by Dr Nir Barak
Whereas many individuals manage to achieve energy homeostasis and stable levels of body fat, rising obesity indicates that many cannot. As obesity levels reach pandemic proportions, with associated health and economic burdens, the need for anti-obesity drugs has become pressing. Histamine acts as a neurotransmitter, regulating appetite and energy metabolism, and has recently started to attract attention as a drug target. This article discusses the roles of the H1 receptor (H1R), one of the post-synaptic receptors that mediates histamine activity, and H3R, which acts as a presynaptic autoreceptor controlling the synthesis and release of histamine.
Obesity is mainly characterised by the accumulation of an excessive amount of body fat. This condition develops over time when the amount of ingested net energy exceeds the energy required for maintenance of normal body functions, physical activity or lean tissue growth. Globally, more than 1 billion adults are overweight with a body mass index (BMI) over 25 and more than 300 million are clinically obese with a BMI over 30. The medical consequences of this condition are serious and associated with a significant decrease in life expectancy as well as a high economic burden. Obesity is on the increase in a significant percentage of the world population and although the primary cause of this epidemic is still disputed, the enormous pressure on energy balance provided by the modern environment and lifestyle remain the most plausible explanation.
For most of us, the composition and amount of food that we eat varies considerably from one meal to the next and from one day to the next. Our common experience, therefore, seems at odds with the hypothesis that food intake is highly regulated. Emotions, social factors, time of day, convenience and cost are but a few of the variables that are not biologically regulated, but nonetheless affect meal-to-meal energy intake. As a consequence, daily energy intake is variable both within and among individuals, and is not well correlated with daily energy expenditure. However, despite such short-term mismatches in energy balance, most of us match cumulative energy intake to energy expenditure with great precision when measured over a period that spans many meals. This phenomenon reflects an active regulatory process, termed energy homeostasis that promotes stability in the amount of body energy stored in the form of fat.
CNS AND FEEDING BEHAVIOUR
Brain lesioning and stimulation studies performed some six decades ago first implicated the hypothalamus as a major centre controlling food intake and body weight. As our knowledge of specific neuronal subpopulations involved in energy homeostasis has expanded, the notion of specific ‘centres’ of the brain that control food intake and body weight has been replaced by that of discrete neuronal pathways that generate integrated responses related to changing body fuel stores. However, the use of ‘centres’ is still an effective way to explore and understand the interactions between feeding behaviour and other systems.
Numerous neurotransmitters have been found to confer orexigenic and anorexigenic effects on feeding. Of these, noradrenalin and serotonin are targets for anti-obesity drugs that are already in use. Other targets, including neuropeptides such as neuropeptide Y (NPY), and alpha-melanocyte stimulating hormone (alpha-MSH), are regarded as potential candidates for drug development. Unlike the classical neurotransmitters which are associated with feeding behaviour, histamine has only recently started to attract attention as a drug target, possibly due to its traditional association with allergic responses. However, since histamine does not cross the blood brain barrier, its actions as a neurotransmitter are independent of its peripheral actions.
HISTAMINE AND FEEDING BEHAVIOUR
Histamine acts as a neurotransmitter, regulating appetite and energy metabolism, arousal, body temperature and the sleep–wake cycle. Histamine mediates all these actions through four distinct G-protein coupled receptors: three post-synaptic receptors that mediate histamine activity (H1R, H2R and H4R) and one receptor (H3R) acting as a presynaptic autoreceptor that exerts a negative feedback control of the synthesis and release of histamine. Of these, the H1 receptor (H1R) seems to be the major receptor involved in feeding behaviour. In 1973, Clineschmidt and Lotti were the first to show that administration of histamine reduces food intake. They administered histamine into the lateral ventricle of cats and observed a long-term suppression of food intake.
Immunocytochemical studies on rat brain sections have revealed that histaminergic nerve cell bodies in the CNS are exclusively located in the tuberomammillary nucleus (TMN) in the lateral part of the posterior hypothalamus. These cells project their axons mainly to two areas with the highest concentration of H1Rs: the paraventricular nucleus (PVN) and ventromedial hypothalamus (VMH) [Figure 1].
HISTAMINE IN THE PVN
The PVN regulates feeding behaviour influenced by the body’s energy stores. Leptin is a hormone secreted by the adipocytes, and its levels are proportional to the fat mass in the body. Leptin inhibits the expression of appetite-stimulating NPY, and induces the expression of appetite-repressing alpha-MSH. Leptin interacts with the neurones that secrete these compounds in the arcuate nucleus, these neurones project their axons to the PVN, where these neuropeptides are secreted, and bind to their receptors on TRH cells. However, leptin-induced suppression of feeding is correlated with histaminergic signaling and may be attenuated either by inhibiting histamine synthesis, or by H1R gene knock-out. Whereas a bolus infusion of leptin into the hypothalamus significantly elevated the turnover rate of hypothalamic neuronal histamine, infusion of NPY or alpha-MSH failed to do so. Thus, leptin appears to exert some of its effect on weight regulation, directly through histamine secretion.
