1,5-Anhydro-D-Fructose Exhibits Satiety Effects via the Activation of Oxytocin Neurons in the Paraventricular Nucleus.

1,5-Anhydro-D-fructose (1,5-AF) is a bioactive monosaccharide that is produced by the glycogenolysis in mammalians and is metabolized to 1,5-anhydro-D-glucitol (1,5-AG). 1,5-AG is used as a marker of glycemic control in diabetes patients. 1,5-AF has a variety of physiological activities, but its effects on energy metabolism, including feeding behavior, are unclarified. The present study examined whether 1,5-AF possesses the effect of satiety. Peroral administration of 1,5-AF, and not of 1,5-AG, suppressed daily food intake. Intracerebroventricular (ICV) administration of 1,5-AF also suppressed feeding. To investigate the neurons targeted by 1,5-AF, we investigated c-Fos expression in the hypothalamus and brain stem. ICV injection of 1,5-AF significantly increased c-Fos positive oxytocin neurons and mRNA expression of oxytocin in the paraventricular nucleus (PVN). Moreover, 1,5-AF increased cytosolic Ca2+ concentration of oxytocin neurons in the PVN. Furthermore, the satiety effect of 1,5-AF was abolished in oxytocin knockout mice. These findings reveal that 1,5-AF activates PVN oxytocin neurons to suppress feeding, indicating its potential as the energy storage monitoring messenger to the hypothalamus for integrative regulation of energy metabolism.

Andaliman (Zanthoxylum acanthopodium DC.) fruit ethanolic extract exerts attenuative effect on hyperglycemia, sensory and motoric function's disorders in alloxan-induced diabetic mice.

Objective: Andaliman (Zanthoxylum acanthopodium) is a potent medicinal plant in Asia. This present study aimed to reveal the effectivity of Andaliman fruit extract in alleviating hyperglycemia, sensory and motoric balance disorders, histopathology of the cerebellum, and tissue oxidative stress in diabetic mice induced by alloxan. Materials and Methods: Diabetes induction was performed by intraperitoneally injecting alloxan monohydrate [200 mg/kg body weight (BW)]. Subsequently, the mice were treated daily with an ethanolic extract of Andaliman fruit (0, 150, 300, 450 mg/kg BW per oral) for 28 days, followed by measurements of blood glucose, paw sensitivity, motoric balance, histopathology of the cerebellum, and malondialdehyde (MDA) levels. Moreover, the phytochemical constituents of the extract were elucidated by liquid chromatography. Results: Higher doses of Andaliman fruit extract could significantly attenuate the elevation of random and fasting blood glucose (p < 0.05) and improve paw sensitivity responses (p < 0.05) and motoric balances (p < 0.05) in diabetic mice. Moreover, Andaliman fruit extract could significantly attenuate the degeneration of cerebellar Purkinje cells (p < 0.05) and suppress MDA levels in the blood (p < 0.05) while blunting the MDA in the brain tissue (p < 0.05). Phytochemical screening revealed 39 compounds in the Andaliman extract belonging to the groups of alkaloids (26 compounds), flavonoids (12 compounds), and terpenoids (1 compound). Conclusion: The ethanolic extract of Andaliman fruit is capable of ameliorating diabetic neuropathy, motor balance disorders, and Purkinje cell degeneration while also reducing oxidative stress in the peripheral system. Hence, Andaliman extract is a promising candidate for formulation as an herbal remedy against the detrimental outcomes of diabetes mellitus.

Extracted yam bean (Pachyrhizus erosus (L.) Urb.) fiber counteracts adiposity, insulin resistance, and inflammation while modulating gut microbiota composition in mice fed with a high-fat diet.

Background and purpose: Yam bean (Pachyrhizus erosus) is a potent medicinal plant exerting therapeutical effects against diseases. However, investigations on the health benefits of its fiber remain limited. This study aimed to investigate the potential of yam bean fiber (YBF) against a high-fat diet (HFD)-induced metabolic diseases, inflammation, and gut dysbiosis. Experimental approach: Adult male mice were assigned to four groups (8 each), namely a normal diet-fed group (ND), HFD-fed group, and HFD supplemented with YBF groups (HFD + YBF) at a dose of 2.5% and 10%, respectively. Treatments were implemented for ten weeks. Thereafter, indicators of metabolic diseases, oxidative stress, inflammation, and gut microbiota composition were determined. Findings / Results: A dosage of 10% YBF significantly inhibited excessive body weight gain (2.3 times lower than HFD group) and white adipose tissue (WAT) mass (2.2 times lower than HFD group) while sustaining brown adipose tissue mass. YBF prevented malondialdehyde elevation, catalase activity reduction, and expression of the interleukin-6 increment (2.7 times lower than the HFD group) within the WAT. Furthermore, YBF sustained normoglycaemia, glucose tolerance, and insulin sensitivity while precluding hyperinsulinemia. YBF modulated the gut microbiota community by increasing health-promoting microbiota including Lactobacillus reuteri, L. johnsonii, and inhibiting a pathogenic Mucispirillum sp. YBF prevented histopathology and inflammation of the colon. Conclusion and implications: YBF at the dose of 10% is proved to be useful in the prevention of diet-induced metabolic diseases, microbiota dysbiosis, and inflammation. Hence, YBF is recommended as a potential natural-based remedy to diminish the detrimental effects of high-fat foods.

