Cotadutide (GLP-1/Glucagon dual receptor agonist) modulates hypothalamic orexigenic and anorexigenic neuropeptides in obese mice.

The hypothalamic neuropeptides linked to appetite and satiety were investigated in obese mice treated with cotadutide (a dual receptor agonist of glucagon-like peptide 1 (GLP-1R)/Glucagon (GCGR)). Twelve-week-old male C57BL/6 mice were fed a control diet (C group, n = 20) or a high-fat diet (HF group, n = 20) for ten weeks. Each group was further divided, adding cotadutide treatment and forming groups C, CC, HF, and HFC for four additional weeks. The hypothalamic arcuate neurons were labeled by immunofluorescence, and protein expressions (Western blotting) for neuropeptide Y (NPY), proopiomelanocortin (POMC), agouti-related protein (AgRP), and cocaine- and amphetamine-regulated transcript (CART). Cotadutide enhanced POMC and CART neuropeptides and depressed NPY and AGRP neuropeptides. In addition, gene expressions (RT-qPCR) determined that Lepr (leptin receptor) and Calcr (calcitonin receptor) were diminished in HF compared to C but enhanced in CC compared to C and HFC compared to HF. Besides, Socs3 (suppressor of cytokine signaling 3) was decreased in HFC compared to HF, while Sst (somatostatin) was higher in HFC compared to HF; Tac1 (tachykinin 1) and Mc4r (melanocortin-4-receptor) were lower in HF compared to C but increased in HFC compared to HF. Also, Glp1r and Gcgr were higher in HFC compared to HF. In conclusion, the findings are compelling, demonstrating the effects of cotadutide on hypothalamic neuropeptides and hormone receptors of obese mice. Cotadutide modulates energy balance through the gut-brain axis and its associated signaling pathways. The study provides insights into the mechanisms underlying cotadutide's anti-obesity effects and its possible implications for obesity treatment.

Phase-shifting the circadian glucocorticoid profile induces disordered feeding behaviour by dysregulating hypothalamic neuropeptide gene expression.

Here we demonstrate, in rodents, how the timing of feeding behaviour becomes disordered when circulating glucocorticoid rhythms are dissociated from lighting cues; a phenomenon most commonly associated with shift-work and transmeridian travel 'jetlag'. Adrenalectomized rats are infused with physiological patterns of corticosterone modelled on the endogenous adrenal secretory profile, either in-phase or out-of-phase with lighting cues. For the in-phase group, food intake is significantly greater during the rats' active period compared to their inactive period; a feeding pattern similar to adrenal-intact control rats. In contrast, the feeding pattern of the out-of-phase group is significantly dysregulated. Consistent with a direct hypothalamic modulation of feeding behaviour, this altered timing is accompanied by dysregulated timing of anorexigenic and orexigenic neuropeptide gene expression. For Neuropeptide Y (Npy), we report a glucocorticoid-dependent direct transcriptional regulation mechanism mediated by the glucocorticoid receptor (GR). Taken together, our data highlight the adverse behavioural outcomes that can arise when two circadian systems have anti-phasic cues, in this case impacting on the glucocorticoid-regulation of a process as fundamental to health as feeding behaviour. Our findings further highlight the need for development of rational approaches in the prevention of metabolic dysfunction in circadian-disrupting activities such as transmeridian travel and shift-work.

On the origin of appetite: GLWamide in jellyfish represents an ancestral satiety neuropeptide.

Food intake is regulated by internal state. This function is mediated by hormones and neuropeptides, which are best characterized in popular model species. However, the evolutionary origins of such feeding-regulating neuropeptides are poorly understood. We used the jellyfish Cladonema to address this question. Our combined transcriptomic, behavioral, and anatomical approaches identified GLWamide as a feeding-suppressing peptide that selectively inhibits tentacle contraction in this jellyfish. In the fruit fly Drosophila, myoinhibitory peptide (MIP) is a related satiety peptide. Surprisingly, we found that GLWamide and MIP were fully interchangeable in these evolutionarily distant species for feeding suppression. Our results suggest that the satiety signaling systems of diverse animals share an ancient origin.

