Hypothalamic Orexigenic Neuropeptide Research Articles

An mPOA-ARCAgRP pathway modulates cold-evoked eating behavior.

Enhanced appetite occurs as a means of behavioral thermoregulation at low temperature. Neural circuitry mediating this crosstalk between behavioral thermoregulation and energy homeostasis remains to be elucidated. We find that the hypothalamic orexigenic agouti-related neuropeptide (AgRP) neurons in the arcuate nucleus (ARC) are profoundly activated by cold exposure. The calcium signals in ARCAgRP neurons display an immediate-response pattern in response to cold stimulation. Cold-responsive neurons in the medial preoptic area (mPOA) make excitatory synapses onto ARCAgRP neurons. Inhibition of either ARCAgRP neurons or ARC-projecting mPOA neurons attenuates cold-evoked feeding, while activation of the mPOA-to-ARC projection increases food intake. These findings reveal an mPOA-ARCAgRP neural pathway that modulates cold-evoked feeding behavior.

Pregnancy-specific Adaptations in Leptin and Melanocortin Neuropeptides in Early Human Gestation.

Pregnancy is characterized by increased appetitive drive beginning early in gestation, yet the central mechanisms underlying this adaptation are poorly understood in humans. To elucidate central mechanisms underlying appetite regulation in early pregnancy, we examine plasma and cerebrospinal fluid (CSF) leptin and Agouti-related peptide (AgRP) as well as CSF proopiomelanocortin (POMC) as surrogates for brain melanocortin activity. Plasma leptin, soluble leptin receptor, AgRP, and CSF leptin, POMC, and AgRP were collected from pregnant women before cerclage placement (16.6 ± 1.1 weeks; N = 24), scheduled cesarean section (39.2 ± 0.2 weeks; N = 24), and from nonpregnant controls (N = 24), matched for age and body mass index. Plasma leptin was 1.5 times higher in pregnancy vs controls (P = 0.01), but CSF leptin did not differ. CSF/plasma leptin percentage was lower in early pregnancy vs controls (0.8 ± 0.1 vs 1.7 ± 0.2; P < 0.0001) and remained unchanged at term (0.9 ± 0.1), supporting a decrease in leptin transport into CSF in pregnancy. Plasma AgRP, a peripheral biomarker of the orexigenic hypothalamic neuropeptide, was higher in early pregnancy vs controls (95.0 ± 7.8 vs 67.5 ± 5.3; P = 0.005). In early gestation, CSF AgRP did not differ from controls, but CSF POMC was 25% lower (P = 0.006). In contrast, at term, CSF AgRP was 42% higher vs controls (P = 0.0001), but CSF POMC no longer differed. Overall, the CSF AgRP/POMC ratio was 1.5-fold higher in early pregnancy vs controls, reflecting a decrease in melanocortin tone favoring appetitive drive. Pregnancy-specific adaptions in the central regulation of energy balance occur early in human gestation and are consistent with decreased leptin transport into brain and resistance to the effects of leptin on target melanocortin neuropeptides.

Persistent sodium conductance contributes to orexin-A-mediated modulation of membrane excitability in neonatal rat mesencephalic V neurons

Orexins are multifunctional hypothalamic neuropeptides that participate in the stimulation of feeding behavior and energy expenditure. However, little is known about their neuromodulatory effects in lower brainstem effector regions, including in the trigeminal neuronal system. The aim of this study was to examine the effects of orexin-A (Ox-A) on the membrane properties of mesencephalic trigeminal (Mes V) neurons that are critically involved in the generation and control of rhythmical oral motor activities. Whole-cell patch clamp recordings were obtained from Mes V neurons in coronal brain slices prepared from Sprague-Dawley rats (postnatal day 12–17). Bath application of Ox-A (100 nM) shortened the duration of the after-hyperpolarization following the action potential, while the interspike frequency of firings during repetitive discharge increased, together with a shift in the frequency-current relationship toward the left. In addition, Ox-A amplified the resonance at the depolarized membrane potential, accompanied with an increase in both Q-value and resonant frequency. A further voltage-clamp experiment demonstrated that Ox-A increased the peak current density of the persistent sodium current (INaP) and shifted its activation curve to the hyperpolarization direction. These results suggested that Ox-A may increase Mes V neuronal excitability by enhancing INaP, possibly sharing a common mechanism with another orexigenic hypothalamic neuropeptide, neuropeptide Y.

