In recent years, cocaine- and amphetamine-regulated transcript (CART) has received much attention as mediators of appetite regulation in mammals. However, the involvement of CART in the feeding behavior of teleosts has not been well understood. In this study, three distinct CARTs were cloned from the Schizothorax prenanti (S. prenanti). Real-time quantitative PCR were applied to characterize the tissue distribution and appetite regulatory effects of CARTs in S. prenanti. The S. prenanti CART-1, CART-2 and CART-3 full-length cDNA sequences were 597 bp, 694 bp and 749 bp in length, encoding the peptides of 125, 120 and 104 amino acid residues, respectively. All the S. prenanti CARTs consisted of three exons and two introns. Tissue distribution analysis showed that the high mRNA levels of S. prenanti CART-1 were observed in the telencephalon and eye, followed by the hypothalamus, myelencephalon, and mesencephalon. The S. prenanti CART-2 mRNA was mainly found in the mesencephalon, hypothalamus, telencephalon and myelencephalon. The S. prenanti CART-3 mRNA was widely distributed among the tissues, with the high levels in the hypothalamus and foregut. In the periprandial experiment, all three CARTs mRNA expressions in the hypothalamus were highly elevated after a meal, suggesting that CARTs are postprandial satiety signals. In the fasting experiment, all three CARTs mRNA expressions decreased after fasting and increased after refeeding, suggesting that CARTs might be involved in regulation of appetite in the S. prenanti.

Adipose tissue patterning has a major influence on the risk of developing chronic disease. Environmental influences on both body fat patterning and appetite regulation are not fully understood. This study was performed to investigate the impact of resistant starch (RS) on adipose tissue deposition and central regulation of appetite in mice.

Recent evidence indicates that leptin regulates appetite and energy expenditure, at least in part by inhibiting serotonin synthesis and release from brainstem neurons. To demonstrate that this pathway works postnatally, we used a conditional, brainstem-specific mouse CreER(T2) driver to show that leptin signals in brainstem neurons after birth to decrease appetite by inhibiting serotonin synthesis. Cell-specific gene deletion experiments and intracerebroventricular leptin infusions reveal that serotonin signals in arcuate nuclei of the hypothalamus through the Htr1a receptor to favor food intake and that this serotonin function requires the expression of Creb, which regulates the expression of several genes affecting appetite. Accordingly, a specific antagonist of the Htr1a receptor decreases food intake in leptin-deficient but not in Htr1a(-/-) mice. Collectively, these results establish that leptin inhibition of serotonin is necessary to inhibit appetite postnatally and provide a proof of principle that selective inhibition of this pathway may be a viable option to treat appetite disorders.

Modulation of salt appetite involves interactions between the circumventricular organs (CVOs) receptive areas and inhibitory hindbrain serotonergic circuits. Recent studies provide support to the idea that the serotonin action in the lateral parabrachial nucleus (LPBN) plays an important inhibitory role in the modulation of sodium appetite. The aim of the present work was to identify the specific groups of neurons projecting to the LPBN that are activated in the course of sodium appetite regulation, and to analyze the associated endocrine response, specifically oxytocin (OT) and atrial natriuretic peptide (ANP) plasma release, since both hormones have been implicated in the regulatory response to fluid reestablishment. For this purpose we combined the detection of a retrograde transported dye, Fluorogold (FG) injected into the LPBN with the analysis of the Fos immunocytochemistry brain pattern after sodium intake induced by sodium depletion. We analyzed the Fos-FG immunoreactivity after sodium ingestion induced by peritoneal dialysis (PD). We also determined OT and ANP plasma concentration by radioimmunoassay (RIE) before and after sodium intake stimulated by PD. The present study identifies specific groups of neurons along the paraventricular nucleus, central extended amygdala, insular cortex, dorsal raphe nucleus, nucleus of the solitary tract and the CVOs that are activated during the modulation of sodium appetite and have direct connections with the LPBN. It also shows that OT and ANP are released during the course of sodium satiety and fluid reestablishment. The result of this brain network activity may enable appropriate responses that re-establish the body fluid balance after induced sodium consumption.

Obesity is rising at an alarming rate globally. Different fermentable carbohydrates have been shown to reduce obesity. The aim of the present study was to investigate if two different fermentable carbohydrates (inulin and β-glucan) exert similar effects on body composition and central appetite regulation in high fat fed mice.

