Search Results (81)

Background: Obesity is a multisystemic health problem causing chronic diseases like diabetes or cardiovascular diseases, but also reproductive dysfunctions like infertility in adults or altered puberty onset in children. Exercise is a recognized intervention to control or prevent energy imbalance, thus deeply contributing to metabolic health in physiological and pathological conditions. The kisspeptin system (KS), the main gatekeeper of reproduction and puberty onset in mammals, is also an upcoming “metabolic sensor”, linking energy homeostasis to reproductive ability both centrally and peripherally. Objectives: This narrative review aims at summarizing recent evidence from animal models and human studies on the role of the KS in energy homeostasis, with a focus on the upcoming role of the KS as a metabolic sensor able to modulate the functionality of the hypothalamus–pituitary–gonad axis in males as an adaptive response to exercise. Methods: PubMed and Scopus search (date: 2015–2025; keywords: kisspeptin and metabolism, male reproduction or exercise; kisspeptin and doping). Results and Conclusions: This review article illustrates the crucial role of the KS in linking energy homeostasis and male reproduction at the central and peripheral levels, and modulation of the KS by exercise in physiological and pathological conditions. Due to the large amount of data from animal models, knowledge gaps occur in the analysis of the relationship among KS, energy homeostasis, male reproduction and exercise in humans, particularly in the case of overtraining. Lastly, kisspeptin inclusion in the doping list is also discussed. Full article

Leptin, an adipocyte-derived hormone, plays a central role in the regulation of energy homeostasis by acting on distinct hypothalamic nuclei. This review explores recent advances in our understanding of leptin’s region-specific actions within the arcuate nucleus, ventromedial hypothalamus, dorsomedial hypothalamus, and lateral hypothalamus, highlighting their contributions to appetite regulation, energy expenditure, and neuroendocrine function. In the hypothalamic arcuate nucleus, leptin’s differential regulation of pro-opiomelanocortin and agouti-related peptide/neuropeptide Y neurons is now complemented by the identification of novel leptin-responsive neuronal populations—such as those expressing prepronociceptin, basonuclin 2, and Pirt—as well as a growing array of cellular and molecular modulators, including secreted factors like angiopoietin-like growth factor, zinc-α2-glycoprotein, and spexin, intracellular regulators such as Rap1, growth factor receptor-bound protein 10, and spliced X-box binding protein 1. In the ventromedial hypothalamus, leptin integrates with both peripheral (e.g., cholecystokinin) and central (e.g., pituitary adenylate cyclase-activating polypeptide) signals, while epigenetic mechanisms, such as those mediated by Jumonji domain-containing protein D3, regulate leptin receptor expression and sensitivity. The dorsomedial hypothalamus is increasingly recognized for coordinating leptin’s effects on metabolism, circadian rhythms, and respiration through distinct neuronal populations, including a subset of neurons co-expressing GLP-1 receptors that mediate leptin’s metabolic effects. In the lateral hypothalamus, leptin modulates reward-driven feeding via GABAergic neuronal populations—circuits that are particularly susceptible to disruption following early life trauma. Together, these insights reveal a sophisticated neurobiological framework through which leptin orchestrates systemic physiology. Understanding the heterogeneity of leptin signaling opens new avenues for restoring leptin sensitivity and developing personalized therapeutic strategies to combat obesity and related metabolic disorders. Full article