Neuropeptides and hormones in hypothalamus-pituitary axis of Chinese sturgeon (Acipenser sinensis).

The hypothalamus and pituitary serve as important neuroendocrine center, which is able to secrete a variety of neuropeptides and hormones to participate in the regulation of reproduction, growth, stress and feeding in fish. Chinese sturgeon is a basal vertebrate lineage fish with a special evolutionary status, but the information on its neuroendocrine system is relatively scarce. Using the transcriptome data on the hypothalamus-pituitary axis of Chinese sturgeon as reference, we found out 46 hypothalamus neuropeptide genes, which were involved in regulation of reproduction, growth, stress and feeding. The results of sequence alignment showed that the neuroendocrine system of Chinese sturgeon evolves slowly, which confirms that Chinese sturgeon is a species with a slow phenotypic evolution rate. In addition, we also isolated six pituitary hormones genes from Chinese sturgeon, including reproductive hormones: follicle-stimulating homone (FSH) and luteinizing hormone (LH), growth-related hormones: growth hormone (GH)/prolactin (PRL)/somatolactin (SL), and stress-related hormone gene: proopiomelanocortin (POMC). Similar to teleost, immunostaining localization analysis in Chinese sturgeon pituitary showed that LH and FSH were located in the pituitary proximal pars distalis, SL was located in the pituitary rostral pars distalis, and POMC was located in the pituitary pars intermedia and pituitary rostral pars distalis. This study will give a contribution to enrich our information on the neuroendocrine system in Chinese sturgeon.

Mapping key neuropeptides involved in the melanocortin system in Atlantic salmon (Salmo salar) brain.

The melanocortin system is a key regulator of appetite and food intake in vertebrates. This system includes the neuropeptides neuropeptide y (NPY), agouti-related peptide (AGRP), cocaine- and amphetamine-regulated transcript (CART), and pro-opiomelanocortin (POMC). An important center for appetite control in mammals is the hypothalamic arcuate nucleus, with neurons that coexpress either the orexigenic NPY/AGRP or the anorexigenic CART/POMC neuropeptides. In ray-finned fishes, such a center is less characterized. The Atlantic salmon (Salmo salar) has multiple genes of these neuropeptides due to whole-genome duplication events. To better understand the potential involvement of the melanocortin system in appetite and food intake control, we have mapped the mRNA expression of npy, agrp, cart, and pomc in the brain of Atlantic salmon parr using in situ hybridization. After identifying hypothalamic mRNA expression, we investigated the possible intracellular coexpression of npy/agrp and cart/pomc in the tuberal hypothalamus by fluorescent in situ hybridization. The results showed that the neuropeptides were widely distributed, especially in sensory and neuroendocrine brain regions. In the hypothalamic lateral tuberal nucleus, the putative homolog to the mammalian arcuate nucleus, npya, agrp1, cart2b, and pomca were predominantly localized in distinct neurons; however, some neurons coexpressed cart2b/pomca. This is the first demonstration of coexpression of cart2b/pomca in the tuberal hypothalamus of a teleost. Collectively, our data suggest that the lateral tuberal nucleus is the center for appetite control in salmon, similar to that of mammals. Extrahypothalamic brain regions might also be involved in regulating food intake, including the olfactory bulb, telencephalon, midbrain, and hindbrain.

Gut Microbiota Restores Central Neuropeptide Deficits in Germ-Free Mice.

