Social stress-induced serotonin dysfunction activates spexin in male Nile tilapia (Oreochromis Niloticus).

Social disturbance in interpersonal relationships is the primary source of stress in humans. Spexin (SPX, SPX1a in cichlid), an evolutionarily conserved neuropeptide with diverse physiological functions, is up-regulated in the brain during chronic social defeat stress in teleost. On the other hand, repeated exposure to social stress can lead to dysregulation of the monoaminergic system and increase the vulnerability of developing depression. Since dysfunction of the serotonin (5-hydroxytryptamine, 5-HT) system is associated with social stress and the pathophysiology of depression, the present study investigated the regulatory relationship between the central 5-HT system and SPX1a in the male teleost, Nile tilapia (Oreochromis niloticus). To identify stress factors that regulate SPX1a gene expression, cortisol, dexamethasone (DEX), and 5-HT were used to treat tilapia brain primary cultures. Our study shows cortisol and DEX treatment had no effect on SPX1a gene expression, but SPX1a gene expression was down-regulated following 5-HT treatment. Anatomical localization showed a close association between 5-HT immunoreactive projections and SPX1a neurons in the semicircular torus. In addition, 5-HT receptors (5-HT2B) were expressed in SPX1a neurons. SPX1a immunoreactive neurons and SPX1a gene expression were significantly increased in socially defeated tilapia. On the other hand, citalopram (antidepressant, 5-HT antagonist) treatment to socially defeated tilapia normalized SPX1a gene expression to control levels. Taken together, the present study shows that 5-HT is an upstream regulator of SPX1a and that the inhibited 5-HT activates SPX1a during social defeat.

Nitric oxide mediated kisspeptin regulation of steroidogenesis and gametogenesis in the catfish, Clarias batrachus.

Nitric oxide (NO) is a gaseous molecule that regulates various reproductive functions. It is a well-recognized regulator of GnRH-FSH/LH-sex steroid secretion in vertebrates including fish. Kisspeptin is a recently discovered neuropeptide which also regulates GnRH secretion. Nitrergic and kisspeptin neurons are reported in close physical contact in the mammalian brain suggesting their interactive role in the release of GnRH. The existence of kisspeptin and NOS is also demonstrated in vertebrate gonads, but information on their reciprocal relation in gonads, if any, is obscure. Therefore, attempts were made to evaluate the functional reciprocal relation between nitric oxide and kisspeptin in the catfish gonads, if any, by administering the nitric oxide synthase (NOS) inhibitor, L-NAME {N(G)-nitro-L-arginine methyl ester}, which reduces NO production, and kisspeptin agonist (KP-10) and assessing their impacts on the expressions of kisspeptin1, different NOS isoforms, NO and steroid production in the gonadal tissue. The results revealed that L-NAME suppressed the expression of kiss1 in gonads of the catfish establishing the role of NO in kisspeptin expression. However, KP-10 increased the expression of all the isoforms of NOSs (iNOS, eNOS, nNOS) and concurrently NO and steroids in the ovary and testis. In vitro studies also indicate that kisspeptin stimulates the production of NO and estradiol and testosterone levels in the gonadal explants and medium. Thus, in vivo results clearly suggest a reciprocal interaction between kisspeptin and NO to regulate the gonadal activity of the catfish. The in vitro findings further substantiate our contention regarding the interactive role of kisspeptin and NO in gonadal steroidogenesis.

Heterogeneity in GnRH and kisspeptin neurons and their significance in vertebrate reproductive biology.

