Neuropeptide Y

Neuropeptide Y Receptor Modulators in Gut Physiology and Therapy.

Kalyani R Thombre, Nikita D Rahangdale, Krishna Radheshyam Gupta +1 more

Gut-brain communication depends on neuropeptides and hormones, and the Neuropeptide Y (NPY) family, which includes NPY, Peptide YY (PYY), and Pancreatic Polypeptide (PP), plays an important role. These peptides also affect gastrointestinal (GI) motility, secretion, nutrient uptake, and intestinal development. Diseases, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), gastroparesis, and obesity, are attributed to disruptions in this signaling axis. In this review, the physiological and pathological functions of NPY and its receptor subtypes (Y1, Y2, Y4, Y5) in the GI tract, the therapeutic potential of Pharmacological and natural modulators of this pathway are evaluated.

Maternal Nutrition and Hypothalamic Programming of Offspring Metabolic Health.

Smita Mall, Busayo Oladun, Min-Hyun Kim

The hypothalamus plays a central role in regulating metabolism by integrating hormonal and nutrient-derived signals to maintain energy homeostasis across the life span. Maternal nutritional status during critical windows of development is a major environmental factor that can permanently alter this regulation. Both maternal overnutrition and undernutrition have been shown to disturb circulating leptin, insulin, and glucagon-like peptide-1 (GLP-1), and to disrupt the normal development of hypothalamic nuclei implicated in energy balance. Experimental and clinical studies indicate that these insults miswire proopiomelanocortin (POMC) and neuropeptide Y/ agouti-related peptide (NPY/AgRP) pathways, alter leptin and insulin receptor signaling, trigger neuroinflammation, glial and vascular changes, and are accompanied by enduring epigenetic alterations, including DNA methylation and chromatin remodelling at genes such as Pomc, Npy, Mc4r, Lepr and Insr. Together, these adaptations establish new set points for appetite, energy expenditure, and glucose regulation, thereby increasing the lifelong risk of obesity and type 2 diabetes in the offspring. In this narrative review, we synthesize evidence from animal models and human studies linking maternal nutrition to hypothalamic programming via leptin, insulin, and GLP-1. We also highlight major gaps, including limited data on GLP-1 in maternal undernutrition, the specific role of individual micronutrients, and the timing and reversibility of hypothalamic programming, to inform future mechanistic, translational, and preventive research.

Central amygdala neuropeptide Y neurons drive hedonic ingestive behaviour independent of energy homeostasis.

Neda Rafiei, Caitlin S Mitchell, Philip Jean-Richard-Dit-Bressel +5 more

Neuropeptide Y (NPY), a key orexigenic neurotransmitter, is widely expressed in the central nervous system, including in a distinct subpopulation of neurons within the central nucleus of the amygdala (CeA). While CeA NPY neurons contribute to energy regulation during chronic stress or high-fat diet exposure, the role of these neurons in modulating ingestive behaviour under standard conditions, particularly in response to caloric and non-caloric cues remains poorly understood.

The role of agomelatine in appetite regulation and body weight in rats.

Engin Korkmaz, Yavuz Erden, Çiğdem Tekin +1 more

The hypothalamic nuclei play a central role in the synthesis of anorexigenic and orexigenic neuropeptides, which are regulated by peripheral hormones, like leptin and ghrelin. Melatonergic receptors (MT1/MT2) are prominently expressed in the arcuate nucleus of the hypothalamus - an essential hub for appetite control - and in peripheral metabolic tissues where leptin and ghrelin are secreted. Agomelatine, an antidepressant drug and potent MT1/MT2 agonist, offers potential for modulating appetite. This study aimed to investigate the impact of agomelatine on appetite regulation. Forty male Sprague-Dawley rats were randomly allocated into four groups, control (no treatment), vehicle control, agomelatine 20 mg/kg (Ago-20), and agomelatine 40 mg/kg (Ago-40), and administered oral gavage for 14 days. Body weight and food intake were recorded daily. At the end of the experiment, rats were euthanized and blood and hypothalamic tissue samples were obtained. Agomelatine significantly reduced body weight (Ago-40: 275.2 ± 7.2 g vs. control: 339.7 ± 8.3 g, P < 0.05) and food intake (Ago-40: 20.21 ± 1.32 g vs. control: 32.09 ± 1.58 g, P < 0.05) by day 14, without affecting water intake. Plasma ghrelin levels decreased (Ago-40: 22.54 ± 3.95 ng/dL vs. control: 46.67 ± 4.84 ng/dL, P < 0.05), while leptin increased (Ago-40: 552.30 ± 41.67 pg/mL vs. control: 271.10 ± 32.12 pg/mL P < 0.05). Hypothalamic orexigenic neuropeptides neuropeptide Y (NPY) and agouti-related peptide (AgRP) were suppressed (NPY, Ago40: 0.61 ± 0.02 vs. Control: 1.36 ± 0.1321; AgRP, Ago40: 0.52 ± 0.03 vs. Control: 1.49 ± 0.27, P < 0.05), while anorexigenic cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC) were elevated (CART: Ago40: 1.19 ± 0.08 vs. Control: 0.92 ± 0.06; POMC: Ago40: 1.49 ± 0.17 vs. Control: 0.67 ± 0.10, P < 0.05). These findings suggest agomelatine promotes weight loss by modulating appetite-related hormones and hypothalamic neuropeptides, highlighting its potential as a therapeutic for obesity and metabolic disorders.