Recent work has demonstrated the ability of the gut microbiota (GM) to alter the expression and release of gut peptides that control appetite and regulate energy homeostasis. However, little is known about the neuronal response of these hormones in germ-free (GF) animals, especially leptin, which is strikingly low in these animals. Therefore, we aimed to determine the response to exogenous leptin in GF mice as compared to conventionally raised (CONV-R) mice. Specifically, we injected and measured serum leptin in both GF and CONV-R mice and measured expression of orexigenic and anorexigenic peptides NPY, AgRP, POMC, and CART in the hypothalamus and hindbrain to examine whether the GM has an impact on central nervous system regulation of energy homeostasis. We found that GF mice had a significant increase in hypothalamic NPY and AgRP mRNA expression and a decrease in hindbrain NPY and AgRP mRNA, while mRNA expression of POMC and CART remained unchanged. Administration of leptin normalized circulating levels of leptin, GLP-1, PYY, and ghrelin, all of which were significantly decreased in GF mice. Finally, brief conventionalization of GF mice for 10 days restored the deficits in hypothalamic and hindbrain neuropeptides present in GF animals. Taken together, these results show that the GM regulates hypothalamic and hindbrain orexigenic/anorexigenic neuropeptide expression. This is in line with the role of gut microbiota in lipid metabolism and fat deposition that may contribute to excess fat in conventionalized animals under high feeding condition.

Forkhead Box i2 Transcription Factor Regulates Systemic Energy Metabolism Via Neuropeptide AgRP.

The neuropeptide AgRP is essential for maintaining systemic energy homeostasis. In the current study, we show that hypothalamic Foxi2, as a novel regulator of nutrient sensing, controls systemic energy metabolism by specifically stimulating AgRP expression. Foxi2 was highly expressed in the hypothalamus, and its expression was induced by fasting. Immunofluorescence assays demonstrated that Foxi2 was localized in AgRP neurons. We stereotactically injected adeno-associated virus to selectively overexpress Foxi2 in AgRP-IRES-Cre mice and found that Foxi2 overexpression in AgRP neurons specifically increased AgRP expression, thereby increasing food intake and reducing energy expenditure, subsequently leading to obesity and insulin resistance. Mechanistically, Foxi2 stimulated AgRP expression by directly binding to it and activating its transcription. Furthermore, Foxi2 overexpression activated AgRP neuron activity, as revealed by whole-cell patch-clamp experiments. Conversely, global Foxi2-mutant mice became leaner with age and were resistant to high-fat diet-induced obesity and metabolic disturbances. Collectively, our data suggest that Foxi2 plays an important role in controlling energy metabolism by regulating AgRP expression.

Co-transmission of neuropeptides and monoamines choreograph the C. elegans escape response.

Co-localization and co-transmission of neurotransmitters and neuropeptides is a core property of neural signaling across species. While co-transmission can increase the flexibility of cellular communication, understanding the functional impact on neural dynamics and behavior remains a major challenge. Here we examine the role of neuropeptide/monoamine co-transmission in the orchestration of the C. elegans escape response. The tyraminergic RIM neurons, which coordinate distinct motor programs of the escape response, also co-express the neuropeptide encoding gene flp-18. We find that in response to a mechanical stimulus, flp-18 mutants have defects in locomotory arousal and head bending that facilitate the omega turn. We show that the induction of the escape response leads to the release of FLP-18 neuropeptides. FLP-18 modulates the escape response through the activation of the G-protein coupled receptor NPR-5. FLP-18 increases intracellular calcium levels in neck and body wall muscles to promote body bending. Our results show that FLP-18 and tyramine act in different tissues in both a complementary and antagonistic manner to control distinct motor programs during different phases of the C. elegans flight response. Our study reveals basic principles by which co-transmission of monoamines and neuropeptides orchestrate in arousal and behavior in response to stress.

