Gαi/o-coupled Htr2c in the paraventricular nucleus of the hypothalamus antagonizes the anorectic effect of serotonin agents.

The anorexigenic effect of serotonergic compounds has largely been attributed to activation of serotonin 2C receptors (Htr2cs). Using mouse genetic models in which Htr2c can be selectively deleted or restored (in Htr2c-null mice), we investigate the role of Htr2c in forebrain Sim1 neurons. Unexpectedly, we find that Htr2c acts in these neurons to promote food intake and counteract the anorectic effect of serotonergic appetite suppressants. Furthermore, Htr2c marks a subset of Sim1 neurons in the paraventricular nucleus of the hypothalamus (PVH). Chemogenetic activation of these neurons in adult mice suppresses hunger, whereas their silencing promotes feeding. In support of an orexigenic role of PVH Htr2c, whole-cell patch-clamp experiments demonstrate that activation of Htr2c inhibits PVH neurons. Intriguingly, this inhibition is due to Gαi/o-dependent activation of ATP-sensitive K+ conductance, a mechanism of action not identified previously in the mammalian nervous system.

Medicinal Plants and Natural Products: More Effective and Safer Pharmacological Treatment for the Management of Obesity.

Obesity is a major lifestyle disorder, and it is correlated with several ailments. The prevalence of obesity has elevated over the years, and it has become a global health problem. The drugs presently used for managing obesity have several side effects, such as diarrhea, leakage of oily stools, etc. On the contrary, herbal plants and natural products are considered safe for use because they have lesser side effects. New compounds isolated from medicinal plants are screened and identified to determine their effectiveness and potential in preventing abnormal weight gain. In this review, the medicinal plants and natural materials are surveyed across the literature to cover those that have the potential for managing and controlling weight gain. Furthermore, their mechanism of action, active components, and experimental methodologies are also reviewed. These herbal products can be developed as formulations for therapeutic use in obesity. The herbal plants mentioned in the review are classified based on their mechanism of action, inhibition of pancreatic lipase, and appetite suppression activities. The ability to inhibit pancreatic lipase enzyme has been used to determine the effectiveness of herbal products for the prevention of abnormal weight gain because of its action on dietary fat and suppression of appetite. This review is an attempt to summarize the herbal plants and natural products that can be used to develop formulations effective in controlling weight gain and obesity.

Therapeutic effects of Gambi-jung for the treatment of obesity.

Obesity is known as metabolic syndrome and it affects many tissues including adipose tissue, liver, and central nervous system (CVS). Gambi-jung (GBJ) is a modified prescription of Taeumjowi-tang (TJT), which has been used to treat obesity in Korea. GBJ is composed of 90% Ephedra sinica Stapf (ES). Therefore, the present study was designed to assess the antiobesity effects of GBJ and to compare the effects of GBJ and ES on obesity. GBJ administration remarkably reduced the body weight, Body mass index (BMI), and body fat percentage compared to the ES administration in human subjects. GBJ-treated mice had lower white adipose tissue (WAT) amounts than ES-treated mice. GBJ and ES administration enhanced adenosine monophosphate-activated protein kinase (AMPK) expression in 3T3-L1 adipocytes, epididymal WAT and liver of HFD-induced obese mice. Moreover, GBJ and ES reduced food intake by suppressing the mRNA levels of orexigenic peptides, agouti-related protein (AgRP) and neuropeptide-Y (NPY), as well as AMPK in the brain of HFD-induced obese mice. Furthermore, GBJ-treated mice had dramatically lower expression of macrophage marker F4/80 in epididymal WAT than those of ES-treated mice. Based on these results, we suggest the use of GBJ as a natural drug to control weight gain.

The effect of an orally-dosed Caralluma Fimbriata extract on appetite control and body composition in overweight adults.