Chemotherapy-induced anorexia (CIA), which may lead to severe nutrition-associated problems, is a common complication associated with anti-cancer therapies. In the present study, the anti-anorexigenic effect of electroacupuncture (EA) was explored through assessing a change in appetite-associated peptides and c-Fos expression in a rat model of cisplatin-induced anorexia. In order to identify the most effective acupuncture point, 20 male Wistar rats (divided into five groups including the normal saline control, cisplatin only control and three groups according to the acupoints stimulated) were subjected to EA for 10 min at CV12, ST36 or PC6 daily for 4 days. Subsequently, the rats received intraperitoneal injections of cisplatin (6 mg/kg) to induce CIA. Food intake and reduction in body weight gain as the anorexia-associated outcomes were assessed daily for up to 3 days after cisplatin injection, and CV12 was eventually chosen as the most effective acupoint to test the anti-anorexigenic effect of EA. Furthermore, food intake, body weight and the concentrations of appetite-associated peptides, including ghrelin, cholecystokinin (CCK) and 5-hydroxytryptamine (5-HT), in addition to c-Fos expression, were comparatively assessed between the CV12 EA group (n=6; rats treated with EA at CV12 daily for 4 days) and a control group (n=6; rats without treatment). The results indicated that the CV12 EA group exhibited a better outcome regarding food intake and body weight compared with the controls. Although there was no statistically significant difference observed, the secretion of serum ghrelin and CCK was increased in the CV12 EA group compared with that in the control group. The plasma level of 5-HT after cisplatin injection in the CV12 EA group was lower compared with that in the control, although no statistical significance was reached. Although not statistically significant, the expression of c-Fos protein in the nucleus tractus solitarius (NTS) was reduced in the CV12 EA rats. In addition, the hypothalamic mRNA levels of brain-derived neurotrophic factor (BDNF) were significantly increased in the CV12 EA group. In the hypothalamus, the expression of neuropeptide Y mRNA slightly increased in the cisplatin + CV12 EA group compared with the cisplatin only control group. In conclusion, the anti-anorexigenic effect of EA on CIA may be associated with an increase in the secretion of ghrelin and CCK and a decrease in the secretion of 5-HT into the serum, a reduction of c-Fos expression in the NTS and an increase in BDNF mRNA expression in the hypothalamus.

There are multiple feedback mechanisms involved in appetite regulation, which is an integral part of maintaining energetic homeostasis. Older forager honey bees, in comparison to newly emerged bees and nurse bees, are known to have highly fluctuating hemolymph trehalose levels, higher appetite changes due to starvation, and higher octopamine levels in the brain. What remains unknown is if the hemolymph trehalose and octopamine levels interact with one another and how this varies as the bee ages. We manipulated trehalose and octopamine levels across age using physiological injections and found that nurse and forager bees increase their appetite levels due to increased octopamine levels in the brain. This is further enhanced by lower trehalose levels in the hemolymph. Moreover, nurse bees with high octopamine levels in the brain and low trehalose levels had the same appetite levels as untreated forager bees. Our findings suggest that the naturally higher levels of octopamine as the bee ages may result in higher sensitivity to fluctuating trehalose levels in the hemolymph that results in a more direct way of assessing the energetic state of the individual. Consequently, forager bees have a mechanism for more precise regulation of appetite in comparison to newly emerged and nurse bees.

Neurotensin (NT) is a peptide expressed in the brain and in the gastrointestinal tract. Brain NT inhibits food intake, but the effects of peripheral NT are less investigated. In this study, peripheral NT decreased food intake in both mice and rats, which was abolished by a NT antagonist. Using c-Fos immunohistochemistry, we found that peripheral NT activated brainstem and hypothalamic regions. The anorexigenic effect of NT was preserved in vagotomized mice but lasted shorter than in sham-operated mice. This in combination with a strong increase in c-Fos activation in area postrema after ip administration indicates that NT acts both through the blood circulation and the vagus. To improve the pharmacokinetics of NT, we developed a pegylated NT peptide, which presumably prolonged the half-life, and thus, the effect on feeding was extended compared with native NT. On a molecular level, the pegylated NT peptide increased proopiomelanocortin mRNA in the arcuate nucleus. We also investigated the importance of NT for the decreased food intake after gastric bypass surgery in a rat model of Roux-en-Y gastric bypass (RYGB). NT was increased in plasma and in the gastrointestinal tract in RYGB rats, and pharmacological antagonism of NT increased food intake transiently in RYGB rats. Taken together, our data suggest that NT is a metabolically active hormone, which contributes to the regulation of food intake.

