Anorexigenic Peptide Research Articles

Review: Gestational and postnatal nutritional effects on the neuroendocrine control of puberty and subsequent reproductive performance in heifers.

Pubertal attainment is an intricate biological process that involves maturation of the reproductive neuroendocrine axis and increased pulsatile release of gonadotropin-releasing hormone (GnRH) and luteinizing hormone. Nutrition is a critical environmental factor controlling the timing of puberty attainment. Nutrient restriction during early postnatal development delays puberty, whereas increased feed intake and adiposity during this period hasten pubertal maturation by imprinting the hypothalamus. Moreover, the dam's nutrition during gestation can program the neuroendocrine system in the developing fetus and has the potential to advance or delay puberty in the offspring. Leptin, a hormone produced primarily by adipose cells, plays an important role in communicating energy status to the brain and regulating sexual maturation. Leptin's regulation of GnRH release is mediated by an upstream neuronal network since GnRH neurons do not contain the leptin receptor. Two groups of neurons located in the arcuate nucleus of the hypothalamus that express neuropeptide Y (NPY), an orexigenic peptide, and alpha melanocyte-stimulating hormone (αMSH), an anorexigenic peptide, are central elements of the neural circuitry that relay inhibitory (NPY) and excitatory (αMSH) inputs to GnRH neurons. Moreover, KNDy neurons, neurons in the arcuate nucleus that co-express kisspeptin, neurokinin B (NKB), and dynorphin, also play a role in the metabolic regulation of puberty. Our studies in beef heifers demonstrate that increased rates of BW gain during early postweaning (4-9 mo of age) result in reduced expression of NPY mRNA, increased expression of proopiomelanocortin and kisspeptin receptor mRNA, reduced NPY inhibitory inputs to GnRH neurons, and increased excitatory αMSH inputs to KNDy neurons. Finally, our most recent data demonstrate that nutrition of the cow during the last two trimesters of gestation can also induce transcriptional and structural changes in hypothalamic neurocircuitries in the heifer progeny that likely persist long-term after birth. Managerial approaches, such as supplementation of the dam during gestation (fetal programming), creep feeding, early weaning, and stair-step nutritional regimens have been developed to exploit brain plasticity and advance pubertal maturation in heifers.

Scd knockout activates β-oxidation of fatty acids via accumulating stearic acid (18:0) and induces anorexia in zebrafish

Stearoyl-CoA desaturase (scd) is the rate-limiting enzyme for the biosynthesis of monounsaturated fatty acids (MUFA), and it plays a critical role in regulating hepatic lipogenesis and lipid oxidation. However, its role in teleosts remains unclear. In this study, we generated scd knockout zebrafish (scd-/-) to explore the role of Scd in regulating growth and metabolism in teleosts. The results showed that scd knockout reduces hepatic lipid deposition by down-regulating the expression of lipogenesis-related genes and up-regulating the expression of lipolysis-related genes. In addition, the knockout of scd suppressed food intake and reduced body weight. Further analysis confirmed that scd knockout suppressed the feeding behavior by decreasing expression of orexigenic peptide genes and increasing expression of anorexigenic peptide genes. The high-level stearic acid (18:0) feeding experiment results showed that the accumulation of 18:0 inhibited feeding behavior, reduced food intake, decreased body weight, and increased lipid β-oxidation, which was essentially consistent with the phenotypes of scd deficiency. Taken together, our results indicate that the knockout of scd inhibited the food intake through the accumulation of 18:0. This study preliminarily reveals the role of Scd in regulating food intake of teleosts, which provides theoretical basis for the functional study of Scd.

The impact of acute exercise on appetite control: Current insights and future perspectives

The interaction of exercise with appetite control and energy intake has been widely studied due to the ability of exercise-related energy expenditure to influence energy and substrate balance. Many empirical studies have explored appetite and energy intake responses to acute (single) exercise bouts involving a variety of protocols in diverse populations revealing several consistent trends. The balance of evidence suggests that acute moderate-to-vigorous intensity land-based exercise suppresses subjective appetite feelings and the orexigenic hormone acylated ghrelin and elevates the anorexigenic hormones peptide YY and glucagon-like peptide-1. These perturbations are transient and hormone concentrations usually return to resting values in the hours after exercise without evoking compensatory increases in appetite or energy intake on the same day. This evidence counters the popular assertion that exercise transiently increases appetite and may prompt greater energy intake at subsequent meals. The indifference of the appetite control system to acute exercise-induced energy deficits contrasts with the immediate increases in appetite and energy intake provoked by equivalent diet-induced energy deficits. There is, however, considerable inter-individual variability in subjective appetite and hormonal responses to acute exercise with some individuals experiencing greater exercise-induced appetite suppression than others. Current evidence supports the promotion of exercise as a strategy for inducing a short-term energy deficit but the relevance of this for long-term appetite regulation and the control of body mass remains uncertain.