An mPOA-ARC &lt;sup&gt;AgRP&lt;/sup&gt;&amp;nbsp;Pathway Modulates Cold-Evoked Eating Behavior

Behavioral thermoregulation involves enhanced appetite under decreased temperature. The neural circuitry mediating the crosstalk between behavioral thermoregulation and energy homeostasis remains to be elucidated. We find that the hypothalamic orexigenic agouti-related neuropeptide (AgRP) neurons in the arcuate nucleus (ARC) are profoundly activated by cold exposure. Inhibition of AgRP neurons attenuates the cold-evoked eating behavior. The calcium signals in AgRP neurons display an immediate-response pattern in response to cold stimulation. We find that the upstream cold-responsive neurons in the medial preoptic area (mPOA) make excitatory synaptic connections onto AgRP neurons. These findings reveal an mPOA-ARC neural pathway that modulates the cold-evoked eating behavior.

Role of Endocrine System and Hypothalamic Neuropeptides in Hyperphagia Associated Obesity

Activities occurring in an animal’s body are performed and regulated via certain chemicals. These chemical on the basis of multiple factors are divided into various classes. Hormones forma major class of such chemicals. Hormones are integral part of animal’s body that are involved in the mediation of a variety of vital functions. Hormonal secretions are precisely regulated in order to mediate relevant function as needed. They are important maintainers of a variety of homeostatic mechanisms including food intake, digestion, absorption and utilization. Like all other parts of animal’s body, adipose tissue is also under the influence of chemical messengers. Some of the endocrine messengers are Leptin, Insulin and Ghrelin hormone while neural chemicals include orexigenic hypothalamic neuropeptides (like Neuropeptide Y). While performing normal assigned function these chemical substances strive to maintain a balance between body energy need and energy intake. If concentration or functionality of any of them is disturbed due to certain change for sufficient time period then they fail to perform their duty resulting gradual increase in body mass index. Deficiency or hypersecretion, structural deformity and functional impairment are some of the aspects that contribute towards hormonal abnormalities. Present review is based on a concise discussion about obesogenic role of Leptin, Insulin and Ghrelin hormones and hypothalamic neuropeptides.

Orexin system is expressed in avian liver and regulates hepatic lipogenesis via ERK1/2 activation

Orexins are originally characterized as orexigenic hypothalamic neuropeptides in mammals. Subsequent studies found orexin to be expressed and perform pleiotropic functions in multiple tissues in mammals. In avian (non-mammalian) species, however, orexin seemed to not affect feeding behavior and its physiological roles are poorly understood. Here, we provide evidence that orexin and its related receptors are expressed in chicken hepatocytes. Double immunofluorescence staining showed that orexin is localized in the ER, Golgi, and in the lysosomes in LMH cells. Brefeldin A treatment reduced orexin levels in the culture media, but increased it in the cell lysates. Administration of recombinant orexins upregulated the expression of orexin system in the liver of 9-day old chicks, but did not affect feed intake. Recombinant orexins increased fatty acid synthase (FASN) protein levels in chicken liver, activated acetyl-CoA carboxylase (ACCα), and increased FASN, ATP citrate lyase(ACLY), and malic enzyme (ME) protein expression in LMH cells. Blockade ERK1/2 activation by PD98059 attenuated these stimulating effects of orexin on lipogenic factors. Overexpression of ERK1/2 increased the expression of lipogenic genes, and orexin treatment induced the phosphorylated levels of ERK1/2Thr202/Tyr204, but not that of p38 Thr180/Tyr182 or JNK1/2 Thr183/Tyr185 in chicken liver and LMH cells. Taken together, this is the first report evidencing that orexin is expressed and secreted from chicken hepatocytes, and that orexin induced hepatic lipogenesis via activation of ERK1/2 signaling pathway.