Adiponectin (AdipoQ) as an adipocytokine has the potential to regulate feeding behavior, but the information about adipoq in fish is limited. In this study, Siberian sturgeon adiponectin (Ssadipoq) gene was cloned encoding 264 amino acids. The amino acid identity of SsAdipoQ was low compared with that of mammals, birds, amphibians and teleost fishes. The expression of Ssadipoq in the hypothalamus was significantly decreased at 1 h and 3 h post feeding, and increased after 15-day fasting. The mature domain of AdipoQ (fAd) was inserted into expression vector pET32a and successfully expressed in Escherichia coli BL21 (DE3) after stimulated by isopropyl-β-d-thiogalactoside. Food intake at 1 h and 3 h post treatment with SsfAd protein decreased significantly (P < 0.05). The mRNA expression of pyy and cck in the valvula intestine was promoted and hypothalamic npy, agrp and pomc mRNA expression were inhibited after treatment with SsfAd protein. Furthermore, hypothalamic ampk subunits expression was associated with peripheral SsfAd treatment. In summary, present study indicate that SsfAd plays an important role in the regulation of food intake and appetite signals in Siberian sturgeon, which provides a basis for further study application of prokaryotic AdipoQ in feeding behavior regulation.

The ability to regulate appetite is essential to avoid food over-consumption. The desire for a particular food can be triggered by its odor before it is even seen. Using fMRI, we identify the neural systems modulated by cognitive regulation when experiencing appetizing food stimuli presented in both olfactory and visual modalities, while being hungry. Regulatory instruction modulated bids for food items and inhalation patterns. Distinct brain regions were observed for up and down appetite-regulation, respectively the dorsomedial prefrontal cortex (dmPFC) and dorsolateral PFC. Food valuation engaged the ventromedial PFC and bilateral striatum. Furthermore, we identified a neurobiological marker for successful appetite upregulation. Individuals with higher blood levels of ghrelin were better at exercising up-regulation, and engaged the dmPFC more. These findings characterize the neural circuitry regulating food consumption within the healthy population and highlight how cognitive regulation modulates olfactomotor measures of olfaction.

Bariatric surgery is associated with significant and sustained weight loss and improved metabolic outcomes. It is unclear if weight loss alone is the main mechanism of improved metabolic health. The purpose of this trial was to compare indices of appetite regulation, insulin sensitivity and energy intake (EI) between participants achieving 10 kg of weight loss via Roux-en-Y Gastric Bypass (RYGB) or dietary restriction (DIET); intake of a very low calorie liquid diet (800 kcal/d; 40% protein, 40% fat, 20% carbohydrate that matched the post-RYGB dietary protocol). Adults qualifying for bariatric surgery were studied before and after 10 kg of weight loss (RYGB [n = 6]) or DIET [n = 17]). Appetite (hunger, satiety, and prospective food consumption [PFC]), appetite-related hormones, and metabolites (ghrelin, PYY, GLP-1, insulin, glucose, free fatty acids [FFA], and triglycerides [TG]) were measured in the fasting state and every 30 min for 180 min following breakfast. Participants were provided lunch to evaluate acute ad libitum EI, which was similarly reduced in both groups from pre to post weight loss. Fasting ghrelin was reduced to a greater extent following RYGB compared to DIET (P = 0.04). Area under the curve (AUC) for ghrelin (P = 0.01), hunger (P < 0.01) and PFC (P < 0.01) increased after DIET compared to RYGB, following 10 kg weight loss. Satiety AUC increased after RYGB and decreased after DIET (P < 0.01). Glucose and insulin (fasting and AUC) decreased in both groups. FFA increased in both groups, with a greater increase in AUC seen after RYGB versus DIET (P = 0.02). In summary, appetite-related indices were altered in a manner that, if maintained, may promote a sustained reduction in energy intake with RYGB compared to DIET. Future work with a larger sample size and longer follow-up will be important to confirm and extend these findings.

This study examined the proteomic profile of the hypothalamus in mice exposed to a high-fat diet (HFD) or with the anorexia of acute illness. This comparison could provide insight on the effects of these two opposite states of energy balance on appetite regulation.