Vertebrate reproduction is essentially controlled by the hypothalamus-pituitary-gonadal (HPG) axis, which is a central dogma of reproductive biology. Two major hypothalamic neuroendocrine cell groups containing gonadotropin-releasing hormone (GnRH) and kisspeptin are crucial for control of the HPG axis in vertebrates. GnRH and kisspeptin neurons exhibit high levels of heterogeneity including their cellular morphology, biochemistry, neurophysiology and functions. However, the molecular foundation underlying heterogeneities in GnRH and kisspeptin neurons remains unknown. More importantly, the biological and physiological significance of their heterogeneity in reproductive biology is poorly understood. In this review, we first describe the recent advances in the neuroendocrine functions of kisspeptin-GnRH pathways. We then view the recent emerging progress in the heterogeneity of GnRH and kisspeptin neurons using morphological and single-cell transcriptomic analyses. Finally, we discuss our views on the significance of functional heterogeneity of reproductive endocrine cells and their potential relevance to reproductive health.

Functions of habenula in reproduction and socio-reproductive behaviours.

Habenula is an evolutionarily conserved structure in the brain of vertebrates. Recent reports have drawn attention to the habenula as a processing centre for emotional decision-making and its role in psychiatric disorders. Emotional decision-making process is also known to be closely associated with reproductive conditions. The habenula receives innervations from reproductive centres within the brain and signals from key reproductive neuroendocrine regulators such as gonadal sex steroids, gonadotropin-releasing hormone (GnRH), and kisspeptin. In this review, based on morphological, biochemical, physiological, and pharmacological evidence we discuss an emerging role of the habenula in reproduction. Further, we discuss the modulatory role of reproductive endocrine factors in the habenula and their association with socio-reproductive behaviours such as mating, anxiety and aggression.

Hypothalamic kisspeptin and kisspeptin receptors: Species variation in reproduction and reproductive behaviours.

Kisspeptin, encoded by the KISS1 gene, was first discovered as a potential metastasis suppressor gene. The prepro-kisspeptin precursor is cleaved into shorter mature bioactive peptides of varying sizes that bind to the G protein-coupled receptor GPR54 (=KISS1R). Over the last two decades, multiple types of Kiss and KissR genes have been discovered in mammalian and non-mammalian vertebrate species, but they are remarkably absent in birds. Kiss neuronal populations are distributed mainly in the hypothalamus. The KissRs are widely distributed in the brain, including the hypothalamic and non-hypothalamic regions, such as the hippocampus, amygdala, and habenula. The role of KISS1-KISS1R in humans and Kiss1-Kiss1R in rodents is associated with puberty, gonadal maturation, and the reproductive axis. However, recent gene deletion studies in zebrafish and medaka have provided controversial results, suggesting that the reproductive role of kiss is dispensable. This review highlights the evolutionary history, localisation, and significance of Kiss-KissR in reproduction and reproductive behaviours in mammalian and non-mammalian vertebrates.

Role of Neurokinin B in gametogenesis and steroidogenesis of freshwater catfish, Clarias batrachus.

Neurokinin B (NKB), a recently discovered neuropeptide, plays a crucial role in regulating the kiss-GnRH neurons in vertebrate's brain. NKB is also characterized in gonadal tissues; however, its role in gonads is poorly understood. Therefore, in the present study, the effects of NKB on gonadal steroidogenesis and gametogenesis through in vivo and in vitro approaches using NKB antagonist MRK-08 were evaluated. The results suggest that the NKB antagonist decreases the development of advanced ovarian follicles and germ cells in the testis. In addition, MRK-08 further reduces the production of 17ß-estradiol in the ovary and testosterone in the testis under both in vivo and in vitro conditions in a dose-dependent manner. Furthermore, the in vitro MRK-08 treatment of gonadal explants attenuated the expression of steroidogenic marker proteins, i.e., StAR, 3ß-HSD, and 17ß-HSD dose-dependently. Moreover, the MAP kinase proteins, pERK1/2 & ERK1/2 and pAkt & Akt were also downregulated by MRK-08. Thus, the study suggests that NKB downregulates steroidogenesis by modulating the expressions of steroidogenic marker proteins involving ERK1/2 & pERK1/2 and Akt/pAkt signalling pathways. NKB also appears to regulate gametogenesis by regulating gonadal steroidogenesis in the catfish.

