Selective Antagonist for the Melanocortin 4 Receptor (HS014) Increases Food Intake in Free-Feeding Rats

doi:10.1006/bbrc.1998.8389

Biochemical and Biophysical Research Communications

Volume 245, Issue 1, 7 April 1998, Pages 90-93

https://doi.org/10.1006/bbrc.1998.8389 Get rights and content

Abstract

Recently, we discovered a cyclic analogue of MSH (melanocyte stimulating hormone), HS014, which is the first selective antagonist of the MC4 receptor. We have here studied the effects of this peptide on food intake in non-deprived male rats. Vehicle or five doses of HS014 (0.1-10 nmol) were administered ICV at midday. HS014 (0.33-3.3 nmol) significantly and in a dose-dependent manner increased food intake for the first 1 h. At 4 h after the injections, food intake was also significantly increased in rats treated with 1 and 3.3 nmol of HS014, whereas the lowest dose tested (0.1 nmol) was without effect. Cumulative food intake increased to 100% at 4 h after the injections. The highest dose of HS014 (10 nmol) induced sedation and inhibited feeding for first hour of testing. However, this dose also increased food consumption later. These data demonstrate that attenuation of central melanocortinergic tone with HS014 induces disinhibition of feeding and provides additional evidence for the hypothesis that activation of the MC4 receptor inhibits food intake. HS014 may be a useful tool for elucidating the role of the MC receptor subtypesin vivo.This is the first report demonstrating an increase in daytime food intake in free-feeding animals caused by a MC receptor active agent.