Cold exposure increased hypothalamic orexigenic neuropeptides but not food intake in fattening Daurian ground squirrels

Energy balance and thermoregulation in many fat-storing seasonal hibernators show a circannual rhythm. To understand the physiological mechanisms of the seasonal pre-hibernation fattening related to the regulation of energy expenditure and thermogenesis, we cold-exposed fattening Daurian ground squirrels (Spermophilus dauricus) in late summer for 3 weeks. We predicted that cold-exposed squirrels would increase food intake rather than express torpor to accommodate both fattening and thermoregulatory fuel allocation. Food intake and body mass were quantified. After 3 weeks, body compositions, serum leptin concentration, expression of hypothalamic neuropeptides related to regulation of energy balance and uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) were measured. There was no change in body mass after 3-weeks of cold exposure. Hypothalamic orexigenic neuropeptides and UCP1 levels in BAT were up-regulated after cold exposure. Food intake, serum leptin concentration and the expression of leptin signal suppressors, suppressor of cytokine signaling 3 and protein tyrosine phosphatase 1B, in hypothalamus showed no differences compared with controls. The core body temperature was unaffected by cold exposure. Our data suggest that cold exposure affected fattening mainly because of the increased heat loss, whereas energy balance and thermoregulation are under control of a strong circannual rhythm in the Daurian ground squirrels.

The energy budget and fat accumulation in striped hamsters (Cricetulus barabensis) during post-lactation

Adaptive adjustments of energy intake and body fat play an important role in allowing animals' to meet the energy demands of thermoregulation during cold conditions and reproduction. Body fat is usually metabolized during lactation, which is one of the most energetically demanding activities of female mammals, however the effect of this on the energy budget and body fat regulation after lactation remains unclear. We compared the energy intake and body fat of female striped hamsters (Cricetulus barabensis) fed either a high-fat or low-fat diet for 21 days after the end of lactation (post-lactation, PL) to those of virgin controls. Serum leptin levels and the expression of hypothalamic orexigenic and anorexigenic neuropeptide genes were also measured and compared. Although lactating females consumed significantly more food, they had significantly lower body fat than virgin controls. The energy intake and body fat levels of the PL females were, however, significantly higher than those of virgin females. This was particularly true for the PL females that were fed high-fat diet. These females had significantly higher serum leptin concentrations, but lower hypothalamic leptin receptor gene expression, than virgin females. Neither orexigenic nor anorexigenic neuropeptide levels in the hypothalamus differed significantly between the PL and virgin females. This suggests that a negative energy balance during lactation drives fat accumulation after lactation. Furthermore, leptin resistance may occur after the end of lactation, causing females to consume more food, and accumulate more fat, than virgin females.

