**6. Histaminergic control of energy expenditure**

Maintenance of core body temperature represent a major energy expenditure of a homeothermic organism. Uncoupling proteins (UCPs) are inner mitochondrial membrane transporters of free fatty acids, which dissipate the proton gradient by releasing stored energy as heat, without coupling to other energy consuming processes [62]. UCP1 in brown adipose tissue (BAT) plays a crucial role in regulating energy expenditure and thermogenesis in rodents and neonates of larger mammalian species, including humans. UCP2 and UCP3 are not involved in adaptive thermogenesis, however their activation *in vivo* by physiological activators or pharmacological intervention has the capacity to be significantly thermogenic [63]. The hypothalamus controls UCP1 and UCP3 expression in BAT and white adipose tissue (WAT) via the sympathetic neuron system. Infusion of histamine in the third ventricle or in the preoptic area (POA) produces similar increases in BAT sympathetic nerve activity (SNA) and in the UCP1 mRNA expression [64]. By contrast injections of histamine in the lateral hypothalamus or the ventromedial hypothalamic nucleus were without effect ([64]), suggesting that the POA is the principal hypothalamic site which mediates the stimulatory effect of histamine of this efferent pathway. Histamine-deficient animals (HDC-/-) have an impaired ability to express UCP1 in BAT [65] further suggesting a role of histamine signaling in the control of energy expenditure. Similarly, the upregulation of UCP1 mRNA expression induced by central infusion of leptin is attenuated in H1R-/- mice [66] suggesting a role of this receptor subtype in mechanisms regulating energy expenditure. The role of the other histamine receptor subtypes also present in the PO/AH in this effect remains to be determined. Increased hypothalamic histamine also results in a decreased respiratory quotient, which indicates increased lipid oxidation [67].

In our study [59] we have determined the effects of activation of histamine receptors in the preoptic area by increasing the concentration of endogenous histamine or by local injection of specific agonists. Both approaches induce an elevation of core body temperature and decreased respiratory exchange ratio (RER). The hyperthermic effect is associated with a rapid increase in mRNA expression of uncoupling proteins in thermogenic tissues, the most pronounced being that of uncoupling protein (UCP) 1 in brown adipose tissue and of UCP2 in white adipose tissue. In diet-induced obese mice histamine had much diminished hyperthermic effects as well as reduced effect on RER. Similarly, the ability of preoptic histamine signaling to increase the expression of uncoupling proteins was abolished. We also found that the expression of mRNA encoding the H1 receptor subtype in the preoptic area was significantly lower in obese animals [59].

198 Hyperthermia

the active phase of the circadian cycle [61].

indicates increased lipid oxidation [67].

**6. Histaminergic control of energy expenditure** 

Our studies have established that in mice histamine induces hyperthermia when administered in either the medial or the median preoptic nuclei [59]. Similarly, when the endogenous concentration of histamine was raised in either nucleus by local injection of histamine *N*-methyl transferase inhibitor a hyperthermia of similar amplitude was observed [59]. H1R and H3R specific agonists were equally potent in inducing a hyperthermia when infused in the median preoptic nucleus [21]. In contrast, H2R specific agonists mimicked the histamine effect when administered intra-MPON, while H1R specific agonists had little effect [60]. Surprisingly, H3R specific agonists were without effect in this nucleus [60].

Our experiments have also revealed that histamine modulation of the activity of GABAergic PO/AH neurons provides a mechanism for selective modulation of body temperature at the beginning of the active phase of the circadian cycle [61]. Thus, injection of a H3 antagonist in the MnPO induces a delay in the onset of the rise of the body temperature associated with

Maintenance of core body temperature represent a major energy expenditure of a homeothermic organism. Uncoupling proteins (UCPs) are inner mitochondrial membrane transporters of free fatty acids, which dissipate the proton gradient by releasing stored energy as heat, without coupling to other energy consuming processes [62]. UCP1 in brown adipose tissue (BAT) plays a crucial role in regulating energy expenditure and thermogenesis in rodents and neonates of larger mammalian species, including humans. UCP2 and UCP3 are not involved in adaptive thermogenesis, however their activation *in vivo* by physiological activators or pharmacological intervention has the capacity to be significantly thermogenic [63]. The hypothalamus controls UCP1 and UCP3 expression in BAT and white adipose tissue (WAT) via the sympathetic neuron system. Infusion of histamine in the third ventricle or in the preoptic area (POA) produces similar increases in BAT sympathetic nerve activity (SNA) and in the UCP1 mRNA expression [64]. By contrast injections of histamine in the lateral hypothalamus or the ventromedial hypothalamic nucleus were without effect ([64]), suggesting that the POA is the principal hypothalamic site which mediates the stimulatory effect of histamine of this efferent pathway. Histamine-deficient animals (HDC-/-) have an impaired ability to express UCP1 in BAT [65] further suggesting a role of histamine signaling in the control of energy expenditure. Similarly, the upregulation of UCP1 mRNA expression induced by central infusion of leptin is attenuated in H1R-/- mice [66] suggesting a role of this receptor subtype in mechanisms regulating energy expenditure. The role of the other histamine receptor subtypes also present in the PO/AH in this effect remains to be determined. Increased hypothalamic histamine also results in a decreased respiratory quotient, which

In our study [59] we have determined the effects of activation of histamine receptors in the preoptic area by increasing the concentration of endogenous histamine or by local injection of specific agonists. Both approaches induce an elevation of core body temperature and Several H1R and H2R antagonists are clinically used in the treatment of several diseases. H1R antagonists (e.g. diphenhydramine hydrochloride, trade name Benadryl) are clinically used in the treatment of histamine-mediated allergic conditions. Clinically-relevant histamine H2R antagonists (e.g. ranitidine and cimetidine, trade names Zanatac and Tagamet, respectively) are used to reduce the secretion of gastric acid by acting on H2 receptors found principally in the parietal cells of the gastric mucosa. Interestingly, few side effects related to thermoregulation have been reported, due probably to the fact that these compounds cross the blood-brain barrier to a small extent. More recently, H3R antagonists have received a great interest from the pharmaceutical industry, with some drugs being in phase I or phase II of clinical trials [68]. Some projects have proposed H3R antagonists for the treatment of narcolepsy and/or cognitive disorders while others are trying H3R antagonists for the treatment of obesity and diabetes mellitus. All these drugs act at central H3Rs and produce increased levels of histamine in the brain, in particular in the hypothalamus. Since these compounds are designed to work centrally, the possibility of thermoregulatory side effects is significantly enhanced.

H1R antagonists have been reported to increase seizure susceptibility in patients with febrile seizures [69,70]. These observations strengthen the idea that these drugs can act centrally to influence body temperature and other centrally regulated functions. Thus, H1R antagonists in most cases should not be prescribed to patients, particularly young infants, with febrile seizures and epilepsy. Drug-induced fever due to H2R blockers was also encountered, however the effect appears to be mediated by an allergic reaction to the drugs, characterized by a marked increase in IgE [71].
