons are reached by a wealth of diet-induced (e.g., leptin, ghrelin, or insulin) or hormonal (e.g., thyroid hormone) signals. These neurons are not only sensitive to temperature signals but also point to both direct and indirect executors of thermoregulation through axonal projection onto the sympathetic system, by producing cleaved proopiomelanocortin products and by reaching endocrine orchestrators, including corticotropin-releasing hormone and thyrotropin-releasing hormone neurons in the paraventricular nucleus. Meanwhile, ambient temperature affects food intake: the warm-cold separated spinobrachial-preoptic area pathways ultimately target agouti-related peptide neurons to attenuate or increase cold-evoked feeding. The brainstem, hypothalamic, and preoptic area centers of these pathways are reached by a wide array of modulatory signals, which refine thermal and dietetic regulation according to conditions such as daily cycle, stress, or fever. We also review regulating mechanisms that are activated in an extreme form of fasting when food becomes unavailable: a specific body temperature control in hibernating animals during the winter months. Understanding this mechanism could likely contribute to medical applications; i.e., artificial induction of a hibernation-like hypometabolic state. Tanycytes uniquely shape energy homeostasis: they dynamically shape the blood–brain barrier to regulate neurohormone sequestration into the brain parenchyme, but also shuttle between the blood circulation and the cerebrospinal fluid bidirectionally. Therefore, blood- or liquorborne signals not only target arcuate hypothalamic neurons from different circulatory systems, but the activity of diverse groups of neurohormone (such as leptin or ghrelin)-sensitive periventricular neurons will be synchronized. Tanycytes can likely link thermal and food-intake regulations: they carry receptors (most importantly transient receptor potential cation channel subfamily V member 1, glucose, and cytokine receptors) which enable them to sensitively monitor and react to both thermal and energy homeostatic challenges, including anorexia, while they reduce feeding in heat exposure via a specific parabrachial-tanycyte-hypothalamic circuitry. Tanycytes also emerge as the source for the regenerative potential of thermal and energy homeostasis: they not only display functional and morphological plasticity but also neural stem cell properties; they supply the arcuate nucleus with new neurons in both temperature- and diet-responsive manners, which are compromised in extreme/pathological heat challenges or diet-induced obesity, respectively.

Key words: agouti-related peptide neurons, heat challenge, heat stress, modulation, paraventricular nucleus, proopiomelanocortin neurons, sympathetic nervous system, thermogenesis