Modulation of feeding behavior and metabolism by dynorphin

The neuronal regulation of metabolic and behavioral responses to different diets and feeding regimens is an important research area. Herein, we investigated if the opioid peptide dynorphin modulates feeding behavior and metabolism. Mice lacking dynorphin peptides (KO) were exposed to either a normal diet (ND) or a high-fat diet (HFD) for a period of 12 weeks. Additionally, mice had either time-restricted (TR) or ad libitum (AL) access to food. Body weight, food intake and blood glucose levels were monitored throughout the 12-week feeding schedule. Brain samples were analyzed by immunohistochemistry to detect changes in the expression levels of hypothalamic peptides. As expected, animals on HFD or having AL access to food gained more weight than mice on ND or having TR access. Unexpectedly, KO females on TR HFD as well as KO males on AL ND or AL HFD demonstrated a significantly increased body weight gain compared to the respective WT groups. The calorie intake differed only marginally between the genotypes: a significant difference was present in the female ND AL group, where dynorphin KO mice ate more than WT mice. Although female KO mice on a TR feeding regimen consumed a similar amount of food as WT controls, they displayed significantly higher levels of blood glucose. We observed significantly reduced levels of hypothalamic orexigenic peptides neuropeptide Y (NPY) and orexin-A in KO mice. This decrease became particularly pronounced in the HFD groups and under AL condition. The kappa opiod receptor (KOR) levels were higher after HFD compared to ND feeding in the ventral pallidum of WT mice. We hypothesize that HFD enhances dynorphin signaling in this hedonic center to maintain energy homeostasis, therefore KO mice have a more pronounced phenotype in the HFD condition due to the lack of it. Our data suggest that dynorphin modulates metabolic changes associated with TR feeding regimen and HFD consumption. We conclude that the lack of dynorphin causes uncoupling between energy intake and body weight gain in mice; KO mice maintained on HFD become overweight despite their normal food intake. Thus, using kappa opioid receptor agonists against obesity could be considered as a potential treatment strategy.

Phytogenic feed- and water-additives improve feed efficiency in broilers via modulation of (an)orexigenic hypothalamic neuropeptide expression

Fueled by consumer preference for natural and antibiotic-free products, phytogenics have become the fastest growing segment of the animal feed additives. Yet, their modes of action are not fully understood. This study was undertaken to determine the effect of 5 phytogenics (3 feed- and 2 water-supplements) on the growth performance of commercial broilers, and their potential underlying molecular mechanisms. Day-old male Cobb 500 chicks (n = 576) were randomly assigned into 48 pens consisting of 6 treatments (Control; AVHGP; SCP; BHGP; AVSSL; SG) in a complete randomized design (12 birds/pen, 8 pens/treatment, 96 birds/treatment). Chicks had ad libitum access to feed and water. Individual body weight (BW) was recorded weekly and feed intake was measured daily. Core body temperatures were continuously recorded using thermo-loggers. At d 35, hypothalamic tissues were excised from the thermo-logger-equipped chickens (n = 8 birds/treatment) to determine the expression of feeding-related neuropeptides.Both feed (AVHGP, SCP, BHGP) and water-supplemented (AVSSL, SG) phytogenics significantly improved feed efficiency (FE) compared to the control birds. This higher FE was achieved via a reduction in core body temperature and improvement of market BW, without changes in feed intake in broilers supplemented with phytogenic water additives as compared to the control group. Broilers fed dietary phytogenics, however, attained higher feed efficiency via a reduction in feed intake while maintaining similar BW as the control group. At the molecular levels, the effects of the phytogenic water additives seemed to be mediated by the activation of the hypothalamic AgRP-ORX-mTOR-S6k1 and inhibition of CRH pathways. The effect of the phytogenic feed additives appeared to be exerted through the activation of AdipoQ, STAT3, AMPK, and MC1R pathways.This is the first report describing the likely central mechanisms through which phytogenic additives improve the growth performance and feed efficiency in broilers.

RhoA in tyrosine hydroxylase neurones regulates food intake and body weight via altered sensitivity to peripheral hormones.