According to the WHO, the number of overweight people (BMI ≥ 25) and obese people (BMI ≥ 30) is constantly growing. On the other hand, the number of elderly people (≥60 years old) in 2020 reached 1.4 billion worldwide. Both mentioned groups demonstrate their individual and characteristic appetite disorders. In light of the side effects of appetite stimulating drugs, which interfere with diabetics, hypertension and thrombosis medicines or diet supplements with doubtful effectiveness in reducing appetite, new and natural alternatives are highly demanded. Therefore, the present study focusses on the search for natural food aromas, which may have potential for appetite regulation. A survey was carried out among consumers with excess body weight (BMI ≥ 25) and the elderly (≥60 years old). Food products and meals pointed out by the survey participants were subjected to volatile analysis by HS-SPME Arrow followed by GC-MS. As a result, a group of volatiles and their odor characteristic were determined for appetite stimulation or reduction, which may suggest that the actual composition of food aroma is more significant than the character of the aroma. Those results may be a basis for designing appetite regulating agents, in which the mechanism of action will be based only on olfaction activity.

Leptin plays a critical role in the central regulation of bone mass. Ghrelin counteracts leptin. In this study, we investigated the effect of chronic intracerebroventricular administration of ghrelin on bone mass in Sprague-Dawley rats (1.5 μg/day for 21 days). Rats were divided into control, ghrelin ad libitum-fed (ghrelin ad lib-fed), and ghrelin pair-fed groups. Ghrelin intracerebroventricular infusion significantly increased body weight in ghrelin ad lib-fed rats but not in ghrelin pair-fed rats, as compared with control rats. Chronic intracerebroventricular ghrelin infusion significantly increased bone mass in the ghrelin pair-fed group compared with control as indicated by increased bone volume percentage, trabecular thickness, trabecular number and volumetric bone mineral density in tibia trabecular bone. There was no significant difference in trabecular bone mass between the control group and the ghrelin ad-lib fed group. Chronic intracerebroventricular ghrelin infusion significantly increased the mineral apposition rate in the ghrelin pair-fed group as compared with control. In conclusion, chronic central administration of ghrelin increases bone mass through a mechanism that is independent of body weight, suggesting that ghrelin may have a bone anabolic effect through the central nervous system.

Unlimited access to calorie-dense, palatable food is a hallmark of Western societies and substantially contributes to the worldwide rise of metabolic disorders. In addition to promoting overconsumption, palatable diets dampen daily intake patterns, further augmenting metabolic disruption. We developed a paradigm to reveal differential timing in the regulation of food intake behavior in mice. While homeostatic intake peaks in the active phase, conditioned place preference and choice experiments show an increased sensitivity to overeating on palatable food during the rest phase. This hedonic appetite rhythm is driven by endogenous circadian clocks in dopaminergic neurons of the ventral tegmental area (VTA). Mice with disrupted clock function in the VTA lose their hedonic overconsumption rhythms without affecting homeostatic intake. These findings assign a functional role of VTA clocks in modulating palatable feeding behaviors and identify a potential therapeutic route to counteract hyperphagy in an obesogenic environment.

Although the use of atypical antipsychotic drugs has been successful in the treatment of schizophrenia, they can cause some complications in the long-term use, including weight gain. Patients using these drugs tend to disrupt treatment primarily due to side effects. The atypical antipsychotic mechanism of action regulates a number of highly disrupted neurotransmitter pathways in the brains of psychotic patients but may also cause impairment of neurohormonal pathways in different brain areas. In this study, we investigated the circulating levels of hypothalamic neurohormones, which are related to appetite regulation; neuropeptide Y (NPY); alpha melanocyte stimulating hormone (α-MSH); cocaine and amphetamine regulated transcript (CART); agouti-related peptide (AgRP); and leptin in male Wistar rats, which were treated with risperidone, a serotonin antagonist, for four weeks. Alterations in the mRNA expression levels of these candidate genes in the hypothalamus were also analyzed. We hypothesized that risperidone treatment might alter both hypothalamic and circulating levels of neuropeptides through serotonergic antagonism, resulting in weight gain. Gene expression studies revealed that the mRNA expression levels of proopiomelanocortin (POMC), AgRP, and NPY decreased as well as their plasma levels, except for NPY. Unexpectedly, CART mRNA levels increased when their plasma levels decreased. Because POMC neurons express the serotonin receptor (5HT2C), the serotonergic antagonism of risperidone on POMC neurons may cause an increase in appetite and thus increase food consumption even in a short-term trial in rats.