HISTAMINE IN THE VMH
For researchers investigating satiety mechanisms in feeding behaviour and body weight regulation, the VMH was once the focus of interest. Between 1940 and 1980, there were hundreds of published studies of the effects of VMH lesions and stimulation or of knife cuts in and around the VMH. Interestingly, lesions in the VMH induce greater weight gain in female rats than in males. It is important to note that VMH neurones are typically involved in sexual arousal and mating behaviour. The relation between these two seemingly distinct systems was recently studied by researchers with the aid of cell patch-clamp recordings that measured the effect of histamine on the membrane potential of VMH neurones. This study showed that the change in the membrane potential observed in ovariectomised female mice was significantly smaller than the change observed when these animals were treated with oestrogens. Therefore it seems that neurones in the VMH are responsible for the integration of nutritional signals with oestrogenic signalling and that together, they influence female reproductive behaviour. This proposal makes sense in that it would not be biologically adaptive for females to reproduce at times when they do not have an adequate food supply.
HISTAMINE AND FEEDING BEHAVIOUR IN HUMANS
It first became apparent that histamine affected feeding behaviour when it was observed that some antipsychotics had side effects which included appetite stimulation and weight gain in humans. Antipsychotic medications are an important component in the medical management of many psychotic conditions. The first-generation antipsychotics were effective at treating positive symptoms of psychosis, however, they produced significant extrapyramidal side effects such as subjective distress and diminished function, resulting in stigma and nonadherence. Therefore, these agents were replaced by the second generation Antipsychotic (SGAs). However, treatment with some SGAs causes a rapid increase in body weight in the first few months of therapy that may not reach a plateau even after one year of treatment. Notably, although the SGAs have differing affinities to serotonin, norepinephrine, dopamine and H1R, studies showed that the affinity of SGA to H1 receptor was the best predictor for weight gain. Furthermore, with olanzapine, an SGA drug with very high H1 blocking properties, the weight gain was associated with hunger and food intake even in healthy subjects.
HISTAMINE AS A TARGET FOR AN ANTI-OBESITY DRUG
Based on the current evidence of the involvement of histamine in the regulation of body weight, pharmacological manipulation of the histaminergic system, targeting either the H3R or the H1R, seems to be an attractive target for anti-obesity drugs. Binding of histamine to the presynaptic auto-inhibitory H3Rs results in inhibition of its further synthesis and release. Hence, it may be expected that H3R antagonists would increase the concentration of histamine in the synaptic cleft, enabling post synaptic H1R activation, suppressing food intake and inducing weight loss. Five such antagonists, GT-2394 (Gliatech Inc), NNC 38-1049 and NNC-0038-1202 (Novo-Nordisk), and A-331440, A-423579 (Abbott Laboratories), have already demonstrated their ability to reduce food intake in animals. However, the H3R is also involved in non-histaminergic neurotransmission and may thus have additional effect. To date, none of these inhibitors have reached the clinic.
Alternatively, histaminergic activation may be a more directly effected by H1R agonists. Obecure Ltd is pursuing this approach, investigating the properties of a well-known drug used for treatment of Menieur’s disease (vertigo), to act as an anti-obesity agent. The drug, Betahistine, is a centrally acting H1R agonist with partial H3R antagonistic properties and is approved world-wide, although not in the US.
In two double-blinded, placebo controlled clinical trials, for 4 weeks in 20 obese women, and for three months in 281 obese patients (male and female), Betahistine, significantly reduced weight only in women younger than 50 years of age, thus presenting a strong gender and age effect [Figure 2]. This suggests that in humans, like in animals, the histaminergic system effect on feeding behaviour is dependent on the oestrogen status.
FURTHER READING
1. Gotoh K, Fukagawa K, Fukagawa T, Noguchi H, Kakuma T, Sakata T, Yoshimatsu H. Hypothalamic neuronal histamine mediates the thyrotropin-releasing hormone-induced suppression of food intake. J Neurochem. 2007; 103: 1102-10.
2. Zhou J, Lee AW, Devidze N, Zhang Q, Kow LM, Pfaff DW. Histamine-induced excitatory responses in mouse ventromedial hypothalamic neurons: ionic mechanisms and estrogenic regulation. J Neurophysiol. 2007; 98: 3143-52
3. Mercer LP. Histamine and the neuroregulation of food intake. Nutrition. 1997; 13: 581-2.
4. Mercer LP, Kelley DS, Bundrant HM, Haq AU, Humphries LL. Gender affects rats’ central nervous system histaminergic responses to dietary manipulation. J Nutr. 1996; 126: 3128-35.
5. Kasaoka S, Kawahara Y, Inoue S, Tsuji M, Kato H, Tsuchiya T, Okuda H, Nakajima S. Gender effects in dietary histidine-induced anorexia. Nutrition. 2005; 21: 855-8.
THE AUTHOR
Dr Nir Barak, M.D.
Chief Scientific Officer
Obecure Ltd.
5-7 Shoham St., Paz Towers
Ramat Gan, Israel 52521
www.obecure.com
e-mail: nirbarak@post.tau.ac.il