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder characterized by a clinical and/or biochemical hyperandrogenism. In addition, PCOS is also associated with the presence of ovarian cysts, anovulation, and menstrual abnormalities such as oligomenorrhea or amenorrhea. The aetiology of the syndrome is multifactorial and heterogeneous due to the interaction of genetic, hormonal, metabolic, and environmental factors, as well as the different phenotypes and responses to treatments exhibited by the patients. Considering this complex interaction, it is essential to continue with the research focused on the mechanisms involved in the development and maintenance of the pathology. The alteration in the pulsatile secretion of the gonadotropin-releasing hormone (GnRH) is considered to be one of the main causes that contributes to its onset. In this review, we discuss recent evidence about the role of the rostral periventricular area of the third ventricle (RP3V), the arcuate nucleus (ARC), and the ventromedial nucleus of the hypothalamus (VMH), key hypothalamic regions that regulate GnRH secretion, in the development of PCOS. In addition, we analyse the clinical, metabolic, and endocrine factors that interact in the patients with PCOS, offering a multifactorial perspective to improve our understanding of this disorder. Full article

Purinergic P2X receptors (P2X) are ATP-gated ion channels that are broadly expressed in the brain, particularly in the hypothalamus. As ionic channels with high permeability to calcium, P2X play an important and active role in neural functions. The hypothalamus contains a number of small nuclei with many molecularly defined types of peptidergic neurons that affect a wide range of physiological functions, including water balance, blood pressure, metabolism, food intake, circadian rhythm, childbirth and breastfeeding, growth, stress, body temperature, and multiple behaviors. P2X are expressed in hypothalamic neurons, astrocytes, tanycytes, and microvessels. This review focuses on cell-type specific expression of P2X in the most important hypothalamic nuclei, such as the supraoptic nucleus (SON), paraventricular nucleus (PVN), suprachiasmatic nucleus (SCN), anteroventral periventricular nucleus (AVPV), anterior hypothalamic nucleus (AHN), arcuate nucleus (ARC), ventromedial hypothalamic nucleus (VMH), dorsomedial hypothalamic nucleus (DMH), tuberomammillary nucleus (TMN), and lateral hypothalamic area (LHA).> The review also notes the possible role of P2X and extracellular ATP in specific hypothalamic functions. The literature summarized here shows that purinergic signaling is involved in the control of the hypothalamic-pituitary endocrine system, the hypothalamic–neurohypophysial system, the circadian systems and nonendocrine hypothalamic functions. Full article

Prolactin-releasing peptide (PrRP) has a regulatory role in both acute and chronic stress, suggesting its potential contribution to stress-related disorders such as depression. However, not all individuals with depression respond equally to stressors. We aimed to determine whether the PrRP system could underlie stress coping, an important aspect of depression. The forced swim test was used both as a stressor and as a method to assess coping strategy. Based on immobility time, active coping and passive coping subgroups were identified, and 10 brain regions were studied using qPCR to measure the mRNA expression levels of PrRP and its receptors (specific: GPR10; non-specific: NPFFR2). Passive coping animals spent more time in an immobile posture and exhibited altered mRNA expression levels in the medullary A1 region, the habenula, and the arcuate nucleus than control or active coping rats. Additionally, we identified corticotropin-releasing hormone and vesicular glutamate transporter 2 positive neurons in the A1 medullary region that contained Prrp, suggesting a modulatory role of PrRP in these excitatory neurons involved in stress regulation. Our findings reinforce the hypothesis that PrRP plays a role in stress coping, a process closely linked to depression. However its effect is brain region-specific. Full article