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Evidence for a feeding related association between melanocortin in the NTS and Neuropeptide-Y in the PVN
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Melanocortin and neuropeptide-Y (NPY) are both involved in feeding and energy regulation, and they have opposite effects in the paraventricular nucleus of the hypothalamus (PVN). The present study examined an interaction between melanocortin in the nucleus of the solitary tract (NTS) and NPY in the PVN. Male Sprague-Dawley rats were implanted with cannulae in the injection sites of interest. In Experiment 1, subjects received either the melanocortin 3/4-receptor (MC3/4) antagonist SHU9119 (0, 10, 50 and 100 pmol/0.5 μl) or the MC3/4 agonist MTII (0, 10, 50, 100 and 200 pmol/0.5 μl) into the NTS. Food intake was measured at 1, 2, 4, 6 and 24-h post-injection. Administration of SHU9119 into the NTS significantly and dose-dependently increased food intake at 1, 2, 4, 6 and 6-24-h, and administration of MTII into the NTS significantly and dose-dependently decreased 24-h free feeding. In Experiment 2, subjects received the MC3/4 agonist MTII (0, 10, 50, 100 and 200 pmol/0.5 μl) into the NTS just prior to NPY (0 and 1μg/0.5 μl) in the PVN. PVN injection of NPY stimulated feeding, and administration of MTII (50, 100 and 200 pmol) into the NTS significantly and dose-dependently decreased NPY-induced feeding at 2, 4, 6 and 6-24-h. These data suggest that there could be a neuronal association between melanocortin in the NTS and NPY in the PVN, and that the melanocortin system in the NTS has an antagonistic effect on NPY-induced feeding in the PVN.
Proopiomelanocortin projections to the nucleus accumbens modulate acquisition and maintenance of operant palatable pellet administration in mice
2023, Physiology and Behavior
Obesity is a crisis in the United States, producing many co-morbid diseases that can drastically decrease quality of life. While diet is a major focus for therapeutic intervention, the need to understand underlying appetitive neurocircuitry persists. Proopiomelanocortin (POMC) peptides are well-known for their anorexigenic activity, but also mediate reward and learning. The nucleus accumbens (NAcc) is best known for its role in reward-based learning, but the contribution of POMC projections to NAcc on feeding are controversial since the two major POMC-derived peptides (β-endorphin and α-MSH) have opposite effects on food intake. Our objective was to determine the effect of stimulating POMC projections in the NAcc on acquisition and maintenance of operant self-administration of a palatable food. Adult POMCCre mice were microinjected into the NAcc with a Cre-dependent retrograde adeno-associated viral vector expressing Gq Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Mice were trained to self-administer palatable 20-mg pellets in daily operant sessions. Acquisition of self-administration (fixed ratio 30) and baseline self-administration were measured in daily sessions, with mice receiving injections of either JHU37152 (DREADD agonist) or saline (i.p.) 15 min prior to the sessions. POMC neuron stimulation (JHU injection) before training sessions produced a significant increase in rate of acquisition and accuracy compared to the saline treated group, with no significant effect on rewards earned. Removal of POMC neuron stimulation before sessions initially reduced consumption with a gradual increase in responding for reinforcer over 3 days of saline injections. Reinstatement of POMC neuron stimulation (JHU) before the session resulted in a significant decrease in responding and rewards earned. These results suggest a complex role of POMC peptides within the NAcc that increase reward learning for a novel palatable food while decreasing consumption of the reinforcer following experience with it.
Investigating the role of the central melanocortin system in stress and stress-related disorders
2022, Pharmacological Research
Citation Excerpt :
However, it is believed that its anxiolytic effect, when injected in the central nucleus of the amygdala, is predominantly mediated by the MC4Rs, considering the low expression of the MC3Rs in this brain region [23,47,87]. Conversely, HS014 and HS024 are two selective MC4R antagonists [88], firstly tested by Kack et al. [88,89], whose ICV injection in rats did not influence any parameters in the EPM and in the open field (OF) test [88], a paradigm used to analyze locomotor activity and anxiety-like behavior [90], when compared to control rats [64,88]. Meanwhile the intra-amygdala co-administration of HS014 with NPY or the NPY Y1 and Y5 receptor agonist [Leu31, Pro34]-NPY elicited significant anxiolytic effects [64].
The melanocortinergic neural circuit, known for its influence on energy expenditure and feeding behavior, also plays a role in stress and stress-induced psychiatric disorders, including anxiety and depression. The major contribution is given by the melanocortin-4 receptor (MC4R) subtype, highly expressed in brain regions involved in the control of stress responses. Furthermore, the MC4R appears to profoundly affect the activity of the hypothalamic-pituitary-adrenal (HPA) axis, and it has been also highlighted a functional and anatomical interaction with the corticotropin-releasing factor (CRF), an important mediator of stress and stress-related behaviors. The MC4R agonists seem to exacerbate stress-inducing anxiety- and depressive-like behavior, while MC4R antagonists have been demonstrated to mitigate such disorders, as shown in several preclinical behavioral tests. The evidence collected in the present review suggests that the melanocortin system, through the MC4R, could possibly modulate behavioral responses to stress, suggesting the use of MC4R antagonists as a possible novel treatment for anxiety and depression induced by stress.
Molecular signatures of human melanocortin receptors for ligand binding and signaling