Liujunzi Decoction ameliorated cisplatin-induced anorexia by inhibiting the JAK-STAT signaling pathway and coordinating anorexigenic and orexigenic neuropeptides in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: As a traditional Chinese formula, Liujunzi Decoction (LJZD) originated from the Yi Xue Zheng Zhuan, and has a promising effect in treating chemotherapy-induced anorexia (CIA). AIM OF THE STUDY: The present study aims to investigate whether LJZD acts on interleukin-6 (IL-6)/leptin mediated janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway that regulates hypothalamus anorexigenic and orexigenic peptides to ameliorate CIA, and also elucidates the potential mechanism by metabolomic analysis. MATERIALS AND METHODS: Network pharmacology analyses were conducted to screen out potential targets and pathways. The CIA rat model was established via an intraperitoneal injection of cisplatin. The histological changes of gastric antrum, liver and ileum were observed by HE staining. The serum levels of leptin, ghrelin, IL-6 and growth differentiation factor 15 (GDF15) were measured by ELISA. The JAK1/2 and STAT levels in gastric antrum and hypothalamus were detected by Western blot. The transcriptions of gastric antrum and hypothalamus IL-6R mRNA, and hypothalamus cocaine- and amphetamine-regulated transcript (CART), pro-opiomelanocortin (POMC), thyrotropin-releasing hormone (TRH), upregulated orexigenic peptides neuropeptide Y (NPY), and agouti-related protein (AGRP) mRNA were assessed by RT-qPCR. The blood samples of control, model and high dose LJZD groups were analyzed by metabolomic. RESULTS: Network pharmacology highlighted the IL-6/leptin mediated JAK-STAT signaling pathway, which regulated downstream anorexigenic and orexigenic peptides in hypothalamus. LJZD ameliorated CIA via stimulating food intake and water consumption in rats. Cisplatin-induced gastric antrum, liver, ileum injuries were ameliorated, serum leptin level reduction was elevated, and ghrelin, IL-6, GDF15 level increases were decreased after LJZD treatments. In gastric antrum and hypothalamus, LJZD inhibited cisplatin-induced activation of JAK-STAT signaling pathway, downregulated the transcriptions of downstream anorexigenic peptides CART, POMC, TRH, and upregulated orexigenic peptides NPY, AGRP in hypothalamus. Importantly, the effect of LJZD in treating CIA might partly relate to the improvements of 23 abnormal metabolites. CONCLUSION: This study implies that inhibiting JAK-STAT signaling pathway, regulating the expressions of anorexigenic and orexigenic peptides, and mediating various metabolic pathways might be potential mechanisms of LJZD's effect against CIA.

Triacylglycerol rich in docosahexaenoic acid regulated appetite via the mediation of leptin and intestinal epithelial functions in high-fat, high-sugar diet-fed mice.

High-fat, high-sugar diet (HFHS) induced leptin resistance and intestinal epithelial dysfunction is implicated in hyperphagia and metabolic disorders. Numerous studies have demonstrated the efficacy of dietary interventions for reducing appetite. This study aims to investigate whether triacylglycerol rich in DHA (DHA-TG) could regulate appetite in mice fed with a HFHS diet and the mechanism by which it achieves that. DHA-TG could reduce food intake and regulate neuropeptides (POMC, AgRP, and NPY) expression in HFHS diet-fed mice. Hypothalamic transcriptome analysis reveals that these effects might be attributed to the role of DHA-TG in modulating hormone secretion and digestive system process. According to ELISA and RT-qPCR analysis, DHA-TG ameliorated leptin secretion and attenuated central leptin resistance induced by HFHS diet feeding. Besides, DHA-TG prevented the damage of intestinal epithelial barrier in nutritive obese mice by improving leptin sensitivity. Based on jejunal transcriptome analysis, DHA-TG also protected intestinal endocrine function, especially the secretion of another anorectic hormone, cholecystokinin (CCK), in HFHS diet-fed mice. Furthermore, DHA-TG was ineffective in repressing appetite, and improving gut leakage in leptin-deficient mice (ob/ob mice). In conclusion, DHA-TG has a potential to regulate appetite with the action of leptin, and intestinal epithelial functions in HFHS diet-fed mice.

Molecular genetics of neurotransmitters and neuropeptides involved in Internet use disorders including first insights on a potential role of hypothalamus' oxytocin hormone.