The therapeutic potential of glucagon-like peptide-1 for persons with addictions based on findings from preclinical and clinical studies.

Although the multifaceted mechanisms underlying alcohol use disorder (AUD) have been partially defined, the neurobiological complexity of this disorder is yet to be unraveled. One of the systems that have gained attention in recent times is the gut-brain axis. Although numerous peptides participate in this axis, glucagon-like peptide-1 (GLP-1) plays a central role. GLP-1 is a crucial anorexigenic peptide, with potent abilities to reduce food intake and body weight. The physiological complexity of GLP-1 entails glucose homeostasis, gastrointestinal motility, and the release of insulin and glucagon. As reviewed in this study, acute or repeated treatment with GLP-1 receptor (GLP-1R) agonists decreases alcohol consumption in rodents. Moreover, the abilities of alcohol to promote hyperlocomotion, dopamine release in the nucleus accumbens, and reward in the conditioned place preference paradigm are all suppressed by GLP-1R ligands. Moreover, activation of GLP-1R suppresses the motivation to consume alcohol, alcohol-seeking behaviors, and relapse drinking in male rodents. Similarly, abstinence symptoms experienced during alcohol withdrawal are attenuated by activation of the GLP-1 pathway. On a similar note, the activation of GLP-1 receptors within areas of the brain that are processing reward modulates these alcohol-related responses. Another area that is crucial for this ability is the nucleus of the solitary tract, which is where GLP-1 is produced and from which GLP-1-containing neurons project to areas of reward. These findings may have clinical relevance as AUD is associated with polymorphisms in GLP-1-related genes. Although a GLP-1R agonist does not alter alcohol intake in AUD patients, it reduces this consumption in a sub-population of obese AUD individuals. Given the uncertainty of this outcome, additional clinical studies of obese AUD patients should explore the effects of the GLP-1R agonists on alcohol intake and body weight. Furthermore, GLP-1 receptors modulate the behavioral and neurochemical responses to addictive drugs. Taken together, these preclinical and clinical findings imply that the GLP-1 pathway plays a role in the complex mechanisms regulating alcohol and drug consumption patterns, unveiling a novel aspect of addiction medicine.

Effects of Lactobacillus acidophilus administration to anorexigenic neuropeptides and some biochemical parameters on rats fed with a high-fat diet

AimOne of the rapidly rising global public health concern is obesity. Over the past three decades, the prevalence of obesity has doubled/tripled in several nations around the world, most likely as a result of urbanization, sedentary lifestyles, and increased intake of high-calorie processed foods. In this study, it was aimed to investigate the effects of Lactobacillus acidophilus administration on rats exposed to high-fat diet experimentally on anorexigenic peptides in the brain and some biochemical parameters in the serum. MethodsIn the study, 4 different experimental groups were formed. Group 1 was designated as the control group and fed with a standard rat chow (SD). Group 2 was designated as the high-fat diet (HFD) fed group. Group 3 fed with SD and L. acidophilus probiotic administered. Group 4 fed with HFD and L. acidophilus probiotic administered. At the end of the experiment, leptin, serotonin, glucagon-like peptide-1 (GLP-1) levels were measured in the brain tissue and serum. Glucose, total cholesterol (TC), triglyceride (TG), total protein (TP), albumin, uric acid, aspartate transaminase (AST), alanine aminotransferase (ALT) levels were determined in the serum. ResultsAt the end of the study, it was found that there was an increase in body weight and body mass index in Group 2 compared to Group 1. It was determined that the levels of AST, ALT, TG, TC, glucose, leptin in the serum were significantly high (P < 0.05). The levels of GLP-1 and serotonin in the serum and in the brain were significantly low (P < 0.05). There was a significant decrease in TG and TC in Groups 3 and 4 compared to Group 2 (P < 0.05). The leptin hormone levels in serum and brain were significantly higher in Group 2 than in other groups (P < 0.05). GLP-1 and serotonin levels were found to be significantly low (P < 0.05). The leptin levels in the serum of Groups 3 and 4 decreased significantly compared to Group 2 (P < 0.05). ConclusionIt was found that probiotic supplementation in high-fat diet had positive effects on anorexigenic peptides. It was concluded that L. acidophilus probiotic can be recommended as a food supplement in the treatment of obesity.