Kisspeptin-10 Mitigates α-Synuclein-Mediated Mitochondrial Apoptosis in SH-SY5Y-Derived Neurons via a Kisspeptin Receptor-Independent Manner.

The hypothalamic neurohormone kisspeptin-10 (KP-10) was inherently implicated in cholinergic pathologies when aberrant fluctuations of expression patterns and receptor densities were discerned in neurodegenerative micromilieus. That said, despite variable degrees of functional redundancy, KP-10, which is biologically governed by its cognate G-protein-coupled receptor, GPR54, attenuated the progressive demise of α-synuclein (α-syn)-rich cholinergic-like neurons. Under explicitly modeled environments, in silico algorithms further rationalized the surface complementarities between KP-10 and α-syn when KP-10 was unambiguously accommodated in the C-terminal binding pockets of α-syn. Indeed, the neuroprotective relevance of KP-10's binding mechanisms can be insinuated in the amelioration of α-syn-mediated neurotoxicity; yet it is obscure whether these extenuative circumstances are contingent upon prior GPR54 activation. Herein, choline acetyltransferase (ChAT)-positive SH-SY5Y neurons were engineered ad hoc to transiently overexpress human wild-type or E46K mutant α-syn while the mitigation of α-syn-induced neuronal death was ascertained via flow cytometric and immunocytochemical quantification. Recapitulating the specificity observed on cell viability, exogenously administered KP-10 (0.1 µM) substantially suppressed wild-type and E46K mutant α-syn-mediated apoptosis and mitochondrial depolarization in cholinergic differentiated neurons. In particular, co-administrations with a GPR54 antagonist, kisspeptin-234 (KP-234), failed to abrogate the robust neuroprotection elicited by KP-10, thereby signifying a GPR54 dispensable mechanism of action. Consistent with these observations, KP-10 treatment further diminished α-syn and ChAT immunoreactivity in neurons overexpressing wild-type and E46K mutant α-syn. Overall, these findings lend additional credence to the previous notion that KP-10's binding zone may harness efficacious moieties of neuroprotective intent.

Gender Differences in Cortisol and Cortisol Receptors in Depression: A Narrative Review.

Stress is known to have a significant impact on mental health. While gender differences can be found in stress response and mental disorders, there are limited studies on the neuronal mechanisms of gender differences in mental health. Here, we discuss gender and cortisol in depression as presented by recent clinical studies, as well as gender differences in the role of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in stress-associated mental disorders. When examining clinical studies drawn from PubMed/MEDLINE (National Library of Medicine) and EMBASE, salivary cortisol generally showed no gender correlation. However, young males were reported to show heightened cortisol reactivity compared to females of similar age in depression. Pubertal hormones, age, early life stressors, and types of bio-samples for cortisol measurement affected the recorded cortisol levels. The role of GRs and MRs in the HPA axis could be different between males and females during depression, with increased HPA activity and upregulated MR expression in male mice, while the inverse happened in female mice. The functional heterogeneity and imbalance of GRs and MRs in the brain may explain gender differences in mental disorders. This knowledge and understanding will support the development of gender-specific diagnostic markers involving GRs and MRs in depression.

Integrative Roles of Dopamine Pathway and Calcium Channels Reveal a Link between Schizophrenia and Opioid Use Disorder.

Several theories have been proposed to explain the mechanisms of substance use in schizophrenia. Brain neurons pose a potential to provide novel insights into the association between opioid addiction, withdrawal, and schizophrenia. Thus, we exposed zebrafish larvae at 2 days post-fertilization (dpf) to domperidone (DPM) and morphine, followed by morphine withdrawal. Drug-induced locomotion and social preference were assessed, while the level of dopamine and the number of dopaminergic neurons were quantified. In the brain tissue, the expression levels of genes associated with schizophrenia were measured. The effects of DMP and morphine were compared to vehicle control and MK-801, a positive control to mimic schizophrenia. Gene expression analysis revealed that α1C, α1Sa, α1Aa, drd2a, and th1 were up-regulated after 10 days of exposure to DMP and morphine, while th2 was down-regulated. These two drugs also increased the number of positive dopaminergic neurons and the total dopamine level but reduced the locomotion and social preference. The termination of morphine exposure led to the up-regulation of th2, drd2a, and c-fos during the withdrawal phase. Our integrated data implicate that the dopamine system plays a key role in the deficits in social behavior and locomotion that are common in the schizophrenia-like symptoms and opioid dependence.