Liraglutide reduces the apoptosis of feeding and appetite-suppressing neurons in the hypothalamus of obese rats association with the PI3K/AKT/Foxo1 pathway.

Wei Yang, Zelin Yang, Shuyu Lu +4 more

Obesity-induced inflammation in the hypothalamus disrupts the function of neurons that regulate appetite, particularly proopiomelanocortin (POMC) and neuropeptide Y (NPY)/agouti-related protein (AgRP) neurons in the arcuate nucleus (ARC). Although Liraglutide, a GLP-1 analogue, exhibits neuroprotective properties, the underlying molecular mechanisms are unclear. In this study, we investigated whether Liraglutide protects hypothalamic neurons via the PI3K/AKT/Foxo1 pathway.

D[His26]NPY, an agonist of NPY receptor 1, averts traumatic stress-induced behavioral deficits in male and female rats.

Arax Tanelian, Bistra Nankova, Moshe Weiss +1 more

Emerging neurobiological targets in psychiatric treatment.

Agampodi Ishan De Zoysa, Janani Govinnage, Frank Giorlando +3 more

Despite significant advancements in psychopharmacology, there are inadequate treatment options for many psychiatric disorders, including major depressive disorder, bipolar disorder, schizophrenia, and anxiety disorders. This review explores emerging neurobiological targets beyond conventional monoaminergic approaches, focusing on sodium channels, Neuropeptide Y (NPY), Neurokinin 1 (NK1) receptors, P2 × 7 purinergic receptors, Sigma-1 receptors, and Orexin. Recent evidence suggests that sodium channel modulators, such as evenamide, may offer therapeutic benefits for treatment-resistant schizophrenia by stabilizing glutamatergic neurotransmission. NPY-based therapies have potential in stress-related disorders, foreshadowing rapid anxiolytic and antidepressant effects through modulation of the stress response. NK1 receptor antagonists, although inconsistent in mood disorders, show promise in addiction treatment by reducing substance cravings. The P2 × 7 receptor, a key regulator of neuroinflammation, has been implicated in mood disorders, and its pharmacological inhibition may provide neuroprotective benefits. Additionally, Sigma-1 receptor agonists, including Blarcamesine and Pridopidine, have shown neuroprotective and cognitive-enhancing properties, making them attractive candidates for psychiatric and neurodegenerative disorders. Orexin receptor antagonists, such as suvorexant and seltorexant, have potential in mood disorders and substance dependence, highlighting the broader therapeutic applications of targeting the orexinergic system. While these emerging therapeutic targets hold promise, challenges remain in translating preclinical findings into effective clinical applications. Large-scale, placebo-controlled trials are necessary to establish their efficacy and safety. The identification of biomarkers for patient stratification will be critical in the hitherto elusive goal of developing precision medicine approaches. Targeted pharmacological interventions offer a path toward more effective, well-tolerated, and potentially individualized treatment options for patients with severe mental illness.

Sex-related differences in aggressive and emotional behavior in mice with the conditional inactivation of limbic Npy1r.

Silvia Paterlini, Laura Gioiosa, Riccardo Panelli +5 more

Anxiety- and depression-related disorders are frequently associated with deficits in social behavior, including excessive aggression and violence, which may arise from disruptions in the neural circuits regulating emotions and social interactions. Sex differences play a crucial role in modulating emotional and social behaviors, particularly aggression and anxiety. Neuropeptide Y (NPY) and its Y1 receptor (Y1R) are involved in regulating various physiological functions, including emotional behavior and stress response. We previously demonstrated that conditional knockout of Npy1r gene in the forebrain excitatory neurons (Npy1rrfb mutant mice) increased anxiety-like behavior and hypothalamus-pituitary-adrenocortical axis reactivity and decreased body weight growth in a sex-dependent manner. In the present study we investigated how the depletion of the Npy1r gene in limbic areas might affect male and female mice by using a test battery aimed at assessing anxiety-like, social and aggressive behavior as well as response to novelty. Our results showed reduced exploratory behavior and increased anxiety in response to a novel environment in Npy1rrfb mice, with females exhibiting more pronounced effects. In contrast, only Npy1rrfb males showed reduced neophobia and increased impulsivity in response to a novel palatable food. Moreover, reduced limbic Npy1r expression decreased territorial aggression and increased defensive behaviors only in males. These findings reveal that limbic Y1R modulates anxiety, social interaction, and aggression in a sex-dependent manner. Moreover, they uncover a novel role for Y1R in regulating intermale aggression and suggest sex-specific links between NPY-Y1R signaling and the modulation of motivational and emotional responses.