To examine the effect of a Caralluma Fimbriata extract (CFE) on biomarkers of satiety and body composition in overweight adults. A double-blind, randomised, placebo controlled trial to examine the effect of a Caralluma Fimbriata extract (CFE) on biomarkers of satiety and body composition in overweight adults. Eighty-three men and women aged between 20 and 50 years of age completed 16 weeks of daily supplementation with either CFE or placebo. Plasma cardiometabolic (lipid profile, glucose, insulin) and satiety (ghrelin, leptin, neuropeptideY) biomarkers, body composition, diet history and gastrointenstinal function were assessed at baseline, weeks 4, 8, 12 and 16. Subjects in the CFE and placebo groups were well matched and predominatly female 93% and 87.5%, with a mean age of 40.9 ± 6.7 and 39.5 ± 7.5 years and body mass index (BMI) of 30.0 ± 3.1 and 30.2 ± 2.9 kg/m2 respectively. There was a significant difference in plasma leptin concentration change between groups at week 16 (p = 0.04), with the placebo group increasing concentration (2.27 ± 4.80 ng/mL) while the CFE group (0.05 ± 4.69 ng/mL) remained the same. At week 16, the CFE group had significantly reduced their calorie intake from baseline compared to the placebo group (245 cal vs 15.8 cal respectively p < 0.01). The CFE group also had a significant reduction in waist circumference of 2.7 cm compared to an increase of 0.3 cm in the placebo group (p = 0.02). A weight increase from baseline was seen in the placebo group that was not observed in the CFE group (1.33 kg weight gain vs 0.37 kg weight loss respectively; p = 0.03). The placebo group also had a significant increase in fat mass, android fat mass, BMI and leptin compared to the CFE group (p = 0.04, 0.02, < 0.01 respectively). CFE was effective at maintaining bodyweight during a non-calorie controlled diet compared to a placebo. The mechanism responsible for this action is requiring further research and could be due to an increase in satiety receptor sensitivity.

Fenugreek Cultivation with Emphasis on Historical Aspects and its uses in Traditional Medicine and Modern Pharmaceutical Science.

Fenugreek (Trigonella foenum-graecum L.) is a native plant found in the parts of Iran to the North of India, and is presently planted also in other regions of the world. Fenugreek is considered a notable multipurpose medicinal and traditional herb in Iran, India, and China for several centuries. The most important components of fenugreek seeds are protein, neutral detergent fiber, gum, lipids, moisture, ash and starch. Fenugreek seeds and leaves are anti-cholesterolemic, anti-tumor, antiinflammatory, carminative, demulcent, deobstruent, emollient, expectorant, galactogogue, febrifuge, laxative, hypoglycaemic, restorative, parasiticide and uterine tonic and useful in burning sensation. Traditionally, fenugreek seeds being used worldwide are beneficial for bone and muscles, respiratory system, gastro-intestinal system, female reproductive system, cardio-vascular system, endocrinology and hepatic. Fenugreek helps reduce cholesterol, reduce cardiovascular risk, control diabetes, a good consolation for sore throats, a remedy for acid reflux, constipation, colon cancer prevention, appropriate for kidney trouble, skin infection, increase milk production, reduce menstrual discomfort, and reduce menopause symptoms. It is also an appetite suppressant that helps in weight loss. Both modern science and traditional medicine integration with novel technologies and discoveries will secure the cultivation of medicinal herbs and promote sustainability in the long-term and a wide-range.

Decreased sensitivity to the anorectic effects of leptin in mice that lack a Pomc-specific neural enhancer.

Enhancer redundancy has been postulated to provide a buffer for gene expression against genetic and environmental perturbations. While work in Drosophila has identified functionally overlapping enhancers, work in mammalian models has been limited. Recently, we have identified two partially redundant enhancers, nPE1 and nPE2, that drive proopiomelanocortin gene expression in the hypothalamus. Here we demonstrate that deletion of nPE1 produces mild obesity while knockout of nPE2 has no discernible metabolic phenotypes. Additionally, we show that acute leptin administration has significant effects on nPE1 knockout mice, with food intake and body weight change significantly impacted by peripheral leptin treatment. nPE1 knockout mice became less responsive to leptin treatment over time as percent body weight change increased over 2 week exposure to peripheral leptin. Both Pomc and Agrp mRNA were not differentially affected by chronic leptin treatment however we did see a decrease in Pomc and Agrp mRNA in both nPE1 and nPE2 knockout calorie restricted mice as compared to calorie restricted PBS-treated WT mice. Collectively, these data suggest dynamic regulation of Pomc by nPE1 such that mice with nPE1 knockout become less responsive to the anorectic effects of leptin treatment over time. Our results also support our earlier findings in which nPE2 may only be critical in adult mice that lack nPE1, indicating that these neural enhancers work synergistically to influence metabolism.