Metabolomics based biomarker identification of anti-diabetes and anti-obesity properties of Malaysian herbs.

BACKGROUND: Today, obesity affects over one-third of the global population and is hugely considered the Industrial Revolution's side effect. This multi-factorial disease is continuously spreading across developing countries, including the Middle East and Southeast Asia region, where Malaysia and Darussalam Brunei are the most affected. The sedentary lifestyle and availability of surplus foods have dramatically increased the number of individuals with type 2 diabetes in these countries. Thus, an adequate medical strategy must be developed urgently to address and remedy these diseases. Natural sources have been attracting attention, especially in Malaysia, where most land areas are under plant cover. Metabolomics, as a prophylactic technique, has been used extensively in Malaysia to investigate the potential use and benefits of herbs to combat obesity and diabetes. AIM OF REVIEW: This review aims to explain the application of the metabolomics approach in the study of anti-diabetes and anti-obesity activity of Malaysian herbs to identify the stand-up point for future advancement in using these herbs as a primary source for drug exploration. KEY SCIENTIFIC CONCEPTS OF REVIEW: This review provides an overview of using metabolomics technique in studying the anti-diabetes and anti-obesity activity of Malaysian herbs. Specific emphasis is given to the changed metabolites in both in vivo and in vitro treatment of Malaysia herbs that might be future drugs for treating diabetes and obesity.

Conserved functions of hypothalamic kisspeptin in vertebrates.

Hypothalamic kisspeptin encoded by KISS1/Kiss1 gene emerged as a regulator of the reproductive axis in mammals following the discovery of the kisspeptin receptor (Kissr) and its role in reproduction. Kisspeptin-Kissr systems have been investigated in various vertebrates, and a conserved sequence of kisspeptin-Kissr has been identified in most vertebrate species except in the avian linage. In addition, multiple paralogs of kisspeptin sequences have been identified in the non-mammalian vertebrates. The allegedly conserved role of kisspeptin-Kissr in reproduction became debatable when kiss/kissr genes-deficient zebrafish and medaka showed no apparent effect on the onset of puberty, sexual development, maturation and reproductive capacity. Therefore, it is questionable whether the role of kisspeptin in reproduction is conserved among vertebrate species. Here we discuss from a comparative and evolutional aspect the diverse functions of kisspeptin and its receptor in vertebrates. Primarily this review focuses on the role of hypothalamic kisspeptin in reproductive and non-reproductive functions that are conserved in vertebrate species.

Kisspeptin-10 Rescues Cholinergic Differentiated SHSY-5Y Cells from α-Synuclein-Induced Toxicity In Vitro.