A coral-derived neuropeptide suppresses pentylenetetrazol (PTZ)-induced epileptic seizures and improves recognition memory deficits by modulating NPY-Y1R.

Qian Chen, Congshuang Deng, Xiaoshan Huang +8 more

Epilepsy is a prevalent neurological disorder characterized by recurrent and unprovoked seizures. Despite the availability of anti-epileptic drugs (AEDs), a significant number of patients are still suffering from drug-resistant epilepsy. Neuropeptide Y (NPY) signaling system has emerged as a potential target for the development of anti-epileptic drugs due to its modulation of epileptic activity. In this study, we investigated the therapeutic potential of our previously discovered Scleractinia-derived NPY-like peptide (TpNPY) in seizure disorders. The anticonvulsant effects of TpNPY were evaluated using PTZ-induced seizures in zebrafish and mice in vivo. Furthermore, the underlying molecular mechanisms of TpNPY were assessed using glutamate-induced excitotoxicity models in HT22 mouse hippocampal cells in vitro. Our findings indicated that TpNPY could alleviate PTZ-induced seizure behavior, reduce the expression of seizure-associated immediate-early genes and the production of Reactive Oxygen Species (ROS) in zebrafish. In mice, TpNPY improved seizure behaviors, decreased inflammatory cytokine levels, and ameliorated abnormal glial activation in a PTZ kindling epileptic model. Besides, the administration of TpNPY could attenuate the PTZ-induced anxiety levels and improve recognition memory deficits. Moreover, TpNPY promotes neurogenesis and neural synaptic plasticity through the BDNF/TrkB signaling pathway. Additionally, TpNPY restored cell injury and attenuated oxidative stress in glutamate-challenged HT22 cells through the Nrf2/HO-1 signaling pathway. These results highlight the potential therapeutic efficacy of TpNPY in the treatment of seizures and provide new insights into the development of coral-derived anti-epileptic peptide-based drugs.

Modulating neuropeptide Y pathways to combat nicotine addiction through emerging evidence and future directions.

Sameer Khidkikar, Divya Malode, Brijesh Taksande +5 more

Nicotine addiction constitutes a significant global health burden, primarily driven by the substance's capacity to dysregulate the brain's reward and stress systems. This chronic relapsing disorder is characterized by robust dependence and high rates of relapse, underscoring the limitations of current therapeutic strategies. Neuropeptide Y (NPY), a 36-amino acid neuromodulator abundantly expressed in the central nervous system, has emerged as a critical regulator of emotional behavior, stress responses, and reward pathways. Its role in the pathophysiology of nicotine addiction is of increasing interest. NPY exerts its pleiotropic effects via G-protein-coupled receptors (Y1, Y2, and Y5), which are strategically positioned to modulate stress-related circuits and attenuate the hyper-dopaminergic state induced by nicotine in the mesolimbic system. Chronic nicotine exposure disrupts endogenous NPYergic signaling in key neuroanatomical loci such as the amygdala and prefrontal cortex, a neuroadaptation that heightens stress sensitivity and addiction vulnerability. The consequent reduction in NPY tone during withdrawal exacerbates the negative affective states of anxiety and stress, precipitating relapse. Preclinical evidence indicates that therapeutic strategies targeting NPY pathways including receptor-specific agonists, gene therapy for region-specific overexpression, and advanced peptide delivery systems show considerable promise for mitigating withdrawal symptomatology and reducing nicotine-seeking behavior. This review synthesizes the compelling preclinical and emerging human evidence supporting the NPY system as a therapeutic target, highlighting the critical need to develop novel, brain-penetrant NPY receptor agonists and biomarkers to bridge the translational gap and improve clinical outcomes for nicotine dependence.

High-fat diet-induced obesity enhances stress vulnerability and promotes a PTSD-like phenotype in rats.