We examined the neuroanatomical substrates and signaling mechanisms underlying the suppressive effect of GLP1 on homeostatic and hedonic feeding. Electrophysiological and behavioral studies were conducted in agouti-related peptide (AgRP)-cre and tyrosine hydroxylase (TH)-cre mice, and AgRP-cre/pituitary adenylyl cyclase-activating polypeptide (PACAP) type I receptor (PAC1R)^fl/fl animals. GLP1 (30 pmol) delivered directly into the arcuate nucleus (ARC) decreased homeostatic feeding and diminished the rate of consumption. This anorexigenic effect was associated with an inhibitory outward current in orexigenic neuropeptide Y (NPY)/AgRP neurons. GLP1 injected into the ventral tegmental area reduced binge feeding, coupled with decrements in the rate of consumption and the percent daily caloric consumption during the binge interval. These reductions were associated with a GLP1-induced outward current in mesolimbic (A₁₀) dopamine neurons. GLP1 administered into the ventromedial nucleus (VMN) reduced homeostatic feeding that again was associated with a diminished rate of consumption and abrogated by the GLP1 receptor antagonist exendin 9–39 and in AgRP-cre/PAC1R^fl/fl mice. This suppressive effect was linked with a GLP-induced inward current in VMN PACAP neurons, and further supported by the fact that GLP1 neurons in the nucleus tractus solitarius project to the VMN. Conversely, intra-VMN GLP1 had modest effects on binge feeding behavior. Finally, apoptotic ablation of VMN PACAP neurons obliterated the anorexigenic effect of intra-VMN GLP1 on homeostatic feeding in PACAP-cre mice but not their wildtype counterparts. Collectively, these data demonstrate that GLP1 acts within the homeostatic and hedonic circuits to curb appetitive behavior by exciting PACAP neurons, and inhibiting NPY/AgRP and A₁₀ dopamine neurons. Full article

The adrenergic system plays an active role in modulating synaptic transmission in hypothalamic neurocircuitry. While α2-adrenergic receptors are widely distributed in various organs and are involved in various physiological functions, their specific role in the regulation of energy metabolism in the brain remains incompletely understood. Herein, we investigated the functions of α2-adrenergic receptors in the hypothalamus on energy metabolism in mice. Our study confirmed the expression of α2-adrenergic receptors in hypothalamic dopaminergic neurons and assessed metabolic phenotypes, including food intake and energy expenditure, after treatment with guanabenz, an α2-adrenergic receptor agonist. Guanabenz treatment significantly increased food intake (0.25 ± 0.03 g vs. 0.98 ± 0.05 g, p < 0.001) and body weight (−0.1 ± 0.04 g vs. 0.33 ± 0.03 g, p < 0.001) within 6 h post-treatment. Furthermore, guanabenz markedly elevated energy expenditure parameters, including respiratory exchange ratio (RER, 1.017 ± 0.007 vs. 1.113 ± 0.03, p < 0.01) and carbon dioxide production (1.512 ± 0.018 mL/min vs. 1.635 ± 0.036 mL/min, p < 0.05), compared to vehicle-treated controls. Furthermore, using chemogenetic techniques, we demonstrated that the altered metabolic phenotypes induced by guanabenz treatment were effectively reversed by inhibiting the activity of dopaminergic neurons in the hypothalamic arcuate nucleus (ARC) using a chemogenetic technique. Our findings suggest functional connectivity between hypothalamic α2-adrenergic receptor signals and dopaminergic neurons in metabolic controls. Full article

Prader-Willi syndrome (PWS) is a rare genetic disorder. The main characteristics are muscular hypotonia, failure to thrive and feeding problems in infancy, which switch to hyperphagia in early childhood and continue into adulthood. Due to hyperphagia, the risk of developing morbid obesity is high without treatment. PWS is considered a hypothalamic disease, and within the hypothalamus the arcuate nucleus (AC) is of central importance for controlling metabolism, hunger, and satiety. The AC has been studied in several animal models as well as in humans, including PWS. The function of AC is regulated by several neuropeptides and proteins produced within the central nervous system such as oxytocin, orexin, tachykinins as well as the hypothalamic hormones, regulating the adeno-hypophyseal hormones, also acting as neurotransmitters. Additionally, there are many peripheral hormones among which insulin, leptin, adiponectin, ghrelin, and glucagon-like peptide (GLP-1) are the most important. High levels of adiponectin and ghrelin have consistently been reported in PWS, but dysregulation and deviating levels of many other factors and hormones have also been demonstrated in both individuals with PWS and in animal models. In this review, we focus on the role of AC and peptides and proteins produced within the central nervous system in the regulation of hunger and satiety in PWS. Full article