The neuropathological substrate of dementia with Lewy bodies (DLB) is defined by the inextricable cross-seeding accretion of amyloid-ß (Aß) and α-synuclein (α-syn)-laden deposits in cholinergic neurons. The recent revelation that neuropeptide kisspeptin-10 (KP-10) is able to mitigate Aß toxicity via an extracellular binding mechanism may provide a new horizon for innovative drug design endeavors. Considering the sequence similarities between α-syn's non-amyloid-ß component (NAC) and Aß's C-terminus, we hypothesized that KP-10 would enhance cholinergic neuronal resistance against α-syn's deleterious consequences through preferential binding. Here, human cholinergic SH-SY5Y cells were transiently transformed to upsurge the mRNA expression of α-syn while α-syn-mediated cholinergic toxicity was quantified utilizing a standardized viability-based assay. Remarkably, the E46K mutant α-syn displayed elevated α-syn mRNA levels, which subsequently induced more cellular toxicity compared with the wild-type α-syn in choline acetyltransferase (ChAT)-positive cholinergic neurons. Treatment with a high concentration of KP-10 (10 µM) further decreased cholinergic cell viability, while low concentrations of KP-10 (0.01-1 µM) substantially suppressed wild-type and E46K mutant α-syn-mediated toxicity. Correlating with the in vitro observations are approximations from in silico algorithms, which inferred that KP-10 binds favorably to the C-terminal residues of wild-type and E46K mutant α-syn with CDOCKER energy scores of -118.049 kcal/mol and -114.869 kcal/mol, respectively. Over the course of 50 ns simulation time, explicit-solvent molecular dynamics conjointly revealed that the docked complexes were relatively stable despite small-scale fluctuations upon assembly. Taken together, our findings insinuate that KP-10 may serve as a novel therapeutic scaffold with far-reaching implications for the conceptualization of α-syn-based treatments.

Receptor-Mediated AKT/PI3K Signalling and Behavioural Alterations in Zebrafish Larvae Reveal Association between Schizophrenia and Opioid Use Disorder.

The link between substance abuse and the development of schizophrenia remains elusive. In this study, we assessed the molecular and behavioural alterations associated with schizophrenia, opioid addiction, and opioid withdrawal using zebrafish as a biological model. Larvae of 2 days post fertilization (dpf) were exposed to domperidone (DMP), a dopamine-D2 dopamine D2 receptor antagonist, and morphine for 3 days and 10 days, respectively. MK801, an N-methyl-D-aspartate (NMDA) receptor antagonist, served as a positive control to mimic schizophrenia-like behaviour. The withdrawal syndrome was assessed 5 days after the termination of morphine treatment. The expressions of schizophrenia susceptibility genes, i.e., pi3k, akt1, slc6a4, creb1 and adamts2, in brains were quantified, and the levels of whole-body cyclic adenosine monophosphate (cAMP), serotonin and cortisol were measured. The aggressiveness of larvae was observed using the mirror biting test. After the short-term treatment with DMP and morphine, all studied genes were not differentially expressed. As for the long-term exposure, akt1 was downregulated by DMP and morphine. Downregulation of pi3k and slc6a4 was observed in the morphine-treated larvae, whereas creb1 and adamts2 were upregulated by DMP. The levels of cAMP and cortisol were elevated after 3 days, whereas significant increases were observed in all of the biochemical tests after 10 days. Compared to controls, increased aggression was observed in the DMP-, but not morphine-, treated group. These two groups showed reduction in aggressiveness when drug exposure was prolonged. Both the short- and long-term morphine withdrawal groups showed downregulation in all genes examined except creb1, suggesting dysregulated reward circuitry function. These results suggest that biochemical and behavioural alterations in schizophrenia-like symptoms and opioid dependence could be controlled by common mechanisms.

The crosstalk of hedgehog, PI3K and Wnt pathways in diabetes.

Hyperglycaemia causes pancreatic ß-cells to release insulin that then attaches to a specific expression of receptor isoform and reverses high glucose concentrations. It is well known that insulin is capable of initiating insulin-receptor substrate (IRS)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling pathways in target cells; such as liver, adipose tissues, and muscles. However, recent discoveries indicate that many other pathways, such as the Hedgehog (Hh) and growth factor-stimulating Wingless-related integration (Wnt) signaling pathways; are activated in hyperglycaemia as well. Although these two pathways are traditionally thought to have a decisive role in cellular growth and differentiation only, recent reports show that they are involved in regulating cellular homeostasis and energy balance. While insulin-activated IRS/PI3K/PKB pathway cascades are primarily known to reduce glucose production, it was recently discovered to increase the Hh signaling pathway's stability, thereby activating the PI3K/PKB/mammalian target of rapamycin complex 2 (mTORC2) signaling pathway. The Hh signaling pathway not only plays a role in lipid metabolism, insulin sensitivity, inflammatory response, diabetes-related complications, but crosstalks with the Wnt signaling pathway resulting in improved insulin sensitivity and decrease inflammatory response in diabetes.