Carmit Cohen, Joseph Zohar, Doron Todder +1 more

The association between post-traumatic stress disorder (PTSD) and subsequent obesity is well-established in humans, however, whether obesity exacerbates vulnerability to PTSD remains underexplored. To investigate this, we employed a rat model fed either a high-fat diet (HFD; 60 % kcal from fat) or a control diet (CD). After confirming significant body mass index differences between HFD and CD groups, rats were exposed to predator scent stress (PSS) or a sham-PSS control. Behavioral phenotyping was conducted using the elevated plus maze (EPM) and acoustic startle response (ASR) to classify stress response profiles, supplemented by the forced swim test to assess depressive-like behavior and the Morris water maze to evaluate spatial learning and memory. Neural cytoarchitecture and molecular mechanisms were examined via Golgi-Cox staining and immunohistochemistry, targeting shared modulators of the orexigenic and anxiolytic systems in the hippocampus and hypothalamus. Our findings reveal that HFD-induced obesity promotes a PTSD-like phenotype, exacerbates depressive-like behavior, and impairs spatial learning and memory acquisition. Morphological alterations in the hippocampus and amygdala of HFD-fed rats resembled those in PSS-exposed CD-fed rats, regardless of stress exposure, suggesting common neurostructural changes. Furthermore, HFD-induced obesity modulated region-specific expression of neuropeptide Y (NPY), NPY-Y1 receptor, and glucocorticoid receptor immunoreactivity in hippocampal and hypothalamic nuclei. These results underscore a bidirectional interplay between diet-induced obesity and stress-related disorders, highlighting the critical role of the orexigenic and anxiolytic systems and their neurobiological underpinnings in mediating these effects.

Dietary medium chain triglycerides impairs orexigenic action of ghrelin in mice.

Daisuke Aotani, Hiroyuki Ariyasu, Tomohiro Tanaka +10 more

Ghrelin, a stomach-derived hormone, increases food intake and body weight. Efforts have been made therefore to modulate ghrelin signaling for the treatment of obesity or emaciation. However, basic biology of the potential effects of dietary nutrients on ghrelin action has not yet been fully uncovered.

Sleeve Gastrectomy with Fundoplication Enhances Metabolic Health in Obese Rats via Ghrelin Pathway Modulation and Multi-Organ Regulation.

Xin Li, Aikebaier Aili, Yusujiang Tusuntuoheti +3 more

Obesity serves as a predominant factor in the progression of metabolic syndrome and type 2 diabetes mellitus. While sleeve gastrectomy (SG) is a well-established surgical intervention, its impact on appetite-regulating hormones, such as ghrelin (GHRL), is limited. Sleeve gastrectomy combined with fundoplication (SGFD) has emerged as a potential strategy to improve metabolic outcomes by modifying both gastric anatomy and gut-brain signaling.

Evaluating methodological constraints in PET imaging of neuropeptide Y2 receptors with N-[11C]-methyl-(R)-JNJ-31020028 in brains of C57BL/6J mice.

Karsten Bamminger, Eduardo Felipe Alves Fernandes, Lena Zachhuber +7 more

The Neuropeptide Y (NPY) system regulates mood, stress, and feeding behavior and plays a central role in neuropsychiatric and metabolic disorders. It exerts its effects primarily through a family of G-protein-coupled NPY receptors (NPYR), comprising the Y1, Y2, Y4, and Y5 subtypes. Among these, the Y2 receptor (NPY2R) has emerged as a promising imaging target through its involvement in mood regulation, anxiety, and feeding behavior. This study evaluated the in vivo performance of the selective NPY2R antagonist PET tracer N-[11C]methyl-(R)-JNJ-31020028 in mice, focusing on tracer metabolism, brain uptake, and blood-brain barrier transport via P-glycoprotein (P-gp).

Acupuncture ameliorates diet-induced obesity via the vagal-GLP-1-ARC circuit: neural mechanism of anorexigenic action.

Yanan Yang, Yuwei Shao, Jun Tian +7 more

Electroacupuncture (EA) has demonstrated efficacy in ameliorating obesity through its marked appetite-suppressing effects. This study aims to elucidate the peripheral-central communication mechanism underlying EA's appetite inhibition mediated by the "vagal afferent fiber-nucleus tractus solitarius (NTS)-hypothalamic arcuate nucleus (ARC)" neural circuit.

Consumption of Unprocessed and Ultraprocessed Foods in Adolescents with Obesity: Associations with Neuroendocrine Mediators of Appetite Regulation and Binge Eating Symptoms.