Elevated proinflammatory cytokines were reported in binge eating spectrum disorders characterized by intermittent overconsumption during periods of otherwise normal or restricted food intake. It is unknown whether binge eating promotes neuroinflammation, similar to that observed following chronic overconsumption of a high fat diet (HFD) in rodents. Here, we used a rodent model of binge-like eating to test the hypothesis that intermittent overconsumption of HFD promotes microglial reactivity in brain areas that control food intake. To promote overconsumption, one group of rats received chow plus intermittent access to HFD (INT). Control groups received either chow only (CHOW) or chow plus continuous access to HFD (CONT). Following behavioral testing, brains were processed to visualize ionized calcium-binding adaptor molecule 1 (Iba1), a microglial marker. INT rats consumed more calories than the control rats on days when the HFD was available, and fewer calories than the control rats on days when they only had access to chow. Despite consuming fewer total calories and 50% fewer fat calories, lean INT rats developed a pattern of microglial reactivity in feeding-relevant brain areas similar to obese CONT rats. We conclude that intermittent overconsumption of HFD, without diet-induced weight gain, promotes microglial reactivity in brain regions that control feeding. Full article

Gastric inhibitory polypeptide (GIP) contributes to energy metabolism regulation. We investigated differences in GIP receptor expression in the brain by feeding status among lean and obese mice and the effect of acute central GIP administration on the expression of appetite-regulating hypothalamic neuropeptides. We divided the mice into four groups: fed/lean, fasted/lean, fed/obese, and fasted/obese. The arcuate nucleus (ARC), paraventricular nucleus of the hypothalamus, and nucleus of the solitary tract in the brainstem were harvested. GIP (6 nmol) or saline was injected for the acute intracerebroventricular administration test, followed by the collection of hypothalamic tissue after 2 h. Fed/obese mice had higher ARC GIP receptor mRNA levels than fasted/obese and lean mice. This difference was not observed among lean mice by feeding status. Obese mice had higher blood GIP levels than lean mice. Fed/obese mice had higher blood GIP levels than fasted/obese mice. This difference was not observed among lean mice by feeding status. GIP administration significantly increased proopiomelano-cortin (Pomc) mRNA levels (GIP: 7.59 ± 0.14; saline: 3.44 ± 1.38 arbitrary units; p = 0.030). Increased GIP receptor expression in the ARC in obese mice indicates its central nervous system involvement in energy balance regulation. GIP potentially regulates POMC-mediated appetite regulation in the hypothalamus. It is possible that POMC neurons are targets of GIP action in the brain. Full article

Continuous advances in neurological research techniques are enabling researchers to further understand the neural mechanisms that regulate energy balance. In this review, we specifically highlight key tools and techniques and explore how they have been applied to study the role of the hypothalamic arcuate nucleus in feeding behaviors. Additionally, we provide a detailed discussion of the advantages and limitations associated with each methodology. Full article

The neuronal etiology of obesity is centered around a diet-induced inflammatory state in the arcuate nucleus of the hypothalamus, which impairs the functionality of pro-opiomelanocortine neurons (POMCs) responsible for whole-body energy homeostasis and feeding behavior. Intriguingly, systemic salt inducible kinase 2 (SIK2) knockout mice demonstrated reduced food intake and energy expenditure along with modestly dysregulated metabolic parameters, suggesting a causal link between the absence of SIK2 activity in POMCs and the observed phenotype. To test this hypothesis, we conducted a comparative secretomics study from POMC neurons following pharmacologically induced endoplasmic reticulum (ER) stress induction, a hallmark of metabolic inflammation and POMC dysregulation in diet-induced obese (DIO) mice. Our data provide significant in vitro evidence for the POMC-specific SIK2 activity in controlling energy metabolism and feeding in DIO mice by regulating the nature of the related POMC secretome. Our data also suggest that under physiological stress conditions, SIK2 may act as a gatekeeper for the secreted inflammatory factors and signaling molecules critical for cellular survival and energy homeostasis. On the other hand, in the absence of SIK2, the gate opens, leading to a surge of inflammatory cytokines and apoptotic cues concomitant with the dysregulation of POMC neurons. Full article