Salt homeostasis is orchestrated by both neural circuits and peripheral endocrine factors. The colon is one of the primary sites for electrolyte absorption, while its potential role in modulating sodium intake remains unclear. Here, we revealed that a gastrointestinal hormone, secretin, is released from colon endocrine cells under body sodium deficiency and is indispensable for inducing salt appetite. As the neural substrate, circulating secretin activates specific receptors in the nucleus of the solitary tracts, which further activates the downstream paraventricular nucleus of the hypothalamus, resulting in enhanced sodium intake. These results demonstrated a previously unrecognized gut-brain pathway for the timely regulation of sodium homeostasis.

Previous studies have shown that habitual physical activity improves postprandial appetite regulation. We evaluated the direct association between physical activity level (PAL) and postprandial appetite regulation, and the effect of day-to-day variations in PAL on improving postprandial appetite regulation in lean young males. Fourteen young male adults wore a triaxial accelerometer for at least 6 consecutive days to evaluate their PAL. Two random liquid preload tests were performed on separate days to evaluate the competence of postprandial appetite regulation. In the preload test, participants ate sandwiches ad libitum 75 min after drinking one of two liquids containing different energy densities. When a participant had an adequate regulation of their postprandial appetite, the difference in energy intake from sandwiches was expected to be close to the energy gap between both liquids. Average daily PAL (r = -0.558, p < 0.05), but not the SD of PAL, which is indicative of the day-to-day variations in PAL (r = -0.437, p > 0.1), correlated with the difference in energy intake from the sandwiches. In addition, higher average PAL was closer to the energy gap between the two liquids. These results suggest that average daily PAL, rather than day-to-day variations in PAL, predicts inter-individual variation in postprandial appetite regulation, at least for lean young males.

Gestational protein restriction causes hypertension in the adult offspring. Very little is known about the food intake regulation and ghrelin signaling in pregnant dams fed a low-protein (LP) diet. We hypothesized that diet intake and ghrelin signaling are altered in pregnant rats fed the low-protein diet. Sprague-Dawley rats were fed a control (CT) or LP diet from Day 3 of pregnancy. Diet intake and body weight were monitored daily. Expression of ghrelin production-related genes in the stomach and appetite-related genes in the hypothalamus was analyzed by real-time PCR. Plasma levels of total and active ghrelin, growth hormone and leptin were measured by ELISA. Main results include: (1) Daily diet intake was greater in the LP group than in the CT group in early pregnancy, but substantially lower in late pregnancy; (2) Daily gain in body weight was substantially lower in the LP group in late pregnancy; (3) Expression of ghrelin production-related genes in the stomach and plasma total ghrelin levels were increased in LP group in late pregnancy; (4) Plasma active ghrelin levels were elevated in the LP group at mid-late pregnancy, but growth hormone and leptin levels were uncorrelated with active ghrelin in late pregnancy; and (5) Hypothalamic expression of ghrelin-stimulated genes in LP rats was unassociated with the changes in both plasma ghrelin levels and the diet intake. Taken together, the appetite in LP rats is greater in early pregnancy but reduced at late pregnancy, possibly due to ghrelin insensitivity in appetite regulation.

Amphetamine (AMPH) treatment can suppress appetite and increase oxidative stress in the brain. AMPH-induced appetite suppression is associated with the regulation of neuropeptide Y (NPY) and cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus. The present study explored whether antioxidants, including glutathione S-transferase (GST) and glutathione peroxidase (GP), were involved in this NPY/CART-mediated appetite control. Rats were treated daily with AMPH for four days. Changes in food intake and expression levels of hypothalamic NPY, CART, GST, and GP were examined and compared. Results showed that, in AMPH-treated rats, (1) food intake and NPY expression decreased, while CART, GST, and GP expression increased; (2) NPY knockdown in the brain enhanced the decrease in NPY and the increases in CART, GST, and GP expression; and (3) central inhibition of reactive oxygen species production decreased GST and GP and modulated AMPH anorexia and the expression levels of NPY and CART. The present results suggest that oxidative stress in the brain participates in regulating NPY/CART-mediated appetite control in AMPH-treated rats. These results may advance the knowledge regarding the molecular mechanism of AMPH-evoked or NPY/CART-mediated appetite suppression.