This chapter covers the phenomenon of Internet use disorders (IUDs) and putative associations with different neurotransmitter and neuropeptide systems. Genes coding for such messengers can be seen as an important starting point in the complicated quest to understand human behavior including new phenomena such as IUDs. Therefore, a special focus of this chapter will lie on individual differences in molecular genetic underpinnings of neurotransmitter and neuropeptide systems and their associations with individual differences in tendencies towards IUDs. By shedding light on these associations, putative predisposing molecular genetic factors for the emergence and maintenance of IUDs can be carved out. Therefore, first an introduction to IUDs and a model that can guide research on putative associations of IUDs with different specific neurotransmitters and neuropeptides will be presented. Subsequently, twin studies on the heritability of IUDs are reviewed. Finally, studies on differences in molecular genetic predispositions and their associations with differences in IUDs will be presented and discussed, including targets related to the dopaminergic and serotonergic system as well as the hypothalamic neuropeptide oxytocin. The chapter closes with a conclusion about what is already known and what needs to be investigated in future studies to gain further insights into putative associations between molecular genetic markers and IUDs.

Alteration of CYP2E1, DBN1, DNMT1, miRNA-335, miRNA-21, c-Fos and Cox-2 gene expression in prefrontal cortex of rats' offspring submitted to prenatal ethanol exposure during their neurodevelopment and the preventive role of nancocurcumin administration: A histological, ultrastructural and molecular study.

Ethanol (EtOH) has been linked to neurotoxic effects on the fetus and prenatal alcohol exposure (PAE) has a negative impact on brain neurodevelopment. Therefore, the present study was aimed to focus on the underlying mechanisms of alcohol-induced oxidative stress and apoptotic cell death in addition to shedding the light on the modulatory effect of nanocurcumin in rats' offspring prefrontal cortices. The current study investigated the effects of prenatal maternal exposure to EtOH intragastric (i.g.) administration of 0.015 mL/g of a 10 % v/v ethanol solution throughout gestation and the concomitant use of nanocurcumin, on 21-day-old offspring Wistar rat prefrontal cortex parameters. CYP2E1, DBN1, DNMT1, miRNA-335, miRNA-21, c-Fos and Cox-2 gene expression as well as the accompanying histological and ultrastructural alterations were assessed. The implemented experimental setting has revealed that ethanol exposure caused significant alterations in the above mentioned parameters. Changes observed in nanocurcumin-treated animals were significantly different to the ethanol-treated group when nanocurcumin was concomitantly administered.

RF-amide related peptide-3 (RFRP-3): a novel neuroendocrine regulator of energy homeostasis, metabolism, and reproduction.

A hypothalamic neuropeptide, RF-amide related peptide-3 (RFRP-3), the mammalian ortholog of the avian gonadotropin-inhibitory hormone (GnIH) has inhibitory signals for reproductive axis via G-protein coupled receptor 147 in mammals. Moreover, RFRP-3 has orexigenic action but the mechanism involved in energy homeostasis and glucose metabolism is not yet known. Though, the RFRP-3 modulates orexigenic action in co-operation with other neuropeptides, which regulates metabolic cues in the hypothalamus. Administration of GnIH/RFRP-3 suppresses plasma luteinizing hormone, at the same time stimulates feeding behavior in birds and mammals. Likewise, in the metabolically deficient conditions, its expression is up-regulated suggests that RFRP-3 contributes to the integration of energy balance and reproduction. However, in many other metabolic conditions like induced diabetes and high-fat diet obesity, etc. its role is still not clear while, RFRP-3 induces the glucose homeostasis by adipocytes is reported. The physiological role of RFRP-3 in metabolic homeostasis and the metabolic effects of RFRP-3 signaling in pharmacological studies need a detailed discussion. Further studies are required to find out whether RFRP-3 is associated with restricted neuroendocrine function observed in type II diabetes mellitus, aging, or sub-fertility. In this context, the current review is focused on the role of RFRP-3 in the above-mentioned mechanisms. Studies from search engines including PubMed, Google Scholar, and science.gov are included after following set inclusion/exclusion criteria. As a developing field few mechanisms are still inconclusive, however, based on the available information RFRP-3 seems to be a putative tool in future treatment strategies towards metabolic disease.