2017, Biochimica et Biophysica Acta - Molecular Basis of Disease
Human melanocortin receptors (hMCRs) belong to the seven-transmembrane (TM) domain proteins. There are five hMCR subtypes and each of these receptor subtypes has different patterns of tissue expression and physiological function. The endogenous agonists for hMCRs are α-, β-, and γ-MSH and ACTH and endogenous antagonists are Agouti and AGRP which are the only known naturally occurring antagonists for the receptors. These peptides have their own profiles regarding the relative potency for specific hMCR subtype. Extensive studies have been performed to examine the molecular basis of the hMCRs for different ligand binding affinity and potency. Studies indicate that natural ligand α-MSH utilizes conserved amino acid residues for MCR specific binding (orthosteric binding) while synthetic ligands utilize non-conserved amino acid residues for receptor subtype specific binding (allosteric binding). ACTH is the only endogenous agonist for hMC2R and more amino acid residues at hMC2R are required for ACTH binding and signaling. HMCR computer modeling provides the detailed information of ligand and MCR interaction. This review provides the latest understanding of the molecular basis of the hMCRs for ligand binding and signaling. This article is part of a Special Issue entitled: Melanocortin Receptors - edited by Ya-Xiong Tao.
Long term ingestion of a preload containing fructo-oligosaccharide or guar gum decreases fat mass but not food intake in mice
2015, Physiology and Behavior
Citation Excerpt :
These 2 types of viscous dietary fibers slow down gastric emptying as well as peristaltism thereby increasing the anorexigenic and homeostatic signaling emanating from the gastro-intestinal tract [5]. The hypothalamic neuropeptides such as the anorexigenic peptides pro-opiomelanocortin (POMC) and cocaine amphetamine regulatory peptide (CART), the orexigenic peptides agouti-related peptide (AgRP) and neuropeptide Y (NPY) [26–30] and the hypothalamic melanocortin-4 receptor [31,32] may be involved in the mechanism underlying the impact of all types of fibers on energy intake since they are well-known to take a prominent role in the control of energy homeostasis. Therefore, the short term effects of both fermentable and viscous dietary fibers on energy intake and fat storage are well described, however their impact over a longer time period (over 3 weeks) is less well characterized.
Fermentable dietary fibre such as fructo-oligosaccharide and viscous dietary fibers such as guar gum and alginate affect energy homeostasis. The goal of this study was to compare the impact of long term intake of these three dietary fibers on food intake, meal pattern, body weight and fat accumulation in mice. Over a period of 3 weeks, the mice were fed daily with a preload containing 32 mg of fructo-oligosaccharide or alginate or 13 mg of guar gum. Food intake and body weight were monitored weekly, while meal patterns, adiposity and the expression of hypothalamic neuropeptide genes were evaluated at the end of the study period. The 3 dietary fibers produced a similar decrease in total daily food intake (14 to 22%) at the end of the first week, and this effect disappeared over time. The 3 dietary fibers induced a slight variation in satiation parameters. Body weight and expression of hypothalamic neuropeptide genes were not affected by any of the treatment. Preload of fructo-oligosaccharide and guar gum induced a similar and substantial decrease in the development of adiposity (17% and 14%, respectively), while alginate had no effect. Our results demonstrate mainly that the inhibitory effect of dietary fiber on food intake is lost over time, and that guar gum limits fat storage.
Glucocorticoids inhibited hypothalamic target of rapamycin in high fat diet-fed chicks
2015, Poultry Science
The present study was conducted with broiler chicks exposed to dexamethasone (DEX) to explore its effects on hypothalamic target of rapamycin (TOR) signaling and regulating appetite in diets containing different energy levels. At 5 d age, 48 chicks were divided into one of 4 groups: high-fat diet (HFD) or low-fat diet (LFD) and intracerebroventricular (ICV) injected with either dexamethasone (DEX; 4 μg/2 μL) or saline at 10 d age. The results showed that DEX significantly inhibited gene expression of cocaine- and amphetamine-regulated transcripts (CART), melanocortin receptor 4 (MC4R), and corticotropin-releasing hormone (CRH), and inhibited the protein level of the phospho-TOR compared with the control in HFD-fed chicks (P < 0.05) but not in LFD-fed chicks (P > 0.05). After DEX treatment, hypothalamic agouti-related peptide levels were decreased significantly in HFD-fed chicks (P < 0.05) but not in LFD-fed chicks (P > 0.05). Compared to the control, DEX-treated chicks did not present any significant changes in neuropeptide Y gene expression with either HFD or LFD (P > 0.05), but pro-opiomelanocortin levels were depressed by ICV DEX treatment with both diets (P < 0.05). In conclusion, glucocorticoids (GC) downregulated hypothalamic gene expression of CART, CRH, and MC4R in HFD-fed chicks, suggesting that the regulatory network formed by these genes is associated with the appetite control during stress. The TOR pathway may be involved in the regulation of GC on appetite-related genes.

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Regular ArticleSelective Antagonist for the Melanocortin 4 Receptor (HS014) Increases Food Intake in Free-Feeding Rats

Abstract

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Immunol. Today

Cell

Cell

Eur. J. Pharmacol.

Life Sciences

Peptides

Brain Res.

Eur. J. Pharmacol.

Science

The Melanotropins: Chemistry, Physiology and Mechanisms of Action

Regular Article
Selective Antagonist for the Melanocortin 4 Receptor (HS014) Increases Food Intake in Free-Feeding Rats