Dopamine-producing tyrosine hydroxylase (TH) neurones in the hypothalamic arcuate nucleus (ARC) have recently been shown to be involved in ghrelin signalling and body weight homeostasis. In the present study, we investigate the role of the intracellular regulator RhoA in hypothalamic TH neurones in response to peripheral hormones. Diet-induced obesity was found to be associated with increased phosphorylation of TH in ARC, indicating obesity-associated increased activity of ARC TH neurones. Mice in which RhoA was specifically knocked out in TH neurones (TH-RhoA-/- mice) were more sensitive to the orexigenic effect of peripherally administered ghrelin and displayed an abolished response to the anorexigenic hormone leptin. When TH-RhoA-/- mice were challenged with a high-fat high-sucrose (HFHS) diet, they became hyperphagic and gained more body weight and fat mass compared to wild-type control mice. Importantly, lack of RhoA prevented development of ghrelin resistance, which is normally observed in wild-type mice after long-term HFHS diet feeding. Patch-clamp electrophysiological analysis demonstrated increased ghrelin-induced excitability of TH neurones in lean TH-RhoA-/- mice compared to lean littermate control animals. Additionally, increased expression of the orexigenic hypothalamic neuropeptides agouti-related peptide and neuropeptide Y was observed in TH-RhoA-/- mice. Overall, our data indicate that TH neurones in ARC are important for the regulation of body weight homeostasis and that RhoA is both a central effector in these neurones and important for the development of obesity-induced ghrelin resistance. The obese phenotype of TH-RhoA-/- mice may be a result of increased sensitivity to ghrelin and decreased sensitivity to leptin, resulting in increased food intake.

Role of Insulin-like Growth Factor-1 in the Central Regulation of Feeding Behavior in Chicks.

Insulin-like growth factor-1 (IGF-1) is a key regulator of muscle development and metabolism in chickens. Recently, we have demonstrated that intracerebroventricular administration of IGF-1 significantly decreased food intake in broiler chicks. However, the molecular mechanisms underlying the IGF-1-induced anorexia and the anorexigenic effect of IGF-1 in different strains of commercial chicks have not been investigated. Neuropeptide Y (NPY, a hypothalamic orexigenic neuropeptide), agouti-related protein (AgRP, a hypothalamic orexigenic neuropeptide), and proopiomelanocortin (POMC, the precursor of hypothalamic anorexigenic neuropeptides) play important roles in the regulation of food intake in both mammals and chickens. Evidence shows that several cell signaling pathways in the hypothalamus are involved in regulating the feeding behavior of mammals. In the present study, we first investigated the effects of IGF-1 on the expression of appetite-regulating neuropeptides and phosphorylation of signaling molecules in the hypothalamus of broiler chicks. Intracerebroventricular administration of IGF-1 significantly increased the mRNA levels of POMC, whereas the mRNA levels of NPY and AgRP were not significantly altered. IGF-1 also significantly induced the phosphorylation of v-Akt murine thymoma viral oncogene homolog 1 (AKT) in the hypothalamus of chicks, but did not influence the phosphorylation of forkhead box O1, S6 protein, AMP-activated protein kinase, and extracellular signal-regulated kinase 1/2. We also compared the effect of IGF-1 on food intake in broiler chicks (a hyperphagic strain of chickens) and layer chicks. Results demonstrated that the threshold of IGF-1-induced anorexia in broiler chicks was higher than that in layer chicks. Our observations suggest that hypothalamic POMC and AKT may be involved in the IGF-1-induced anorexigenic pathway and that high threshold of IGF-1-induced anorexia in broiler chicks might be one of the causes of hyperphagia in broiler chicks. Overall, it appears that IGF-1 plays important roles in the central regulation of feeding behavior in chicks.

Effects of Bisphenol S on hypothalamic neuropeptides regulating feeding behavior and apelin/APJ system in mice

Since 2010, Bisphenol A (BPA), an endocrine disruptor has been restricted and replaced by analogues like Bisphenol S (BPS). However, little is known about BPS effects and growing concern have suspected the “BPA-free” Label. Several recent studies suggest that BPS is associated with increased risk of diabetes and obesity. However, the underlying mechanisms remain unidentified. The current study investigates investigate BPS effects on hypothalamic neuropeptides regulating feeding behavior, either orexigenic or anorexigenic in Swiss Albino mice. We also studied the effect of BPS on the apelinergic system (apelin/apelin receptor (APJ)) as an original physiological system with pleiotropic actions.Bisphenol S at 25, 50, 100 µg/kg was administered to mice in water drink for 10 weeks started after weaning. Our results showed that BPS exposure alters orexigenic hypothalamic neuropeptide (AgRP) regulating feeding behavior but not anorexigenic neuropeptides (POMC, CART). Such orexigenic alterations may underlay appetite disorders leading to a concomitant food intake and body weight gain increase. In addition, data show that BPS affects the hypothalamic apelinergic system. We found a significant decrease in APJ mRNA but not in apelin expression. Based on hypothalamic APJ distribution, we suggested a potent specific physiological alteration of this receptor in mediating neuroendocrine responses in hypothalamus.Thus, our findings provide that BPS exposure could contribute to the development of obesity and metabolic disorders.