Prepubertal exposure to high dose of cadmium induces hypothalamic injury through transcriptome profiling alteration and neuronal degeneration in female rats.

Cadmium (Cd) is a toxic metal, which seems to be crucial during the prepubertal period. Cd can destroy the structural integrity of the blood-brain barrier (BBB) and enters into the brain. Although the brain is susceptible to neurotoxicity induced by Cd, the effects of Cd on the brain, particularly hypothalamic transcriptome, are still relatively poorly understood. Therefore, we investigated the molecular effects of Cd exposure on the hypothalamus by profiling the transcriptomic response of the hypothalamus to high dose of Cd (25 mg/kg bw/day cadmium chloride (CdCl2)) during the prepubertal period in Sprague-Dawley female rats. After sequencing and annotation, differential expression analysis revealed 1656 genes that were differentially expressed that 108 of them were classified into 37 transcription factor (TF) families. According to gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, these differentially expressed genes (DEGs) were involved in different biological processes and neurological disorders including Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD), prolactin signaling pathway, PI3K/Akt signaling, and dopaminergic synapse. Five transcripts were selected for further analyses with Real-time quantitative PCR (RT-qPCR). The RT-qPCR results were mostly consistent with those from the high throughput RNA sequencing (RNA-seq). Cresyl violet staining clearly showed an increased neuronal degeneration in the dorsomedial hypothalamus (DMH) and arcuate (Arc) nuclei of the CdCl2 group. Overall, this study demonstrates that prepubertal exposure to high doses of Cd induces hypothalamic injury through transcriptome profiling alteration in female rats, which reveals the new mechanisms of pathogenesis of Cd in the hypothalamus.

Chemerin impairs food intake and body weight in chicken: Focus on hypothalamic neuropeptides gene expression and AMPK signaling pathway.

Unlike mammals, the role of adipokines and more particularly of chemerin in the regulation of food intake is totally unknown in avian species. Here we investigated the effect of chemerin on the food and water consumption and on the body weight in chicken. We studied the effects on the plasma glucose and insulin concentrations and the hypothalamic neuropeptides and AMPK signaling pathway. Female broiler chickens were intraperitoneally injected, daily for 13 days with either vehicle (saline; n = 25) or chemerin (8 µg/kg; n = 25 and 16 µg/kg; n = 25). Food and water intakes were recorded 24 h after each administration. Overnight fasted animals were sacrificed at day 13 (D13), 24 h after the last injection and hypothalamus and left cerebral hemispheres were collected. Chemerin and its receptors protein levels were determined by western-blot. Gene expression of neuropeptide Y (Npy), agouti-related peptide (Agrp), corticotrophin releasing hormone (Crh), pro-opiomelanocortin (Pomc), cocaine and amphetamine-regulated transcript (Cart) and Taste 1 Receptor Member 1 (Tas1r1) were evaluated by RT-qPCR. In chicken, we found that the protein amount of chemerin, CCRL2 and GPR1 was similar in left cerebral hemisphere and hypothalamus whereas CMKLR1 was higher in hypothalamus. Chemerin administration (8 and 16 µg/kg) decreased both food intake and body weight compared to vehicle without affecting water intake and the size or volume of different brain subdivisions as determined by magnetic resonance imaging. It also increased plasma insulin levels whereas glucose levels were decreased. These data were associated with an increase in Npy and Agrp expressions and a decrease in Crh, Tas1r1 mRNA expression within the hypothalamus. Furthermore, chemerin decreased hypothalamic CMKLR1 protein expression and AMPK activation. Taken together, these results support that chemerin could be a peripheral appetite-regulating signal through modulation of hypothalamic peptides expression in chicken.