A Novel Synthetic Interfering Peptide Tat-3L4F Attenuates Olanzapine-Induced Weight Gain Through Disrupting Crosstalk Between Serotonin Receptor 2C and Protein Phosphatase and Tensin Homolog in Rats.

BACKGROUND: Accompanied with profound efficacy, atypical antipsychotics (AAPs) contribute to metabolic adverse effects with few effective strategies to attenuate. Serotonin 5-HT2C receptor (HTR2C) plays a critical role in hyperphagia and weight gain induced by AAPs, and expression of phosphatase tensin homolog (PTEN) in the hypothalamus also affects feeding behavior and weight change. Moreover, PTEN has a physical crosstalk between PTEN and a region in the third intracellular loop (3L4F) of the HTR2C. Tat-3L4F has the property to disrupt crosstalk between PTEN and HTR2C. This is the first study to our knowledge to investigate the effect of Tat-3L4F on olanzapine-induced metabolic abnormalities and PTEN/ phosphatidylinositol 3-kinase/protein kinase B expression in the hypothalamus in rats. METHODS: The effects of Tat-3L4F were investigated through measuring body weight, food intake, and blood glucose. In addition, PTEN/phosphatidylinositol 3-kinase/protein kinase B level in the hypothalamus was detected by immunofluorescence assay and western blot. Metabolites in the liver tissue were detected by liquid chromatography-mass spectrometry and analyzed by multivariate analyses and pairwise comparison. RESULTS: Our results showed that hyperphagia and weight gain were evident in the olanzapine alone-fed rats but was attenuated after Tat-3L4F treatment. In addition, oral glucose tolerance test indicated blood glucose at 120 minutes was higher in the olanzapine alone-treated group than in groups treated with vehicle and olanzapine + Tat-3L4F (10 µmol kg-1 per day). Furthermore, compared with olanzapine alone treatment, treatment with Tat-3L4F (10 µmol kg-1 per day) significantly inhibited PTEN expression in the hypothalamus. The olanzapine alone-treated group had the highest bile acid level, followed by the olanzapine with Tat-3L4F (1 µmol kg-1) group, olanzapine with Tat-3L4F (10 µmol kg-1) group, and vehicle group. CONCLUSIONS: Our present results reveal that Tat-3L4F is a potential pharmacological strategy for suppressing hyperphagia and weight gain induced by olanzapine, which acts through disrupting crosstalk between HTR2C and PTEN as a result of PTEN downregulation in the hypothalamus.

Dietary daidzein decreases food intake accompanied with delayed gastric emptying in ovariectomized rats.

We previously found that equol, a metabolite of intestinal bacterial conversion from soy isoflavone daidzein, has female-specific anorectic effects. In the present study, we used seven-week-old female ovariectomized (OVX) Sprague Dawley rats to test the hypothesis that the anorectic effect of dietary daidzein may be attributed to delayed gastric emptying. Results suggest that dietary daidzein delays gastric emptying and that it has an anorectic effect with residual gastric contents, but not without gastric contents. Dietary equol significantly decreased daily food intake in the OVX rats without sleeve gastrectomy, but not in those with sleeve gastrectomy, suggesting that the accumulation of food in the stomach is required for the anorectic effect of equol to occur. These results support the hypothesis that the anorectic effect of dietary daidzein is attributed to delayed gastric emptying.