The molecular mechanism of vgf in appetite, lipids, and insulin regulation.

Obesity is an indication of an imbalance between energy expenditure and food intake. It is a complicated disease of epidemic proportions as it involves many factors and organs. Sedentary lifestyles and overeating have caused a substantial rise in people with obesity and type 2 diabetes. Thus, the discovery of successful and sustainable therapies for these chronic illnesses is critical. However, the mechanisms of obesity and diabetes and the crosstalk between these diseases are still ambiguous. Numerous studies are being done to study these mechanisms, with updates made frequently. VGF peptide and its derivatives are anticipated to have a role in the development of obesity and diabetes. However, contradictory studies have produced conflicting findings on the function of VGF. Therefore, in this review, we attempt to clarify and explain the role of VGF peptides in the brain, pancreas, and adipose tissue in the development of obesity.

Murine in vitro cellular models to better understand adipogenesis and its potential applications.

Adipogenesis has been extensively studied using in vitro models of cellular differentiation, enabling long-term regulation of fat cell metabolism in human adipose tissue (AT) material. Many studies promote the idea that manipulation of this process could potentially reduce the prevalence of obesity and its related diseases. It has now become essential to understand the molecular basis of fat cell development to tackle this pandemic disease, by identifying therapeutic targets and new biomarkers. This review explores murine cell models and their applications for study of the adipogenic differentiation process in vitro. We focus on the benefits and limitations of different cell line models to aid in interpreting data and selecting a good cell line model for successful understanding of adipose biology.

MicroRNAs Regulate Cell Cycle and Cell Death Pathways in Glioblastoma.

Glioblastoma (GBM), a grade IV brain tumor, is known for its heterogenicity and its resistance to the current treatment regimen. Over the last few decades, a significant amount of new molecular and genetic findings has been reported regarding factors contributing to GBM's development into a lethal phenotype and its overall poor prognosis. MicroRNA (miRNAs) are small non-coding sequences of RNA that regulate and influence the expression of multiple genes. Many research findings have highlighted the importance of miRNAs in facilitating and controlling normal biological functions, including cell differentiation, proliferation, and apoptosis. Furthermore, miRNAs' ability to initiate and promote cancer development, directly or indirectly, has been shown in many types of cancer. There is a clear association between alteration in miRNAs expression in GBM's ability to escape apoptosis, proliferation, and resistance to treatment. Further, miRNAs regulate the already altered pathways in GBM, including P53, RB, and PI3K-AKT pathways. Furthermore, miRNAs also contribute to autophagy at multiple stages. In this review, we summarize the functions of miRNAs in GBM pathways linked to dysregulation of cell cycle control, apoptosis and resistance to treatment, and the possible use of miRNAs in clinical settings as treatment and prediction biomarkers.

Challenges and Perspectives of Standard Therapy and Drug Development in High-Grade Gliomas.

Despite their low incidence rate globally, high-grade gliomas (HGG) remain a fatal primary brain tumor. The recommended therapy often is incapable of resecting the tumor entirely and exclusively targeting the tumor leads to tumor recurrence and dismal prognosis. Additionally, many HGG patients are not well suited for standard therapy and instead, subjected to a palliative approach. HGG tumors are highly infiltrative and the complex tumor microenvironment as well as high tumor heterogeneity often poses the main challenges towards the standard treatment. Therefore, a one-fit-approach may not be suitable for HGG management. Thus, a multimodal approach of standard therapy with immunotherapy, nanomedicine, repurposing of older drugs, use of phytochemicals, and precision medicine may be more advantageous than a single treatment model. This multimodal approach considers the environmental and genetic factors which could affect the patient's response to therapy, thus improving their outcome. This review discusses the current views and advances in potential HGG therapeutic approaches and, aims to bridge the existing knowledge gap that will assist in overcoming challenges in HGG.