Patrícia Sousa Neres, Aline de Piano Ganen, Raquel Munhoz da Silveira Campos +4 more

Background/Objectives: Obesity is a multifactorial disease associated with increased consumption of ultraprocessed foods and reduced intake of unprocessed foods. Binge eating, one of the most prevalent eating disorders among adolescents, is closely linked to obesity. Food intake is regulated by both the hedonic system, responsible for reward responses, and the physiological system, which controls hunger and satiety through hormones, such as ghrelin and leptin. The present study aimed to investigate associations between the intake of unprocessed and ultraprocessed foods, neuroendocrine mediators of appetite regulation, and binge eating in adolescents with obesity. Methods: This cross-sectional study included 96 adolescents with obesity who were recruited in São Paulo, Brazil, between 2010 and 2012. Anthropometric and body composition assessments were performed. Binge eating symptoms were evaluated using the binge eating scale (BES), and dietary intake was assessed with a validated Food Frequency Questionnaire, with items classified according to the Nova system. Frequency data were converted into annual consumption scores. Serum levels of ghrelin, leptin, neuropeptide Y (NPY), agouti-related peptide (AgRP), melanin-concentrating hormone (MCH), and alpha-melanocyte-stimulating hormone (α-MSH) were analyzed. Results: Lower consumption of unprocessed foods was associated with higher ghrelin concentrations (p = 0.023), accompanied by a greater percentage of body fat (p = 0.047) and a reduced percentage of lean mass (p = 0.047) compared with adolescents in the second tertile. AgRP was a positive predictor of annual consumption score of ultraprocessed food (β = 0.30; p = 0.04), independent of age, body fat, and binge eating symptoms. Conclusions: In conclusion, lower intake of unprocessed foods was associated with alterations in orexigenic and anorexigenic mediators, suggesting that dietary patterns in adolescents with obesity may influence the neuroendocrine mediators of appetite regulation.

From tradition to evidence: exploring the neurochemical basis of medicinal plants in anxiety therapy.

Acharya Balkrishna, Upasana Agarwal, Deepika Arya +2 more

Anxiety disorders are associated with dysfunction in key neurotransmitter systems like, GABAergic, serotonergic, dopaminergic, noradrenergic, and endocannabinoid, alongside oxidative stress, neuroinflammation, and hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. Conventional pharmacotherapies offer symptomatic relief but often cause adverse effects and dependency. This review explores medicinal plants as alternative anxiolytic agents due to their multi-targeted mechanisms of action.

Bromelain Improves Hypothalamic Control of Energy Homeostasis in High-Fat Diet-Induced Obese Rats.

Raviye Ozen Koca, Mustafa Berk Basaran, Hatice Solak +1 more

Obesity remains a major global health challenge with limited therapeutic options. Bromelain, a proteolytic enzyme complex derived from pineapple, has been recognized for its natural anti-inflammatory, anti-edematous, and appetite-suppressing properties. This study aimed to investigate the effects of bromelain on hypothalamic neuropeptides and metabolic markers in a high-fat diet (HFD)-induced obesity model in rats. Thirty-six male Wistar albino rats were randomly divided into four groups: standard diet (SD), standard diet with bromelain (SDBro), high-fat diet (HFD), and high-fat diet with bromelain (HFDBro). Obesity was induced by a 3-month HFD regimen, followed by bromelain supplementation (200 mg/kg/day, orally) for one month. Hypothalamic tissues were analyzed via ELISA for neuropeptide Y (NPY), pro-opiomelanocortin (POMC), glucose transporter 2 (GLUT2), fibroblast growth factor 2 (FGF2), and insulin-like growth factor 1 receptor (IGF1R). While NPY levels showed no significant changes, POMC increased in the HFD and was normalized with bromelain. GLUT2 was downregulated in the HFD and significantly restored by bromelain. FGF2 levels remained unchanged. IGF1R was upregulated in the HFD but reduced by bromelain, with an unexpected increase in SDBro. Overall, bromelain partially reversed HFD-induced disruptions in hypothalamic energy-regulating pathways, particularly affecting GLUT2 and POMC. These findings highlight bromelain's potential role in central metabolic regulation under dietary stress.

Neuropeptide Y neurons surrounding the locus coeruleus inhibit noradrenergic system activity to reduce anxiety.

Danai Riga, Karlijn L Kooij, Kelly Rademakers +3 more

Adaptive responses to challenging environments depend on optimal function of the locus coeruleus (LC), the brain's main source of noradrenaline and primary mediator of the initial stress response. Combining functional circuit dissection and causal in vivo interventions in mice, we here investigate a built-in peptidergic regulatory system that restricts LC noradrenergic output. In particular, we characterize a population of neuropeptide Y (NPY)-expressing neurons surrounding LC noradrenergic cells. We show that this peri-LCNPY population exerts neuromodulatory inhibitory control over the LC via NPY-Y1R signaling. Under naïve conditions, this results in bidirectional control of anxiety-like behaviors. Stressful experiences recruit peri-LCNPY neurons, leading to local NPY release in vivo, whereas enhanced peri-LCNPY neuronal activity curbs anxiety after stress. Together, we establish a causal role for peri-LCNPY-mediated neuromodulation of the LC in the regulation of anxiety, providing mechanistic insights into the endogenous systems underlying adaptive responses to adversity.