Hypophagic and weight reducing effect of Momardica charinta fruit by Enhancing 5-HT neurotransmitter in rats brain.

Momardica charint seed as vegetable and folk medicine in Pakistan, India, China, Bangladesh and other Asian countries Momardica charinta also known as Kerala, bittergourd ,balsam pear. It possesses many biological active constituents including glycosides, saponins, phenolic and flavonoids compound, protein, triterpenes, steroid, saponins, alkaloid. It also contain thiamine ,beta carotene, folate, riboflavin, calcium, iron, potassium, zinc and fiber. Several studies have been done to show medicinal importance of its fruit which has different biological functions such as anti-diabetes antihypertension, antiviral, antibacterial and antifungal infection, anti-tumorous as well as anti-carcinogenic effects. The present research is big contribution of Momardicacharinta activity as weight reducing plant through serotonergic neurotransmitter Decrease in body weight and food intake might be due to increased concentration of serotonin in their respective receptors in brain, which produce hypophagic effect in rats treated with water extract of Momardicacharinttia. More animal and human trials needed to confirm, the safety and antiobesity effect of MC and the role of neurotransmitter involve in reduction of body weight.

Methyl Donor Deficiency during Gestation and Lactation in the Rat Affects the Expression of Neuropeptides and Related Receptors in the Hypothalamus.

The micronutrients vitamins B9 and B12 act as methyl donors in the one-carbon metabolism involved in transmethylation reactions which critically influence epigenetic mechanisms and gene expression. Both vitamins are essential for proper development, and their deficiency during pregnancy has been associated with a wide range of disorders, including persisting growth retardation. Energy homeostasis and feeding are centrally regulated by the hypothalamus which integrates peripheral signals and acts through several orexigenic and anorexigenic mediators. We studied this regulating system in a rat model of methyl donor deficiency during gestation and lactation. At weaning, a predominance of the anorexigenic pathway was observed in deficient pups, with increased plasma peptide YY and increased hypothalamic pro-opiomelanocortin (POMC) mRNA, in line with abnormal leptin, ghrelin, and insulin secretion and/or signaling during critical periods of fetal and/or postnatal development of the hypothalamus. These results suggest that early methyl donor deficiency can affect the development and function of energy balance circuits, resulting in growth and weight deficits. Maternal administration of folic acid (3 mg/kg/day) during the perinatal period tended to rectify peripheral metabolic signaling and central neuropeptide and receptor expression, leading to reduced growth retardation.

The anorexigenic effect of neuropeptide K in chicks involves the paraventricular nucleus and arcuate nucleus of the hypothalamus.

Neuropeptide K (NPK) induces satiety in birds and mammals. We demonstrated that in birds this effect was associated with the hypothalamus, but beyond this little is known in any species regarding the central mechanism of action. Thus, this study was designed to identify hypothalamic molecular mechanisms associated with the food intake-inhibiting effects of NPK in chicks. In Experiment 1, intracerebroventricular (ICV) injection of 1.0 and 3.0 nmol of NPK reduced food intake and we identified an effective dose for microinjection. In Experiment 2, food intake was reduced when NPK was microinjected into the PVN. In Experiment 3, whole hypothalamus was collected from chicks at 1 h post-ICV NPK injection. The abundance of corticotropin-releasing factor (CRF) and agouti-related peptide (AgRP) mRNA was reduced in NPK-injected chicks. In Experiment 4, within the isolated paraventricular nucleus (PVN) there was less CRF mRNA, and within the arcuate nucleus (ARC) there was less AgRP mRNA, in NPK- than vehicle-treated chicks at 1 h post-injection. We conclude that there are first order neurons for NPK that reside within the PVN, and the anorexigenic effect of NPK is associated with a decrease in AgRP in the ARC.

Mannan Oligosaccharide Suppresses Lipid Accumulation and Appetite in Western-Diet-Induced Obese Mice Via Reshaping Gut Microbiome and Enhancing Short-Chain Fatty Acids Production.