Dietary Slowly Digestible Starch Triggers the Gut-Brain Axis in Obese Rats with Accompanied Reduced Food Intake.

Slowly digestible starch (SDS), as a functional carbohydrate providing a slow and sustained glucose release, may be able to modulate food intake through activation of the gut-brain axis. Diet-induced obese rats were used to test the effect on feeding behavior of high-fat (HF) diets containing an SDS, fabricated to digest into the ileum, as compared to rapidly digestible starch (RDS). Ingestion of the HF-SDS diet over an 11-week period reduced daily food intake, through smaller meal size, to the same level as a lean body control group, while the group consuming the HF-RDS diet remained at a high food intake. Expression levels (mRNA) of the hypothalamic orexigenic neuropeptide Y (NPY) and Agouti-related peptide (AgRP) were significantly reduced, and the anorexigenic corticotropin-releasing hormone (CRH) was increased, in the HF-SDS fed group compared to the HF-RDS group, and to the level of the lean control group. SDS with digestion into the ileum reduced daily food intake and paralleled suppressed expression of appetite-stimulating neuropeptide genes associated with the gut-brain axis. This novel finding suggests further exploration involving a clinical study and potential development of SDS-based functional foods as an approach to obesity control.

4-hydroxy-3-methoxycinnamic acid regulates orexigenic peptides and hepatic glucose homeostasis through phosphorylation of FoxO1

4-hydroxy-3-methoxycinnamic acid (ferulic acid, FA) is known to have numerous beneficial health effects, including anti-obesity and anti-hyperglycemic properties. However, the molecular networks that modulate the beneficial FA-induced metabolic effects have not been well elucidated. In this study, we explored the molecular mechanisms mediating the beneficial metabolic effects of FA. In mice, FA protected against high-fat diet-induced weight gain, reduced food intake and exhibited an overall improved metabolic phenotype. The food intake suppression by FA was accompanied by a specific reduction in hypothalamic orexigenic neuropeptides, including agouti-related protein and neuropeptide Y, with no significant changes in the anorexigenic peptides pro-opiomelanocortin and cocaine and amphetamine-regulated transcript. FA treatment also inhibited fat accumulation in the liver and white adipose tissue and suppressed the expression of gluconeogenic genes, including phosphoenolpyruvate carboxylase and glucose-6-phosphatase. Furthermore, we show that FA phosphorylated and inactivated the transcription factor FoxO1, which positively regulates the expression of gluconeogenic and orexigenic genes, providing evidence that FA might exert its beneficial metabolic effects through inhibition of FoxO1 function in the periphery and the hypothalamus.

Prenatal High Estradiol Exposure Induces Sex-Specific and Dietarily Reversible Insulin Resistance Through Decreased Hypothalamic INSR.