Jicama (Pachyrhizus erosus) fiber prevents excessive blood glucose and body weight increase without affecting food intake in mice fed with high-sugar diet.

OBJECTIVE: Jicama (Pachyrhizus erosus) fiber has been documented to exert an immunomodulatory effect both in vitro and in vivo. However, its beneficial effect against metabolic syndrome remains unknown. This study aimed to reveal whether the jicama fiber (JF) could prevent the development of diabetes and obesity caused by a high-sugar diet (HSD). MATERIALS AND METHODS: The JF was isolated from its tuberous part and subsequently used as a supplemental diet for adult male Bagg and Albino (BALB)/c mice fed with a HSD. Four different diet paradigms including normal diet, HSD (30% sucrose), and HSD in combination with 10% and 25% of JF, respectively, were deployed continuously for 8 weeks. Furthermore, the blood glucose level, glucose tolerance, body weight, food and water consumption as well as epididymal white adipose tissue (WAT) and interscapular brown adipose tissue (BAT) mass were determined. RESULTS: Our results revealed that supplementation of 25% JF could significantly prevent the blood glucose increase, excessive body weight gain, and glucose intolerance in mice fed with HSD. Moreover, 10% and 25% JF blunted the HSD-induced WAT mass gain but failed to counteract the depletion of BAT mass. Furthermore, the fiber supplementation elicited a minimum effect on rhythm and total food and water intake. CONCLUSION: The JF could effectively sustain blood glucose homeostasis as well as improve body weight and WAT mass profile against the development of diabetes and obesity caused by HSD.

Suprachiasmatic vasopressin to paraventricular oxytocin neurocircuit in the hypothalamus relays light reception to inhibit feeding behavior.

Light synchronizes the body's circadian rhythms by modulating the master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. In modern lifestyles that run counter to normal circadian rhythms, the extended and/or irregular light exposure impairs circadian rhythms and, consequently, promotes feeding and metabolic disorders. However, the neuronal pathway through which light is coupled to feeding behavior is less elucidated. The present study employed the light exposure during the dark phase of the day in rats and observed its effect on neuronal activity and feeding behavior. Light exposure acutely suppressed food intake and elevated c-Fos expression in the AVP neurons of SCN and the oxytocin (Oxt) neurons of paraventricular nucleus (PVN) in the hypothalamus. The light-induced suppression of food intake was abolished by blockade of the Oxt receptor in the brain. Retrograde tracer analysis demonstrated the projection of SCN AVP neurons to the PVN. Furthermore, intracerebroventricular injection of AVP suppressed food intake and increased c-Fos in PVN Oxt neurons. Intra-PVN injection of AVP exerted a stronger anorexigenic effect than intracerebroventriclar injection. AVP also induced intracellular Ca2+ signaling and increased firing frequency in Oxt neurons in PVN slices. These results reveal the novel neurocircuit from SCN AVP to PVN Oxt that relays light reception to inhibition of feeding behavior. This light-induced neurocircuit may serve as a pathway for forming the circadian feeding rhythm and linking irregular light exposure to arrhythmic feeding and, consequently, obesity and metabolic diseases.

Fibroblast growth factor 21, assisted by elevated glucose, activates paraventricular nucleus NUCB2/Nesfatin-1 neurons to produce satiety under fed states.

Fibroblast growth factor 21 (FGF21), liver-derived hormone, exerts diverse metabolic effects, being considered for clinical application to treat obesity and diabetes. However, its anorexigenic effect is debatable and whether it involves the central mechanism remains unclarified. Moreover, the neuron mediating FGF21's anorexigenic effect and the systemic energy state supporting it are unclear. We explored the target neuron and fed/fasted state dependence of FGF21's anorexigenic action. Intracerebroventricular (ICV) injection of FGF21 markedly suppressed food intake in fed mice with elevated blood glucose. FGF21 induced c-Fos expression preferentially in hypothalamic paraventricular nucleus (PVN), and increased mRNA expression selectively for nucleobindin 2/nesfatin-1 (NUCB2/Nesf-1). FGF21 at elevated glucose increased [Ca2+]i in PVN NUCB2/Nesf-1 neurons. FGF21 failed to suppress food intake in PVN-preferential Sim1-Nucb2-KO mice. These findings reveal that FGF21, assisted by elevated glucose, activates PVN NUCB2/Nesf-1 neurons to suppress feeding under fed states, serving as the glycemia-monitoring messenger of liver-hypothalamic network for integrative regulation of energy and glucose metabolism.