SCOPE: Obesity is associated with gut microbiome dysbiosis. Mannose oligosaccharide (MOS) has been reported to be a potential prebiotic. The present study is aimed to determine the effects of MOS on western-diet-induced obesity and to uncover the mediating roles of the gut microbiota and microbial metabolites. METHODS AND RESULTS: Three-month-old male ICR mice are fed with a high-fat and high-fructose diet for 8 weeks. The diet-induced obese mice are then orally administrated with MOS (100 and 200 mg kg-1  d-1 ) for 4 weeks. MOS significantly reduces bodyweight gain, insulin resistance, fatty liver, and inflammatory responses in obese mice. MOS also stimulates lipolysis and inhibits lipogenesis in the adipose tissues. Moreover, MOS restructures the gut microbiome by enhancing the abundance of Bifidobacterium and Lactobacillus in obese mice. The microbial metabolite SCFAs are also increased in the feces and serum. Correlation analysis indicates that the appetite suppression and lipid-lowering effects of MOS are highly correlated with the butyrate levels. CONCLUSION: MOS suppresses the appetite, which results in less lipid deposition. The lower appetite is likely due to an altered gut microbiome and elevated SCFAs production. MOS may be a potential nutraceutical used in body weight management and gut health improvement.

Proanthocyanidins Limit Adipose Accrual Induced by a Cafeteria Diet, Several Weeks after the End of the Treatment.

A dose of proanthocyanidins with satiating properties proved to be able to limit body weight increase several weeks after administration under exposure to a cafeteria diet. Here we describe some of the molecular targets and the duration of the effects. We treated rats with 500 mg grape seed proanthocyanidin extract (GSPE)/kg BW for ten days. Seven or seventeen weeks after the last GSPE dose, while animals were on a cafeteria diet, we used reverse transcriptase-polymerase chain reaction (RT-PCR) to measure the mRNA of the key energy metabolism enzymes from the liver, adipose depots and muscle. We found that a reduction in the expression of adipose Lpl might explain the lower amount of adipose tissue in rats seven weeks after the last GSPE dose. The liver showed increased expression of Cpt1a and Hmgs2 together with a reduction in Fasn and Dgat2. In addition, muscle showed a higher fatty oxidation (Oxct1 and Cpt1b mRNA). However, after seventeen weeks, there was a completely different gene expression pattern. At the conclusion of the study, seven weeks after the last GSPE administration there was a limitation in adipose accrual that might be mediated by an inhibition of the gene expression of the adipose tissue Lpl. Concomitantly there was an increase in fatty acid oxidation in liver and muscle.

Role of hypoxia-inducible factor-1α in regulating oxidative stress and hypothalamic neuropeptides-mediated appetite control.

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator responding to hypoxia. Amphetamine (AMPH), however, can activate HIF-1 under normoxic conditions, which is associated with the co-activation of oxidative stress. Hypothalamic neuropeptides and anti-oxidative enzymes have been found to participate in amphetamine (AMPH)-mediated appetite control. The present study examined whether HIF-1 was involved in the oxidative stress and anorectic action of AMPH. Rats were daily treated with AMPH for 4 days, and expression levels of HIF-1α, superoxide dismutase (SOD), catalase, neuropeptide Y (NPY), proopiomelanocortin (POMC), phosphatidylinositol 3-kinase (PI3K), and nuclear factor-kappaB (NF-κB) were assessed and compared. Results revealed that feeding behavior and NPY decreased, whereas HIF-1α/DNA binding activity and SOD, POMC, PI3K, and NF-κB expression levels increased in AMPH-treated rats. Further experiment revealed that intracerebroventricular (i.c.v.) pretreatment with HIF-1α inhibitor modified feeding behavior and expression levels of hypothalamic protein assessed. Another experiment revealed that pretreatment (i.c.v.) with reactive oxygen species scavenger modulated HIF-1α, NPY, POMC, PI3K, and NF-κB expression levels in AMPH-treated rats. It is suggested that HIF-1α plays a functional role in the increase of oxidative stress and the modulation of NFκB/NPY/POMC-mediated appetite control in AMPH-treated rats. These findings advance the knowledge of HIF-1α in the regulation of central dopamine agonist-mediated appetite control.

