The temperature regulation responses involve intricate circuitry and physiological processes. Key components in the regulation of body temperature include the preoptic area and dorsal medial hypothalamic nucleus. The preoptic area serves as the target for various sources of sensory information. Thermosensitive primary afferents carry cutaneous temperature information to the dorsal horn of the spinal cord, where they synapse with neurons that project to and stimulate the parabrachial nucleus in the caudal midbrain. Visceral afferents transmit information to the parabrachial nucleus via the solitary nucleus. The parabrachial neurons, in turn, excite neurons in the median nucleus of the preoptic area. Many of these median nucleus neurons are responsive to changes in local blood temperature and contain the prostaglandin E2 (PGE2) receptor 3 (EP3), which plays a role in fever responses. The median preoptic nucleus integrates information from different types of thermoreceptors and sends output to the neighboring medial preoptic area. From there, projections are directed to regions of the rostral medulla, both directly and via the dorsal medial hypothalamic nucleus. The rostral medulla houses spinally projecting neurons that innervate the lateral horn of the spinal cord, where preganglionic sympathetic neurons are located. The activity of these neurons controls brown adipose tissue (BAT) thermogenesis and modulates cutaneous vasomotor tone. Additionally, the rostral medulla projects to the ventral horn of the spinal cord, which contains somatic motor neurons responsible for skeletal muscle contraction and the shivering response.

Fever, often accompanying infections, can be viewed as an elevation of the body temperature setpoint. This elevation can be caused by the release of pyrogens by microorganisms or cells involved in the inflammatory response. Prostaglandin PGE2, binding to EP3 receptors on neurons in the preoptic area, primarily mediates the pyrogen's effect of raising the setpoint. PGE2 is released by peripheral tissues and blood vessels that supply the preoptic area. Binding of PGE2 to EP3 receptors leads to a reduction in the activity of preoptic neurons. This reduction in neuronal activity triggers increased heat production through shivering and BAT thermogenesis, as well as heat conservation through cutaneous vasoconstriction. The combined effect is an elevation in body temperature. Evidence supporting this mechanism of fever production includes studies in which injection of PGE2 into the preoptic area induced fever and others in which the selective deletion of the EP3 receptor from preoptic neurons abolished the ability of PGE2 injection to induce fever.

The regulation of feeding and body weight is essential for maintaining energy homeostasis. Animals face the challenge of needing a continuous supply of nutrients for cellular function despite not constantly eating. To achieve energy homeostasis, feeding behavior is controlled by various factors that operate on both short-term and long-term bases. These factors ensure sufficient energy stores by controlling ingestion and body weight. Both hedonic and homeostatic factors play a role, but this chapter focuses on the latter due to the central role of the hypothalamus in energy homeostasis.
Many details of the circuitry and physiologic processes underlying the temperature regulation responses are now known, and they indicate that the preoptic area and dorsal medial hypothalamic nucleus are key components in the regulation of body temperature. The preoptic area in particular appears to be the target of the various sources of sensory information. Cutaneous temperature information is conveyed by thermosensitive primary afferents that synapse in the dorsal horn of the spinal cord onto neurons that project up to and excite the parabrachial nucleus in the caudal midbrain. Information from visceral afferents is relayed by the solitary nucleus to the parabrachial nucleus as well. The parabrachial neurons in turn excite neurons within a specific part of the preoptic area, the median nucleus (of the preoptic area). Many median nucleus neurons are also sensitive to local changes in blood temperature and contain prostaglandin E2 (PGE2) receptor 3 (EP3), which mediates fever responses (see the following “In the Clinic” box).
Thus the median preoptic nucleus is a key component of the thermoregulatory control system in which information from the various types of thermoreceptors is integrated. Output from this nucleus is directed to the neighboring medial preoptic area, which projects to regions of the rostral medulla, both directly and via the dorsal medial hypothalamic nucleus. The rostral medulla has spinally projecting neurons that project to the lateral horn of the spinal cord, where the preganglionic sympathetic neurons are located, and the activity of these neurons regulates BAT thermogenesis and modulates cutaneous vasomotor tone. The rostral medulla also projects to the ventral horn of the spinal cord, which contains the somatic motor neurons that contract skeletal muscle and thus mediate the shivering response.
Fever,whichaccompaniessomeinfections,canbethoughtofasanelevationofthesetpointforbodytemperature.Thiselevationcanbecausedbythereleaseofpyrogens bymicroorganismsorbycellsmediatingtheinflammatoryresponse.Thepyrogen’seffecttoraisethesetpointismediatedprimarilybytheactionofprostaglandinPGE2’sbindingtoEP3receptorsonneuronsinthepreopticarea.PGE2isreleasedbyperipheraltissuesandbybloodvesselssupplyingthepreopticarea.ThebindingofPGE2toEP3receptorscausesareductionintheactivityofpreopticneurons.ThisreductioninneuronalactivityleadstoincreasedheatproductionthroughshiveringandBATthermogenesisandtoheatconservationbycutaneousvasoconstriction,thecombinedeffectofwhichistoraisebodytemperature.EvidenceofthismechanismoffeverproductionincludesstudiesinwhichinjectionofPGE2intothepreopticareainducedfeverandothersinwhichselectivedeletionoftheEP3receptorfrompreopticneuronsabolishedtheabilityofPGE2injectionstoinducefever.
Regulation of Feeding and Body Weight
Energy homeostasis is crucial for the survival of the animal. The challenge is that most cells need a continuous supply of nutrients to function, but most animals do not constantly eat; instead, they have periodic meals. Thus to achieve energy homeostasis, feeding behavior is controlled by many factors, which operate both on a short-term basis to control ingestion and on a long-term basis to control body weight in order to ensure sufficient energy stores. Both hedonic and homeostatic factors are involved; however, in this chapter, the focus is on the latter because of the central role that the hypothalamus plays in energy homeostasis.