An adverse intrauterine environment may induce adult disease in offspring, but the mechanisms are not well understood. It is reported that fresh embryo transfer (ET) in assisted reproductive technology leads to high maternal estradiol (E2), and prenatal high E2 exposure increases the risk of organ disorders in later life. We found that male newborns and children of fresh ET showed elevated fasting insulin and homeostasis model of assessment for insulin resistance index (HOMA-IR) scores. Male mice with high prenatal estradiol exposure (HE) grew heavier than control mice and developed insulin resistance; they also showed increased food intake, with increased orexigenic hypothalamic neuropeptide Y (NPY) expression. The hypothalamic insulin receptor (INSR) was decreased in male HE mice, associated with elevated promoter methylation. Chronic food restriction (FR) in HE mice reversed insulin resistance and rescued hypothalamic INSR expression by correcting the elevated Insr promoter methylation. Our findings suggest that prenatal exposure to high E2 may induce sex-specific metabolic disorders in later life through epigenetic programming of hypothalamic Insr promoter, and dietary intervention may reverse insulin resistance by remodeling its methylation pattern.

Lateral hypothalamic Orexin-A-ergic projections to the arcuate nucleus modulate gastric function in vivo.

It has been well-known that hypothalamic orexigenic neuropeptides, orexin-A, and melanin-concentrating hormone (MCH), play important roles in regulation of gastric function. However, what neural pathway mediated by the two neuropeptides affects the gastric function remains unknown. In this study, by way of nucleic stimulation and extracellular recording of single unit electrophysiological properties, we found that electrically stimulating the lateral hypothalamic area (LH) or microinjection of orexin-A into the arcuate nucleus (ARC) excited most gastric distension-responsive neurons in the nuclei and enhanced the gastric function including motility, emptying, and acid secretion of conscious rats. The results indicated that LH-ARC orexin-A-ergic projections may exist and the orexin-A in the ARC affected afferent and efferent signal transmission between ARC and stomach. As expected, combination of retrograde tracing and immunohistochemistry showed that some orexin-A-ergic neurons projected from the LH to the ARC. In addition, microinjection of MCH and its receptor antagonist PMC-3881-PI into the ARC affected the role of orexin-A in the ARC, indicating a possible involvement of the MCH pathway in the orexin-A role. Our findings suggest that there was an orexin-A-ergic pathway between LH and ARC which participated in transmitting information between the central nuclei and the gastrointestinal tract and in regulating the gastric function of rats.

Involvement of the CXCL12 System in the Stimulatory Effects of Prenatal Exposure to High-Fat Diet on Hypothalamic Orexigenic Peptides and Behavior in Offspring.

Exposure to a high fat diet (HFD) during gestation stimulates neurogenesis and expression of hypothalamic orexigenic neuropeptides that affect consummatory and emotional behaviors. With recent studies showing a HFD to increase inflammation, this report investigated the neuroinflammatory chemokine, CXCL12, and compared the effects of prenatal CXCL12 injection to those of prenatal HFD exposure, first, by testing whether the HFD affects circulating CXCL12 in the dam and the CXCL12 system in the offspring brain, and then by examining whether prenatal exposure to CXCL12 itself mimics the effects of a HFD on hypothalamic neuropeptides and emotional behaviors. Our results showed that prenatal exposure to a HFD significantly increased circulating levels of CXCL12 in the dam, and that daily injections of CXCL12 induced a similar increase in CXCL12 levels as the HFD. In addition, prenatal HFD exposure significantly increased the expression of CXCL12 and its receptors, CXCR4 and CXCR7, in the hypothalamic paraventricular nucleus (PVN) of the offspring. Finally, the results revealed strong similarities in the effects of prenatal HFD and CXCL12 administration, which both stimulated neurogenesis and enkephalin (ENK) expression in the PVN, while having inconsistent or no effect in other regions of the hypothalamus, and also increased anxiety as measured by several behavioral tests. These results focus attention specifically on the CXCL12 chemokine system in the PVN of the offspring as being possibly involved in the stimulatory effects of prenatal HFD exposure on ENK-expressing neurons in the PVN and their associated changes in emotional behavior.

Neuropeptide-Y alters VTA dopamine neuron activity through both pre- and postsynaptic mechanisms.

