Histaminergic regulation of appetite

Food intake is essential to all animals. However, when energy consumption through food overtakes energy expenditure, obesity can result. Obesity has been identified as a worldwide health problem associated with diseases such as type 2 diabetes and hypertension. Thus, it is essential to find effective anti-obesity therapies. The aim of this thesis was to determine whether the histaminergic system could be pharmacologically manipulated to alter food intake and whether in particular the H3R is a suitable therapeutic target. Histamine is a central neurotransmitter that plays a major role in controlling energy balance by acting through specific hypothalamic sites. Injections of histamine receptor-1 (H1R) antagonists into the ventromedial hypothalamic nucleus (VMN) cause hyperphagia, whereas antagonism of presynaptic histamine receptor-3 (H3R) causes hypophagia, leading to the hypothesis that selective antagonists or inverse agonists might be potential treatments for obesity through their actions on central H3R. My aim was to assess the precise mode of action of histamine and H3R drugs to affect acute, appetitive behaviour. Using feeding and behavioural studies I demonstrated the acute anorexigenic actions of histamine (ICV) and the H3R inverse agonist, thioperamide (ICV or IP), in rats without disrupting the behavioural satiety sequence. In accordance with predictions, the H3R agonist, imetit (ICV or IP), increased feeding. The actions of both thioperamide and imetit were blocked by the drug proxyfan, which in our model is acting as a neutral H3R antagonist. Interestingly, both thioperamide and imetit caused anorexia in mice. C-Fos functional immunostaining revealed that systemic administration of thioperamide and imetit increased the activity of neurones in the key feeding nuclei of the hypothalamus, including the VMN. To further investigate the mode of action of histaminergic drugs, I carried out extracellular electrophysiological recordings from neurones of the rat VMN in vitro. Of the 197 VMN cells recorded, 62% were histamine-responsive, with 97% of these showing an increase in neuronal firing rates in response to histamine. The excitatory response to histamine was blocked in 90% of instances by pyrilamine, a selective H1R antagonist. Neurones that responded to histamine previously were treated also with thioperamide. 88% of these neurones also responded with an increase in firing. The effect of thioperamide was blocked in all cases by co-administrating pyrilamine, proving that H3R in the VMN are presynaptic autoreceptors, rather than heteroreceptors modulating the release of other transmitters. Imetit had an inhibitory effect on VMN neuronal firing in 86% of recorded cells. Proxyfan was able to block the changes in neuronal firing that both thioperamide and imetit caused. This suggests it is acting as a neutral H3R antagonist in both our in vivo and in vitro models. Thus, using a neutral H3R antagonist we have proven the effects imetit and thioperamide had on feeding and neuronal VMN firing were a direct result of activating a H3R and, therefore, these compounds are receptor-specific for the H3R. In conclusion, our results support a role for histaminergic receptors, including postsynaptic H1R and presynaptic H3R autoreceptors in the VMN, to modulate feeding.EThOS - Electronic Theses Online ServiceBBSRC : Novo NordiskGBUnited Kingdo

Heterogeneity in Karakoram glacier surges

Many Karakoram glaciers periodically undergo surges during which large volumes of ice and debris are rapidly transported down-glacier, usually at a rate of one to two orders of magnitude greater than during quiescence. Here we identify eight recent surges in the region, and map their surface velocities using cross-correlation feature tracking on optical satellite imagery. In total, we present 44 surface velocity datasets, which show that Karakoram surges are generally short-lived, lasting between 3 and 5 years in most cases, and have rapid build-up and relaxation phases, often lasting less than a year. Peak velocities of up to 2 km a-1 are reached during summer months and the surges tend to diminish during winter months. Otherwise, they do not follow a clearly identifiable pattern. In two of the surges, the peak velocity travels down-ice through time as a wave, which we interpret as a surge front. Three other surges are characterised by high velocities that occur simultaneously across the entire glacier surface and acceleration and deceleration is close to monotonic. There is also no consistent seasonal control on surge initiation or termination. We suggest that the differing styles of surge can be partly accounted for by individual glacier configurations, and that while some characteristics of Karakoram surges are akin to thermally-controlled surges elsewhere (e.g. Svalbard), the dominant surge mechanism remains unclear. We thus propose that these surges represent a spectrum of flow instabilities and the processes controlling their evolution may vary on a glacier by glacier basis

Do oxytocin neurones affect feeding?

From Wiley via Jisc Publications RouterHistory: received 2021-06-02, rev-recd 2021-07-30, accepted 2021-08-19, pub-electronic 2021-09-08Article version: VoRPublication status: PublishedFunder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100000265; Grant(s): MR/P024017/1Abstract: There has been a long history of research on the effects of oxytocin on feeding behaviour. The classic‐held view is that the neurohormone is anorexigenic at least in rodents, although the data for humans are not so clear cut. Likewise, a physiological role for oxytocin is disputed. Thus, although pharmacological, anatomical and physiological data suggest oxytocin may have a function in satiety signalling, this view is not supported by the latest research using the genetic recording and manipulation of oxytocin neurones. Here, we avoid a discussion of the pharmacological effects of oxytocin and examine evidence, from both sides of the argument, concerning whether the endogenous oxytocin system has a role in the regulation of normal feeding