Paraventricular NUCB2/Nesfatin-1 Supports Oxytocin and Vasopressin Neurons to Control Feeding Behavior and Fluid Balance in Male Mice.

Nesfatin-1, derived from nucleobindin-2 (NUCB2), is expressed in the hypothalamus, including the paraventricular nucleus (PVN), an integrative center for energy homeostasis. However, precise role of the NUCB2/nesfatin-1 in PVN remains less defined. The present study aimed to clarify physiological and/or pathophysiological roles of endogenous NUCB2/nesfatin-1 in PVN by using adeno-associated virus vectors encoding short hairpin RNAs targeting NUCB2 in mice. PVN-specific NUCB2 knockdown primarily increased food intake and decreased plasma oxytocin level specifically in light phase, leading to increased body weight gain without affecting energy expenditure. Furthermore, high-salt diet increased the systolic blood pressure, plasma arginine vasopressin (AVP) and AVP mRNA expression in PVN, and all these changes were blunted by PVN-specific NUCB2 knockdown. These results reveal that the endogenous NUCB2/nesfatin-1 in PVN regulates PVN AVP and oxytocin and consequently the fluid and energy balance.

Central action of ELABELA reduces food intake and activates arginine vasopressin and corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus.

ELABELA (ELA) is a novel hormone consisting of 32 amino acid peptides found in humans as well as other vertebrates and is considered to play an important role in the circulatory system through the apelin receptor (APJ). However, whether ELA also acts in the central nervous system remains unknown. Here, we show that ELA functions as an anorexigenic hormone in adult mouse brain. An intracerebroventricular injection of ELA reduces food intake and activates arginine vasopressin (AVP) and corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN), a hypothalamic region that regulates food intake. Cytosolic calcium ([Ca]i) measurement shows that ELA dose dependently increases [Ca]i in single AVP and CRH-immunoreactive neurons isolated from the PVN. Our data suggest that ELA functions as an anorexigenic hormone through activation of AVP and CRH neurons in the PVN.

Arcuate Na+,K+-ATPase senses systemic energy states and regulates feeding behavior through glucose-inhibited neurons.

Feeding is regulated by perception in the hypothalamus, particularly the first-order arcuate nucleus (ARC) neurons, of the body's energy state. However, the cellular device for converting energy states to the activity of critical neurons in ARC is less defined. We here show that Na(+),K(+)-ATPase (NKA) in ARC senses energy states to regulate feeding. Fasting-induced systemic ghrelin rise and glucose lowering reduced ATP-hydrolyzing activity of NKA and its substrate ATP level, respectively, preferentially in ARC. Lowering glucose concentration (LG), which mimics fasting, decreased intracellular NAD(P)H and increased Na(+) concentration in single ARC neurons that subsequently exhibited [Ca(2+)]i responses to LG, showing that they were glucose-inhibited (GI) neurons. Third ventricular injection of the NKA inhibitor ouabain induced c-Fos expression in agouti-related protein (AgRP) neurons in ARC and evoked neuropeptide Y (NPY)-dependent feeding. When injected focally into ARC, ouabain stimulated feeding and mRNA expressions for NPY and AgRP. Ouabain increased [Ca(2+)]i in single NPY/AgRP neurons with greater amplitude than in proopiomelanocortin neurons in ARC. Conversely, the specific NKA activator SSA412 suppressed fasting-induced feeding and LG-induced [Ca(2+)]i increases in ARC GI neurons. NPY/AgRP neurons highly expressed NKAα3, whose knockdown impaired feeding behavior. These results demonstrate that fasting, via ghrelin rise and LG, suppresses NKA enzyme/pump activity in ARC and thereby promotes the activation of GI neurons and NPY/AgRP-dependent feeding. This study identifies ARC NKA as a hypothalamic sensor and converter of metabolic states to key neuronal activity and feeding behaviour, providing a new target to treat hyperphagic obesity and diabetes.

Nasal oxytocin administration reduces food intake without affecting locomotor activity and glycemia with c-Fos induction in limited brain areas.