The mesocorticolimbic dopamine system, the brain's reward system, regulates many different behaviors including food intake, food reward, and feeding-related behaviors, and there is increasing evidence that hypothalamic feeding-related neuropeptides alter dopamine neuron activity to affect feeding. For example, neuropeptide-Y (NPY), a strong orexigenic hypothalamic neuropeptide, increases motivation for food when injected into the ventral tegmental area (VTA). How NPY affects the activity of VTA dopamine neurons to regulate feeding behavior is unknown, however. In these studies we have used whole cell patch-clamp electrophysiology in acute brain slices from mice to examine how NPY affects VTA dopamine neuron activity. NPY activated an outward current that exhibited characteristics of a G protein-coupled inwardly rectifying potassium channel current in ~60% of dopamine neurons tested. In addition to its direct effects on VTA dopamine neurons, NPY also decreased the amplitude and increased paired-pulse ratios of evoked excitatory postsynaptic currents in a subset of dopamine neurons, suggesting that NPY decreases glutamatergic transmission through a presynaptic mechanism. Interestingly, NPY also strongly inhibited evoked inhibitory postsynaptic currents onto dopamine neurons by a presynaptic mechanism. Overall these studies demonstrate that NPY utilizes multiple mechanisms to affect VTA dopamine neuron activity, and they provide an important advancement in our understanding of how NPY acts in the VTA to control feeding behavior.NEW & NOTEWORTHY Neuropeptide-Y (NPY) has been shown to act on mesolimbic dopamine circuits to increase motivated behaviors toward food, but it is unclear exactly how NPY causes these responses. Here, we demonstrate that NPY directly inhibited a subset of ventral tegmental area (VTA) dopamine neurons through the activation of G protein-coupled inwardly rectifying potassium currents, and it inhibited both excitatory postsynaptic currents and inhibitory postsynaptic currents onto subsets of dopamine neurons through a presynaptic mechanism. Thus NPY uses multiple mechanisms to dynamically control VTA dopamine neuron activity.

Development of ghrelin resistance in a cancer cachexia rat model using human gastric cancer-derived 85As2 cells and the palliative effects of the Kampo medicine rikkunshito on the model.

Cancer cachexia (CC) is a multifactorial disease characterized by decreased food intake and loss of body weight due to reduced musculature with or without loss of fat mass. Patients with gastric cancer have a high incidence of cachexia. We previously established a novel CC rat model induced by human gastric cancer-derived 85As2 cells in order to examine the pathophysiology of CC and identify potential therapeutics. In patients with CC, anorexia is often observed, despite elevation of ghrelin, suggesting that ghrelin resistance may develop in these patients. In this study, we aimed to clarify the occurrence of ghrelin resistance in CC rats accompanied by anorexia and we investigated whether rikkunshito (RKT), a traditional Japanese Kampo medicine that potentiates ghrelin signaling, ameliorated CC-related anorexia through alleviation of ghrelin resistance. 85As2-tumor-bearing rats developed severe CC symptoms, including anorexia and loss of body weight/musculature, with the latter symptoms being greater in cachectic rats than in non-tumor-bearing or pair-fed rats. CC rats showed poor responses to intraperitoneal injection of ghrelin. In CC rats, plasma ghrelin levels were elevated and hypothalamic anorexigenic peptide mRNA levels were decreased, whereas hypothalamic growth hormone secretagogue receptor (GHS-R) mRNA was not affected. In vitro, RKT directly enhanced ghrelin-induced GHS-R activation. RKT administrated orally for 7 days partly alleviated the poor response to ghrelin and ameliorated anorexia without affecting the elevation of plasma ghrelin levels in CC rats. The expression of hypothalamic orexigenic neuropeptide Y mRNA but not hypothalamic GHS-R mRNA was increased by RKT. Thus, the 85As2 cell-induced CC rat model developed ghrelin resistance, possibly contributing to anorexia and body weight loss. The mechanism through which RKT ameliorated anorexia in the CC rat model may involve alleviation of ghrelin resistance by enhancement of ghrelin signaling. These findings suggest that RKT may be a promising agent for the treatment of CC.