Influence of peripheral lipopolysaccharide (LPS) on feed intake, body temperature and hypothalamic expression of neuropeptides involved in appetite regulation in broilers and layer chicks.

1. This study examined the expression of genes related to appetite-regulating neuropeptides in the hypothalamus of broiler and layer chicks (Gallus gallus) after intraperitoneal (IP) injection of lipopolysaccharide (LPS). 2. Both broiler and layer chicks received (n = 10 per group) LPS at doses of 0 and 200 µg and feed intake was measured up to 6 h after injection. In a further experiment, (n = 8 per group) mRNA abundance of some hypothalamic neuropeptides was measured 2 h after injection. The rectal temperature of each chick was measured before and 2 h post-injection. 3. Feed intake was significantly decreased by LPS from 2 h after injection and thereafter, while the rectal temperature did not change. 4. LPS decreased the expression of appetite-enhancing neuropeptides: neuropeptide Y (NPY) and agouti-related peptide (AgRP) in broilers and, NPY in layer chicks. The expression of appetite-suppressing neuropeptides (corticotrophin-releasing factor (CRF), proopiomelanocortin (POMC) and, cocaine and amphetamine regulated-transcript (CART) was not changed in broilers, while CRF tended to decrease and POMC was significantly decreased in layers. The abundance of the cytokine tumour necrosis factor-alpha (TNF-α) did not change in broilers but was decreased in layers. 5. The findings indicated that the reduction in gene expression of hypothalamic appetite-enhancing neuropeptides NPY and AgRP is responsible for anorexia caused by LPS at a dose that did not influence body temperature.

Preconditioning by ultra-low dose of tramadol reduces the severity of tramadol-induced seizure: Contribution of glutamate receptors.

Tramadol, a weak agonist of mu-opioid receptors, causes seizure via several mechanisms. Preconditioning has been purposed to reduce the epileptic seizures in animal models of epilepsy. The preconditioning effect of tramadol on seizure is not studied yet. This study was designed to evaluate the preconditioning effect of ultra-low dose of tramadol on the seizures induced by tramadol at high dose. Furthermore, regarding the critical role of glutamate signaling in the pathogenesis of epilepsy, the effect of preconditioning on some glutamate signaling elements was also examined. Male Wistar rats received tramadol (2 mg/kg, i.p) or normal saline (1 mL/kg, i.p) in preconditioning and control groups, respectively. After 4 days, the challenging tramadol dose (150 mg/kg) was injected to all rats. Epileptic behaviors were recorded during 50 min. The expression of Norbin (as a regulator of metabotropic glutamate receptor 5), Calponin3 (as a regulator of excitatory synaptic markers), NR1 (NMDA receptor subunit 1) and GluR1 (AMPA receptor subunit 1) was measured in hippocampus, prefrontal cortex (PFC) and amygdala. Preconditioning decreased the number and duration of tremors and tonic-clonic seizures. Norbin, Calponin3, NR1 and GluR1 expression were decreased in hippocampus, and preconditioning had no effect on them. In contrast, it increased Norbin expression in PFC and amygdala, and attenuated NR1 and GluR1 upregulation following tramadol at high dose. These findings indicated that preconditioning by ultra-low dose of tramadol protected the animals against seizures following high dose of tramadol mediated, at least in part, by Norbin up regulation, and NR1 and GluR1 down regulation.

Evaluation of VGF peptides as potential anti-obesity candidates in pre-clinical animal models.