The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that is expressed in several brain locations encompassing the hypothalamus and the brainstem, where the receptor controls several body functions, including metabolism. In a well-defined pathway to decrease appetite, hypothalamic proopiomelanocortin (POMC) neurons localized in the arcuate nucleus (Arc) project to MC4R neurons in the paraventricular nuclei (PVN) to release the natural MC4R agonist α-melanocyte-stimulating hormone (α-MSH). Arc neurons also project excitatory glutamatergic fibers to the MC4R neurons in the PVN for a fast synaptic transmission to regulate a satiety pathway potentiated by α-MSH. By using super-resolution microscopy, we found that in hypothalamic neurons in a primary culture, postsynaptic density protein 95 (PSD95) colocalizes with GluN1, a subunit of the ionotropic N-methyl-D-aspartate receptor (NMDAR). Thus, hypothalamic neurons form excitatory postsynaptic specializations. To study the MC4R distribution at these sites, tagged HA-MC4R under the synapsin promoter was expressed in neurons by adeno-associated virus (AAV) gene transduction. HA-MC4R immunofluorescence peaked at the center and in proximity to the PSD95- and NMDAR-expressing sites. These data provide morphological evidence that MC4R localizes together with glutamate receptors at postsynaptic and peri-postsynaptic sites. Full article

Obesity is a major public health concern that is associated with negative health outcomes. Exercise and dietary restriction are commonly recommended to prevent or combat obesity. This study investigates how voluntary exercise mitigates abnormal gene expression in the hypothalamic arcuate nucleus (ARC) of diet-induced obese (DIO) rats. Using a transcriptomic approach, novel genes in the ARC affected by voluntary wheel running were assessed alongside physiology, pharmacology, and bioinformatics analysis to evaluate the role of miR-211 in reversing obesity. Exercise curbed weight gain and fat mass, and restored ARC gene expression. High-fat diet (HFD) consumption can dysregulate satiety/hunger mechanisms in the ARC. Transcriptional clusters revealed that running altered gene expression patterns, including inflammation and cellular structure genes. To uncover regulatory mechanisms governing gene expression in DIO attenuation, we explored miR-211, which is implicated in systemic inflammation. Exercise ameliorated DIO overexpression of miR-211, demonstrating its pivotal role in regulating inflammation in the ARC. Further, in vivo central administration of miR-211-mimic affected the expression of immunity and cell cycle-related genes. By cross-referencing exercise-affected and miR-211-regulated genes, potential candidates for obesity reduction through exercise were identified. This research suggests that exercise may rescue obesity through gene expression changes mediated partially through miR-211. Full article

Thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2) is an intercellular signal produced mainly by neurons. Among the multiple pharmacological effects of TRH, that on food intake is not well understood. We review studies demonstrating that peripheral injection of TRH generally produces a transient anorexic effect, discuss the pathways that might initiate this effect, and explain its short half-life. In addition, central administration of TRH can produce anorexic or orexigenic effects, depending on the site of injection, that are likely due to interaction with TRH receptor 1. Anorexic effects are most notable when TRH is injected into the hypothalamus and the nucleus accumbens, while the orexigenic effect has only been detected by injection into the brain stem. Functional evidence points to TRH neurons that are prime candidate vectors for TRH action on food intake. These include the caudal raphe nuclei projecting to the dorsal motor nucleus of the vagus, and possibly TRH neurons from the tuberal lateral hypothalamus projecting to the tuberomammillary nuclei. For other TRH neurons, the anatomical or physiological context and impact of TRH in each synaptic domain are still poorly understood. The manipulation of TRH expression in well-defined neuron types will facilitate the discovery of its role in food intake control in each anatomical scene. Full article