High-throughput screening for selective appetite modulators: A multibehavioral and translational drug discovery strategy.

How appetite is modulated by physiological, contextual, or pharmacological influence is still unclear. Specifically, the discovery of appetite modulators is compromised by the abundance of side effects that usually limit in vivo drug action. We set out to identify neuroactive drugs that trigger only their intended single behavioral change, which would provide great therapeutic advantages. To identify these ideal bioactive small molecules, we quantified the impact of more than 10,000 compounds on an extended series of different larval zebrafish behaviors using an in vivo imaging strategy. Known appetite-modulating drugs altered feeding and a pleiotropy of behaviors. Using this multibehavioral strategy as an active filter for behavioral side effects, we identified previously unidentified compounds that selectively increased or reduced food intake by more than 50%. The general applicability of this strategy is shown by validation in mice. Mechanistically, most candidate compounds were independent of the main neurotransmitter systems. In addition, we identified compounds with multibehavioral impact, and correlational comparison of these profiles with those of known drugs allowed for the prediction of their mechanism of action. Our results illustrate an unbiased and translational drug discovery strategy for ideal psychoactive compounds and identified selective appetite modulators in two vertebrate species.

Caralluma fimbriata extract activity involves the 5-HT2c receptor in PWS Snord116 deletion mouse model.

INTRODUCTION: In Prader-Willi syndrome (PWS), nonprotein coding small nucleolar (sno) RNAs are involved in the paternally deleted region of chromosome 15q11.2-q13, which is believed to cause the hyperphagic phenotype of PWS. Central to this is SnoRNA116. The supplement Caralluma fimbriata extract (CFE) has been shown to decrease appetite behavior in some individuals with PWS. We therefore investigated the mechanism underpinning the effect of CFE on food intake in the Snord116del mouse. Experiments utilized appetite stimulants which included a 5-hydroxytryptamine (5-HT) 2c receptor antagonist (SB242084), as the 5-HT2cR is implicated in central signaling of satiety. METHODS: After 9-week chronic CFE treatment (33 mg or 100 mg kg-1  day-1 ) or placebo, the 14-week-old Snord116del (SNO) and wild-type mice (n = 72) were rotated through intraperitoneal injections of (a) isotonic saline; (b) 400 mg/kg of 2-deoxyglucose (2DG) (glucose deprivation); (c) 100 mglkg beta-mercaptoacetate (MA), fatty acid signaling; and (d) SB242084 (a selective 5HT2cR antagonist), with 5 days between reagents. Assessments of food intake were from baseline to 4 hr, followed by immunohistochemistry of neural activity utilizing c-Fos, neuropeptide Y, and alpha-melanocyte-stimulating hormone within hypothalamic appetite pathways. RESULTS: Caralluma fimbriata extract administration decreased food intake more strongly in the SNO100CFE group with significantly stimulated food intake demonstrated during coadministration with SB242084. Though stimulatory deprivation was expected to stimulate food intake, 2DG and MA resulted in lower intake in the snord116del mice compared to the WT animals (p = <0.001). Immunohistochemical mapping of hypothalamic neural activity was consistent with the behavioral studies. CONCLUSIONS: This study identifies a role for the 5-HT2cR in CFE-induced appetite suppression and significant stimulatory feeding disruptions in the snord116del mouse model.

Resveratrol promotes the arcuate nucleus architecture remodeling to produce more anorexigenic neurons in high-fat-diet-fed mice.