VGF is a peptide precursor expressed in neuroendocrine cells that is suggested to play a role in the regulation of energy homeostasis. VGF is proteolytically cleaved to yield multiple bioactive peptides. However, the specific actions of VGF-derived peptides on energy homeostasis remain unclear. The aim of the present work was to investigate the role of VGF-derived peptides in energy homeostasis and explore the pharmacological actions of VGF-derived peptides on body weight in preclinical animal models. VGF-derived peptides (NERP-1, NERP-2, PGH-NH2, PGH-OH, NERP-4, TLQP-21, TLQP-30, TLQP-62, HHPD-41, AQEE-30, and LQEQ-19) were synthesized and screened for their ability to affect neuronal activity in vitro on hypothalamic brain slices and modulate food intake and energy expenditure after acute central administration in vivo. In addition, the effects of NERP-1, NERP-2, PGH-NH2, TLQP-21, TLQP-62, and HHPD-41 on energy homeostasis were studied after chronic central infusion. NERP-1, PGH-NH2, HHPD-41, and TLQP-62 increased the functional activity of hypothalamic neuronal networks. However, none of the peptides altered energy homeostasis after either acute or chronic ICV administration. The present data do not support the potential use of the tested VGF-derived peptides as novel anti-obesity drug candidates.

Melanin-concentrating hormone and food intake control: Sites of action, peptide interactions, and appetition.

Given the increased prevalence of obesity and its associated comorbidities, understanding the mechanisms through which the brain regulates energy balance is of critical importance. The neuropeptide melanin-concentrating hormone (MCH) is produced in the lateral hypothalamic area and the adjacent incerto-hypothalamic area and promotes both food intake and energy conservation, overall contributing to body weight gain. Decades of research into this system has provided insight into the neural pathways and mechanisms (behavioral and neurobiological) through which MCH stimulates food intake. Recent technological advancements that allow for selective manipulation of MCH neuron activity have elucidated novel mechanisms of action for the hyperphagic effects of MCH, implicating neural "volume" transmission in the cerebrospinal fluid and sex-specific effects of MCH on food intake control as understudied areas for future investigation. Highlighted here are historical and recent findings that illuminate the neurobiological mechanisms through which MCH promotes food intake, including the identification of various specific neural signaling pathways and interactions with other peptide systems. We conclude with a framework that the hyperphagic effects of MCH signaling are predominantly mediated through enhancement of an "appetition" process in which early postoral prandial signals promote further caloric consumption.

Bifidobacterium longum counters the effects of obesity: Partial successful translation from rodent to human.

BACKGROUND: The human gut microbiota has emerged as a key factor in the development of obesity. Certain probiotic strains have shown anti-obesity effects. The objective of this study was to investigate whether Bifidobacterium longum APC1472 has anti-obesity effects in high-fat diet (HFD)-induced obese mice and whether B. longum APC1472 supplementation reduces body-mass index (BMI) in healthy overweight/obese individuals as the primary outcome. B. longum APC1472 effects on waist-to-hip ratio (W/H ratio) and on obesity-associated plasma biomarkers were analysed as secondary outcomes. METHODS: B. longum APC1472 was administered to HFD-fed C57BL/6 mice in drinking water for 16 weeks. In the human intervention trial, participants received B. longum APC1472 or placebo supplementation for 12 weeks, during which primary and secondary outcomes were measured at the beginning and end of the intervention. FINDINGS: B. longum APC1472 supplementation was associated with decreased bodyweight, fat depots accumulation and increased glucose tolerance in HFD-fed mice. While, in healthy overweight/obese adults, the supplementation of B. longum APC1472 strain did not change primary outcomes of BMI (0.03, 95% CI [-0.4, 0.3]) or W/H ratio (0.003, 95% CI [-0.01, 0.01]), a positive effect on the secondary outcome of fasting blood glucose levels was found (-0.299, 95% CI [-0.44, -0.09]). INTERPRETATION: This study shows a positive translational effect of B. longum APC1472 on fasting blood glucose from a preclinical mouse model of obesity to a human intervention study in otherwise healthy overweight and obese individuals. This highlights the promising potential of B. longum APC1472 to be developed as a valuable supplement in reducing specific markers of obesity. FUNDING: This research was funded in part by Science Foundation Ireland in the form of a Research Centre grant (SFI/12/RC/2273) to APC Microbiome Ireland and by a research grant from Cremo S.A.