Stress and high fat diet reconfigure the active translatome of CeA-NPY neurons.

Chi Kin Ip, Lei Zhang, Ramon Tasan +1 more

The interplay between calorie-dense food and chronic stress significantly accelerates obesity development, with neural circuits expressing Neuropeptide Y (NPY) in the central amygdala (CeA) emerging as the key mediator of this process. While these circuits are known to enhance hedonic feeding behavior and promote weight gain, the precise molecular mechanisms regulating NPY neuron activity at the translational level under the combined influence of high fat diet and stress conditions have remained poorly understood.

Hypothalamic PNOC/NPY neurons constitute mediators of leptin-controlled energy homeostasis.

Marie H Solheim, Sima Stroganov, Weiyi Chen +13 more

Leptin acts in the brain to suppress appetite, yet the responsible neurocircuitries underlying leptin's anorectic effect are incompletely defined. Prepronociceptin (PNOC)-expressing neurons mediate diet-induced hyperphagia and weight gain in mice. Here, we show that leptin regulates appetite and body weight via PNOC neurons, and that loss of leptin receptor (Lepr) expression in PNOC-expressing neurons in the arcuate nucleus of the hypothalamus (ARC) causes hyperphagia and obesity. Restoring Lepr expression in PNOC neurons on a Lepr-null obese background substantially reduces body weight. Lepr inactivation in PNOC neurons increases neuropeptide Y (Npy) expression in a subset of hypothalamic PNOC neurons that do not express agouti-related peptide (Agrp). Selective chemogenetic activation of PNOC/NPY neurons promotes feeding to the same extent as activating all PNOCARC neurons, and overexpression of Npy in PNOCARC neurons promotes hyperphagia and obesity. Thus, we introduce PNOC/NPYARC neurons as an additional critical mediator of leptin action and as a promising target for obesity therapeutics.

New players in the leptin orchestra: PNOC/NPY neurons tune appetite and obesity.

Olivier Lavoie, Natalie J Michael, Alexandre Caron

Leptin regulates energy balance through the brain, yet its key neuronal targets remain unclear. Solheim et al.1 identify hypothalamic GABAergic PNOC/NPY neurons as mediators of leptin's anorectic effects, advancing our understanding of neurocircuits linking adiposity signals to feeding control.

Modulation of temporoammonic-CA1 synapses by neuropeptide Y is through Y1 receptors in mice.

Mariana A Cortes, Aundrea F Bartley, Qin Li +7 more

Reduced levels of neuropeptide Y (NPY), an abundant neuromodulator in the brain, are linked to multiple neuropsychiatric disorders, including post-traumatic stress disorder (PTSD). The CA1 region of hippocampus is important for anxiety regulation and highly expresses NPY. Injecting NPY into CA1 is anxiolytic and alleviates behavioral symptoms in a model of traumatic stress; these anxiolytic effects are blocked by a Y1 receptor antagonist. However the location of Y1Rs that mediate NPY's anxiolytic effects in CA1 remains unclear. CA1 receives inputs from entorhinal cortex through the temporammonic pathway (TA), which is important for fear learning and sensitive to stress. Our lab previously showed that NPY reduces TA-evoked synaptic responses, however, the subtype of NPY receptor mediating this reduction is unknown. Here we demonstrate that in mice both exogenous (bath-applied) and endogenously-released NPY act through Y1 receptors in the TA pathway. This is the first demonstration of Y1 receptor-mediated effect on synaptic function in CA1. Interestingly, chronic overexpression of NPY (in NPY-expressing interneurons) impairs the sensitivity of the TA-evoked synaptic response to a Y1 receptor agonist. However, the long-known NPY Y2 receptor-mediated effect on the Schaffer collateral (SC) pathway is unaffected by NPY overexpression. Therefore, NPY can have a pathway-specific impact on synaptic transmission in CA1 based on the differential expression of NPY receptors and their response to overexpression of NPY. Our results demonstrating that NPY acts at Y1 receptors in the TA pathway are consistent with the idea that the TA pathway underlies the anxiolytic effects of NPY in CA1.

A single injection of neuropeptide QRFP in the lateral hypothalamus decreased food intake.

Olga Zagorácz, Tamás Ollmann, László Péczely +9 more

Severe eating disorders, such as obesity, bulimia, and anorexia, keep increasing to epidemic proportions worldwide. Understanding of neuropeptides' role in complex hunger/satiety mechanisms may allow new prospects for treatment and prevention. Pyroglutamylated arginine-phenylalanine-amide peptides (QRFPs) are thought to enhance feeding following the central administration.