Recent studies have considered oxytocin (Oxt) as a possible medicine to treat obesity and hyperphagia. To find the effective and safe route for Oxt treatment, we compared the effects of its nasal and intraperitoneal (IP) administration on food intake, locomotor activity, and glucose tolerance in mice. Nasal Oxt administration decreased food intake without altering locomotor activity and increased the number of c-Fos-immunoreactive (ir) neurons in the paraventricular nucleus (PVN) of the hypothalamus, the area postrema (AP), and the dorsal motor nucleus of vagus (DMNV) of the medulla. IP Oxt administration decreased food intake and locomotor activity and increased the number of c-Fos-ir neurons not only in the PVN, AP, and DMNV but also in the nucleus of solitary tract of the medulla and in the arcuate nucleus of the hypothalamus. In IP glucose tolerance tests, IP Oxt injection attenuated the rise of blood glucose, whereas neither nasal nor intracerebroventricular Oxt affected blood glucose. In isolated islets, Oxt administration potentiated glucose-induced insulin secretion. These results indicate that both nasal and IP Oxt injections reduce food intake to a similar extent and increase the number of c-Fos-ir neurons in common brain regions. IP Oxt administration, in addition, activates broader brain regions, reduces locomotor activity, and affects glucose tolerance possibly by promoting insulin secretion from pancreatic islets. In comparison with IP administration, the nasal route of Oxt administration could exert a similar anorexigenic effect with a lesser effect on peripheral organs.

Oxytocinergic circuit from paraventricular and supraoptic nuclei to arcuate POMC neurons in hypothalamus.

Intracerebroventricular injection of oxytocin (Oxt), a neuropeptide produced in hypothalamic paraventricular (PVN) and supraoptic nuclei (SON), melanocortin-dependently suppresses feeding. However, the underlying neuronal pathway is unclear. This study aimed to determine whether Oxt regulates propiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus. Intra-ARC injection of Oxt decreased food intake. Oxt increased cytosolic Ca(2+) in POMC neurons isolated from ARC. ARC POMC neurons expressed Oxt receptors and were contacted by Oxt terminals. Retrograde tracer study revealed the projection of PVN and SON Oxt neurons to ARC. These results demonstrate the novel oxytocinergic signaling from PVN/SON to ARC POMC, possibly regulating feeding.

Hexosamine pathway but not interstitial changes mediates glucotoxicity in pancreatic ß-cells as assessed by cytosolic Ca2+ response to glucose.

Hyperglycemia impairs insulin secretion as well as insulin action, being recognized as the glucotoxicity that accelerates diabetes. However, the mechanism underlying the glucotoxicity in pancreatic ß-cells is not thoroughly understood. Hyperglycemia alters glucose metabolism within ß-cells and interstitial conditions around ß-cells, including elevated osmolarity and increased concentrations of insulin and ATP released from overstimulated ß-cells. In this study, to explore direct effects of these alterations on ß-cells, single ß-cells isolated from rat islets were cultured for 3 days with high (22.3 mM) glucose (HG), compared with control 5.6 mM glucose, followed by their functional assessment by measuring cytosolic Ca2+ concentration ([Ca2+]i). The [Ca2+]i response to a physiological rise in glucose concentration to 8.3 mM was impaired in b-cells following culture with HG for 3 days, while it was preserved in ß-cells following culture with non-metabolizable L-glucose and with elevated osmolarity, insulin and ATP. This HG-induced impairment of [Ca2+]i response to 8.3 mM glucose was prevented by adding azaserine, a hexosamine pathway inhibitor, into HG culture. Conversely, culture with glucosamine, which increases the hexosamine pathway flux, impaired [Ca2+]i response to 8.3 mM glucose, mimicking HG. These results suggest that the HG-associated abnormal glucose metabolism through hexosamine pathway, but not elevated osmolarity, insulin and ATP, plays a major role in the glucotoxicity to impair the secretory function of pancreatic ß-cells.

Chronic phencyclidine treatment induces long-lasting glutamatergic activation of VTA dopamine neurons.

Use of phencyclidine (PCP) can mimic some aspects of schizophrenia. However, the underlying mechanism is unclear. Administration of PCP is known to activate mesolimbic dopamine pathway. In this study, we focused on ventral tegmental area (VTA) of mesolimbic dopamine pathway as target of PCP for inducing schizophrenia-like symptoms. Single VTA neuron was isolated and its neural activity was monitored by measuring cytosolic Ca(2+) concentration ([Ca(2+)]i) followed by immunocytochemical identification of dopamine neurons. Administration of glutamate increased [Ca(2+)]i in dopamine neurons from control rats, and the [Ca(2+)]i increase was inhibited in the presence of PCP. In contrast, in VTA dopamine neurons from rats chronically treated with PCP for 7 days, administration of glutamate was able to induce [Ca(2+)]i increase in the presence of PCP. Furthermore, this glutamate-induced [Ca(2+)]i increase in the presence of PCP continued even after washout of glutamate and this effect lasted as long as PCP was present. This long-lasting glutamate-induced [Ca(2+)]i increase in the presence of PCP was not observed or significantly attenuated under Ca(2+) free condition and by N-type Ca(2+) channel blocker ω-conotoxin. The results indicate that chronic treatment with PCP reverses the acute PCP effect on VTA dopamine neurons from inhibitory to stimulatory tone, and consequently induces long-lasting activation of dopamine neurons by glutamate.