Distribution of Kiss2 receptor in the brain and its localization in neuroendocrine cells in the zebrafish.

Kisspeptin is a hypothalamic neuropeptide, which acts directly on gonadotropin-releasing hormone (GnRH)-secreting neurons via its cognate receptor (GPR54 or Kiss-R) to stimulate GnRH secretion in mammals. In non-mammalian vertebrates, there are multiple kisspeptins (Kiss1 and Kiss2) and Kiss-R types. Recent gene knockout studies have demonstrated that fish kisspeptin systems are not essential in the regulation of reproduction. Studying the detailed distribution of kisspeptin receptor in the brain and pituitary is important for understanding the multiple action sites and potential functions of the kisspeptin system. In the present study, we generated a specific antibody against zebrafish Kiss2-R (=Kiss1Ra/GPR54-1/Kiss-R2/KissR3) and examined its distribution in the brain and pituitary. Kiss2-R-immunoreactive cell bodies are widely distributed in the brain including in the dorsal telencephalon, preoptic area, hypothalamus, optic tectum, and in the hindbrain regions. Double-labeling showed that not all but a subset of preoptic GnRH3 neurons expresses Kiss2-R, while Kiss2-R is expressed in most of the olfactory GnRH3 neurons. In the posterior preoptic region, Kiss2-R immunoreactivity was seen in vasotocin cells. In the pituitary, Kiss2-R immunoreactivity was seen in corticotropes, but not in gonadotropes. The results in this study suggest that Kiss2 and Kiss2-R signaling directly serve non-reproductive functions and indirectly subserve reproductive functions in teleosts.

Selected neuropeptide genes show genetic differentiation between Africans and non-Africans.

BACKGROUND: Publicly available genome data provides valuable information on the genetic variation patterns across different modern human populations. Neuropeptide genes are crucial to the nervous, immune, endocrine system, and physiological homeostasis as they play an essential role in communicating information in neuronal functions. It remains unclear how evolutionary forces, such as natural selection and random genetic drift, have affected neuropeptide genes among human populations. To date, there are over 100 known human neuropeptides from the over 1000 predicted peptides encoded in the genome. The purpose of this study is to analyze and explore the genetic variation in continental human populations across all known neuropeptide genes by examining highly differentiated SNPs between African and non-African populations. RESULTS: We identified a total of 644,225 SNPs in 131 neuropeptide genes in 6 worldwide population groups from a public database. Of these, 5163 SNPs that had ΔDAF |(African - non-African)| ≥ 0.20 were identified and fully annotated. A total of 20 outlier SNPs that included 19 missense SNPs with a moderate impact and one stop lost SNP with high impact, were identified in 16 neuropeptide genes. Our results indicate that an overall strong population differentiation was observed in the non-African populations that had a higher derived allele frequency for 15/20 of those SNPs. Highly differentiated SNPs in four genes were particularly striking: NPPA (rs5065) with high impact stop lost variant; CHGB (rs6085324, rs236150, rs236152, rs742710 and rs742711) with multiple moderate impact missense variants; IGF2 (rs10770125) and INS (rs3842753) with moderate impact missense variants that are in linkage disequilibrium. Phenotype and disease associations of these differentiated SNPs indicated their association with hypertension and diabetes and highlighted the pleiotropic effects of these neuropeptides and their role in maintaining physiological homeostasis in humans. CONCLUSIONS: We compiled a list of 131 human neuropeptide genes from multiple databases and literature survey. We detect significant population differentiation in the derived allele frequencies of variants in several neuropeptide genes in African and non-African populations. The results highlights SNPs in these genes that may also contribute to population disparities in prevalence of diseases such as hypertension and diabetes.