Sex-specific alterations in emotional behavior and neurotransmitter systems in LPA1 receptor-deficient mice.

Laura Sánchez-Marín, Violeta Jiménez-Castilla, María Flores-López +7 more

Lysophosphatidic acid (LPA) and the endocannabinoid system (ECS) are critical lipid signaling pathways involved in emotional regulation and behavior. Despite their interconnected roles and shared metabolic pathways, the specific contributions of LPA signaling through the LPA1 receptor to stress-related disorders remain poorly understood. This study investigates the effects of LPA1 receptor deficiency on emotional behavior and neurotransmitter-related gene expression, with a focus on sex-specific differences, using maLPA1-null mice of both sexes. We hypothesized LPA1 receptor loss disrupts the interplay between LPA and the endocannabinoid 2-arachidonoylglycerol (2-AG) signaling, resulting in distinct behavioral and molecular alterations. maLPA1-null mice exhibited increased anxiety-like behaviors and altered stress-coping responses compared to wild-type counterparts, with more pronounced effects observed in females. Female mice also displayed higher corticosterone levels, though no genotype-related differences were observed. Plasma analyses revealed elevated LPA levels in maLPA1-null mice, suggesting a compensatory mechanism, and reduced 2-AG levels, indicating impaired ECS signaling. Gene expression profiling in the amygdala and medial prefrontal cortex showed significant alterations in the gene expression of key components of LPA and 2-AG signaling pathways, as well as neuropeptide systems such as corticotropin-releasing hormone (CRH) and neuropeptide Y (NPY). Glutamatergic signaling components also exhibited sex-specific variations. These findings suggest that LPA1 receptor deficiency impacts behavioral response and disrupts sex-specific neurotransmitter signaling, emphasizing the importance of LPA-ECS crosstalk in emotional regulation. This study provides insights into the molecular mechanisms underlying stress-related disorders such as depression and anxiety, which may inform the development of sex-specific therapeutic approaches.

Peptide pharmacology: Pioneering interventions for alcohol use disorder.

Ramkumar Katturajan, Sabina Evan Prince, Abilash Valsala Gopalakrishnan

Alcohol use disorder (AUD) is a substantial public health issue, with few treatment choices and a high social cost. This review investigates the possibility of peptide pharmacology as a new treatment for AUD. Peptides, or short chains of amino acids, provide specific manipulation of neuronal pathways involved in addiction, such as the opioid, corticotropin-releasing factor (CRF), neuropeptide Y (NPY), and glutamate systems. Preclinical research has shown that peptide-based therapies can reduce alcohol intake, demand, and relapse in animal models of AUD. Opioid peptides like β-endorphin and enkephalins affect alcohol reward processing by interacting with µ, ∂, and κ opioid receptors. CRF peptides reduce stress-induced alcohol-seeking behavior by targeting the dysregulated CRF system. NPY and associated peptides reduce cravings and anxiety by regulating stress and emotional processing. Peptide-based therapies have strong translational potential, as evidenced by early clinical trial results. There are also challenges in converting preclinical discoveries into clinical practice, such as establishing the safety, tolerability, and effectiveness of peptide therapies in humans. Future initiatives include identifying new peptide targets, optimizing pharmacokinetics, and incorporating peptide-based therapies into established therapy methods. Overall, peptide pharmacology represents a potential prospect in AUD therapy, as it provides tailored therapies that address the complex neurobiological pathways that underpin addiction.

The intricate relationship between circadian rhythms and gastrointestinal peptides in obesity.

Filipe M Ribeiro, Luiz Arnaldo, Lana P Milhomem +2 more

There are different molecular pathways that regulate appetite, particularly the role of the hypothalamus, circadian rhythms, and gastrointestinal peptides. The hypothalamus integrates signals from orexigenic peptides like neuropeptide Y (NPY) and agouti-related protein (AgRP), which stimulate appetite, and anorexigenic peptides such as pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART), which promote satiety. These signals are influenced by peripheral hormones like leptin, ghrelin, insulin, and cortisol, as well as gut peptides including glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and cholecystokinin (CCK). The circadian rhythm, regulated by proteins like circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1), modulates the secretion of these peptides, aligning feeding behaviors with the sleep-wake cycle. In obesity, these regulatory systems are disrupted, leading to leptin resistance, increased ghrelin sensitivity, and altered gut peptide secretion. This results in heightened appetite and impaired satiety, contributing to overeating and metabolic dysfunction. Additionally, circadian disruptions further impair metabolic processes, exacerbating obesity. The present article underscores the importance of understanding the molecular interplay between circadian rhythms and gastrointestinal peptides, particularly in the context of obesity. While some molecular interactions, such as the regulation of GLP-1 and PYY by reverberation of circadian rhythm α (REV-ERBα) and retinoic acid-related orphan receptor α (RORα), are well-established, clinical studies are scarce. Future research is expected to explore these pathways in obesity management, especially with the rise of incretin-based treatments like semaglutide. A deeper understanding of hypothalamic molecular mechanisms could lead to novel pharmacological and non-pharmacological therapies for obesity.