OBJECTIVE: Adult hypothalamic neurogenesis has been considered a central regulator of energy balance. Resveratrol (RSV), a natural polyphenol, influences the body fat mass and reduces the amount of adipose tissue. The present study was designed to evaluate the effect of RSV on dynamic of hypothalamic neurons in a diet-induced obesity model of mice. METHODS: Apoptosis, neurogenesis, the expression of the main trophic factors, and the fate of newborn cells were evaluated in the hypothalamus of adult male C57 BL/6 J mice fed a normal diet, a high-fat (HF) diet, or an HF diet supplemented with 400 mg/kg RSV (HF + RSV) for 6 wk. RESULTS: The HF diet caused an increase in neuronal apoptosis in the hypothalamus, which coincided with an increase in the number of newborn cells in the arcuate nucleus, suggesting that compensatory mechanisms developed to overcome deleterious effects of the HF diet. Addition of RSV to the HF diet enhanced the production of newborn cells in all studied regions of the hypothalamus. These changes were paralleled by enhancement of the expression of ciliary neurotrophic factor. Interestingly, a considerable proportion of newborn cells expressed neuropeptide Y in the arcuate nucleus of the HF group, and conversely, most of them differentiated to proopiomelanocortin neurons in HF + RSV mice. CONCLUSIONS: Diets rich in fat changed hypothalamic neuronal balance toward orexigenic versus anorexigenic neurons. Administration of RSV to the HF diet reversed this balance toward generation of anorexigenic neurons. These data point to the potential for RSV in regulation of body weight, possibly via modulation of hypothalamic neurogenesis.

Role of hypothalamic leptin-LepRb signaling in NPY-CART-mediated appetite suppression in amphetamine-treated rats.

Leptin is an adipose tissue hormone which plays an important role in regulating energy homeostasis. Amphetamine (AMPH) is a drug of appetite suppressant, which exerts its effect by decreasing the expression of hypothalamic neuropeptide Y (NPY) and increasing that of cocaine- and amphetamine-regulated transcript (CART). This study investigated whether leptin, the leptin receptor (LepRb) and the signal transducer and activator of transcription-3 (STAT3) were involved in NPY/CART-mediated appetite suppression in AMPH-treated rats. Rats were given AMPH daily for four days, and changes in the levels of blood leptin and hypothalamic NPY, CART, LepRb, Janus kinases 2 (JAK2), and STAT3 were assessed and compared. During the AMPH treatment, blood leptin levels and hypothalamic NPY expression decreased, with the largest reduction observed on Day 2. By contrast, the expression of hypothalamic CART, LepRb, JAK2, and STAT3 increased, with the maximum response on Day 2. Furthermore, the binding activity of pSTAT3/DNA increased and was expressed in similar pattern to that of CART, LepRb, and JAK2. An intracerebroventricular infusion of NPY antisense 60min prior to AMPH treatment increased the levels of leptin, as well as the expression in LepRb, JAK2, and CART, whereas an infusion of STAT3 antisense decreased these levels and the expression of these parameters. The results suggest that blood leptin and hypothalamic LepRb-JAK2-STAT3 signaling involved in NPY-CART-regulated appetite suppression in AMPH-treated rats. The findings may aid understanding the role of leptin-LepRb during the treatment of anorectic drugs.

Phytochemical analysis and effects on ingestive behaviour of a Caralluma fimbriata extract.

Caralluma fimbriata Wall. is currently used as a "natural slimming" food supplement, likely due to its content in pregnane glycosides. In the present study, a commercially available Caralluma fimbriata extract (Slimaluma®; CFE, 100 mg/kg) has been evaluated for its ability to affect the ingestive behaviour in female rats, also with reference to the modulation of the brain neuropeptides NPY and ORX.The interference of CFE with α-amylase and lipase enzymes has been investigated in vitro, as possible peripheral mechanism of action. Also, the chemical composition of CFE has been assessed by NMR and spectrophotometric analysis. Results from in vivo study showed that CFE induced effects neither on blood parameters, nor on liver and gut histomorphology. Interestingly, a reduction in body weight gain with an increase in water intake and hypothalamic levels of NPY and ORX peptides were found. Phytochemical analysis, showed CFE contained about 12% of pregnane glycosides and 1.3% of polyphenols. Present results suggest possible effects of C. fimbriata on ingestive behaviour, likely mediated by central and peripheral mechanisms.