Neuromedin U receptors in GtoPdb v.2023.1

Neuromedin U receptors (provisional nomenclature as recommended by NC-IUPHAR [30]) are activated by the endogenous 25 amino acid peptide neuromedin U (neuromedin U-25, NmU-25), a peptide originally isolated from pig spinal cord [92]. In humans, NmU-25 appears to be the sole product of a precursor gene (NMU, P48645) showing a broad tissue distribution, but which is expressed at highest levels in the upper gastrointestinal tract, CNS, bone marrow and fetal liver. Much shorter versions of NmU are found in some species, but not in human, and are derived at least in some instances from the proteolytic cleavage of the longer NmU. Despite species differences in NmU structure, the C-terminal region (particularly the C-terminal pentapeptide) is highly conserved and contains biological activity. Neuromedin S (neuromedin S-33) has also been identified as an endogenous agonist [97]. NmS-33 is, as its name suggests, a 33 amino-acid product of a precursor protein derived from a single gene and contains an amidated C-terminal heptapeptide identical to NmU. NmS-33 appears to activate NMU receptors with equivalent potency to NmU-25

Neuromedin U receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Neuromedin U receptors (provisional nomenclature as recommended by NC-IUPHAR [29]) are activated by the endogenous 25 amino acid peptide neuromedin U (neuromedin U-25, NmU-25), a peptide originally isolated from pig spinal cord [90]. In humans, NmU-25 appears to be the sole product of a precursor gene (NMU, P48645) showing a broad tissue distribution, but which is expressed at highest levels in the upper gastrointestinal tract, CNS, bone marrow and fetal liver. Much shorter versions of NmU are found in some species, but not in human, and are derived at least in some instances from the proteolytic cleavage of the longer NmU. Despite species differences in NmU structure, the C-terminal region (particularly the C-terminal pentapeptide) is highly conserved and contains biological activity. Neuromedin S (neuromedin S-33) has also been identified as an endogenous agonist [95]. NmS-33 is, as its name suggests, a 33 amino-acid product of a precursor protein derived from a single gene and contains an amidated C-terminal heptapeptide identical to NmU. NmS-33 appears to activate NMU receptors with equivalent potency to NmU-25

Sequential Exposure to Obesogenic Factors in Females Rats: From Physiological Changes to Lipid Metabolism in Liver and Mesenteric Adipose Tissue

During their lifetime, females are subjected to different nutritional and hormonal factors that could increase the risk of obesity and associated comorbidities. From early postnatal periods until the postmenopausal phase, exposure to over nutrition, high-energy diet and oestrogen deficiency, are considered as significant obesity risk factors in women. In this study, we assessed how key transitional life events and exposure to different nutrition influence energy homeostasis in a rat model. Specifically, we assessed the sequential exposure to postnatal over nutrition, high-fat diet (HFD) after weaning, followed later by ovariectomy (OVX; as a model of menopause). Each obesity risk factor increased significantly body weight (BW) and adiposity, with additive effects after sequential exposure. Increased energy intake in both HFD and/or OVX groups, and decreased locomotor activity and energy expenditure after OVX can explain these metabolic changes. Our study also documents decreased lipogenic pathway in mesenteric adipose tissue after HFD and/or OVX, independent of previous postnatal programming, yet only HFD evoked this effect in liver. In addition, we report an increase in the expression of the hepatic PEPCK depending on previous metabolic status. Overall, our results identify the impact of different risk factors, which will help in understanding the development of obesity in females

Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation

This work was funded by an MRC Career Development Award (MR/ P009824/1 and MR/P009824/2) to GD’A, as well as an MRC grant to SML/GD’A (MR/T032669/1), a BBSRC grant to SML (BB/M001067/1), and an additional direct contribution from Eli Lilly. D.J.H. was sup- ported by MRC (MR/N00275X/1 and MR/S025618/1), Diabetes UK (17/ 0005681), and the European Research Council (ERC) under the Eu- ropean Union’s Horizon 2020 research and innovation programme (Starting Grant 715884 to D.J.H.). AC was supported for part of this project by a travel grant from the Italian Society of Pharmacology and a fellowship from the Veronesi Foundation (Italy).Peer reviewedPublisher PD

Set points, settling points and some alternative models: theoretical options to understand how genes and environments combine to regulate body adiposity

The close correspondence between energy intake and expenditure over prolonged time periods, coupled with an apparent protection of the level of body adiposity in the face of perturbations of energy balance, has led to the idea that body fatness is regulated via mechanisms that control intake and energy expenditure. Two models have dominated the discussion of how this regulation might take place. The set point model is rooted in physiology, genetics and molecular biology, and suggests that there is an active feedback mechanism linking adipose tissue (stored energy) to intake and expenditure via a set point, presumably encoded in the brain. This model is consistent with many of the biological aspects of energy balance, but struggles to explain the many significant environmental and social influences on obesity, food intake and physical activity. More importantly, the set point model does not effectively explain the ‘obesity epidemic' - the large increase in body weight and adiposity of a large proportion of individuals in many countries since the 1980s. An alternative model, called the settling point model, is based on the idea that there is passive feedback between the size of the body stores and aspects of expenditure. This model accommodates many of the social and environmental characteristics of energy balance, but struggles to explain some of the biological and genetic aspects. The shortcomings of these two models reflect their failure to address the gene-by-environment interactions that dominate the regulation of body weight. We discuss two additional models - the general intake model and the dual intervention point model - that address this issue and might offer better ways to understand how body fatness is controlled