Effects of Illumination Color on Hypothalamic Appetite-Regulating Gene Expression and Glycolipid Metabolism.

Qi Wang, Qianru Li, Tuo Quan +6 more

Irregular illumination is a newly discovered ambient factor that affects dietary and metabolic processes. However, the effect of the modulation of long-term light exposure on appetite and metabolism remains elusive. Therefore, in this current study, we systematically investigated the effects of up to 8 weeks of exposure to red (RL), green (GL), and white light (WL) environments on appetite, food preferences, and glucose homeostasis in mice on both high-fat and low-fat dietary patterns. It was found that the RL group exacerbated high-fat-induced obesity in mice compared with GL- or WL-treated mice. RL-exposed mice exhibited worsened metabolic profiles, including impaired glucose tolerance/insulin sensitivity, elevated lipid levels, and reduced serum insulin levels. Serological analyses showed that RL exposure resulted in decreased leptin levels and increased levels of orexigenic and hunger hormones in mice. Further qPCR analysis showed that the expression levels of the hypothalamic appetite-related genes NPY and AgRP mRNA were upregulated in RL-treated mice, while the expression level of the appetite suppressor gene POMC mRNA was downregulated. The results of this study will be instructive for the regulation of appetite and metabolism from the perspective of illumination colors.

Acute effect of exercise on appetite-related factors in males with obesity: A pilot study.

Sogand Asri, Farhad Rahmani-Nia, Payam Saidie +2 more

To investigate the role of appetite-related factors, including interleukin 6 (IL-6), irisin, interleukin 7 (IL-7), neuropeptide Y (NPY), and leptin, on appetite perception in males with obesity. Eleven males (BMI 35.3 ± 4.2 kg/m2, V̇O2peak 29 ± 3.1 mL/kg/min) participated in two experimental trials (MICE: 60 min of cycling at 60% of V̇O2peak; CTRL: 60 min of quiet resting) using a crossover design. Appetite parameters, including IL-6, IL-7, irisin, and leptin, were measured. Additionally, appetite perception was assessed. IL-6 concentration increased significantly immediately post-exercise (95% CI: [2.207-12.192] pg/mL, p = 0.007) and remained elevated 1 hour post-exercise (95% CI: [2.326-11.855] pg/mL, p = 0.006) compared to CTRL. Irisin also rose significantly immediately post-exercise (95% CI: [0.084-3.061] ng/mL, p = 0.039). NPY decreased significantly 1 h post-exercise (95% CI: [(-20.601) - (-1.380)] ng/L, p = 0.027). No significant differences were observed for IL-7 (p = 0.748, η p 2 $$ {\eta}_p^2 $$ = 0.077) and leptin (p = 0.285, η p 2 = 0.061 $$ {\eta}_p^2=0.061 $$ ). Appetite perceptions were suppressed immediately post-exercise (95% CI: [3.407-19.547] mm, p = 0.008) compared to CTRL. Sixty minutes of MICE increased IL-6 and irisin concentrations while suppressed NPY and appetite perceptions in males with obesity.

Exploring the Anxiolytic Potential of NPY by a Dipeptidyl Peptidase-IV Inhibitor in an Animal Model of PTSD.

Matan Dahan, Joseph Zohar, Doron Todder +2 more

The regulatory neuropeptide Y (NPY) is implicated in anxiety and post-traumatic stress disorder (PTSD)-related behaviors. NPY exerts its effects through 5 receptor subtypes, with Y1 and Y2 receptors being predominantly expressed in the rat brain. Activation of Y1 by full-length NPY1-36 induces anxiolytic effects, whereas Y2 binds truncated peptides, eliciting region-specific anxiogenic responses. Dipeptidyl peptidase-IV (DPP-IV) cleaves NPY, thereby modulating its functionality. Sitagliptin, a DPP-IV inhibitor (DPP-IV-I), inhibits the degradation of various vasoactive peptides, including cerebral NPY. As such, the therapeutic potential of DPP-IV-I following a traumatic event remains inconclusive. We assessed the effects of a highly selective DPP-IV-I, administered either shortly after the stressor or intermittently over 3 days, on behavioral outcomes using the predator scent stress (PSS) model of PTSD.