Circulating Levels of Nesfatin-1 and Spexin in Children with Prader-Willi Syndrome during Growth Hormone Treatment and Dietary Intervention.

Despite observable improvement in the treatment outcomes of patients with Prader-Willi syndrome (PWS), adequate weight control is still a clinical problem. Therefore, the aim of this study was to analyze the profiles of neuroendocrine peptides regulating appetite-mainly nesfatin-1 and spexin-in children with PWS undergoing growth hormone treatment and reduced energy intake. Twenty-five non-obese children (aged 2-12 years) with PWS and 30 healthy children of the same age following an unrestricted age-appropriate diet were examined. Serum concentrations of nesfatin-1, spexin, leptin, leptin receptor, total adiponectin, high molecular weight adiponectin, proinsulin, insulin-like growth factor-I, and total and functional IGF-binding protein-3 concentrations were determined using immunoenzymatic methods. The daily energy intake in children with PWS was lower by about 30% (p < 0.001) compared with the controls. Daily protein intake was similar in both groups, but carbohydrate and fat intakes were significantly lower in the patient group than the controls (p < 0.001). Similar values for nesfatin-1 in the PWS subgroup with BMI Z-score < -0.5 and the control group, while higher values in the PWS subgroup with BMI Z-score ≥ -0.5 (p < 0.001) were found. Spexin concentrations were significantly lower in both subgroups with PWS than the controls (p < 0.001; p = 0.005). Significant differences in the lipid profile between the PWS subgroups and the controls were also observed. Nesfatin-1 and leptin were positively related with BMI (p = 0.018; p = 0.001, respectively) and BMI Z-score (p = 0.031; p = 0.027, respectively) in the whole group with PWS. Both neuropeptides also correlated positively in these patients (p = 0.042). Altered profiles of anorexigenic peptides-especially nesfatin-1 and spexin-in non-obese children with Prader-Willi syndrome during growth hormone treatment and reduced energy intake were found. These differences may play a role in the etiology of metabolic disorders in Prader-Willi syndrome despite the applied therapy.

Relationship Between Appetite-Related Peptides and Frailty in Older Adults

ABSTRACT Background Frailty, is a geriatric syndrome that reduces the resistance to stress situations caused by activities of daily living and increases morbidity and mortality. We hypothesized that a decrease in orexigenic peptides or an increase in anorexigenic peptides might be associated with frailty. We aimed to investigate the relationship between frailty and six appetite-related peptides: ghrelin, neuropeptide Y (NPY), agouti-related peptide (AgRP), cocaine-amphetamine-associated peptide (CART), peptide YY, and alpha MSH (α-MSH). Methods This cross-sectional study was conducted on 85 older adults who visited the outpatient clinic. All patients underwent comprehensive geriatric assessment. Frailty status was assessed using the Fried frailty index. Plasma levels of six appetite-related peptides were studied. Results The mean age was 73.7 ± 5.4 years, 27 (31.8%) of the patients were male, and 32 of the patients (37.6%) were frail. While plasma levels of ghrelin, NPY and AgRP were significantly lower in frail patients, CART and α-MSH levels were higher compared to non-frail patients (p < .05 for all). Peptide YY was found to be higher in the frail group, however, the difference did not reach statistical significance (p = .052). In multivariate logistic regression analysis, the ghrelin, AgRP, CART, and α-MSH levels were independent predictors of frailty. Moreover, a weak correlation was found between all peptides(except NPY) and handgrip strength and Lawton-Brody score. Conclusion Ghrelin, AgRP, CART, and α-MSH levels were found to be independent predictors of frailty. Our results suggest that appetite-related peptides might be playing roles in the pathogenesis of frailty. Further larger prospective studies are needed to test this hypothesis.

Insight into the role of the gut-brain axis in alcohol-related responses: Emphasis on GLP-1, amylin, and ghrelin.

Alcohol use disorder (AUD) contributes substantially to global morbidity and mortality. Given the heterogenicity of this brain disease, available pharmacological treatments only display efficacy in sub-set of individuals. The need for additional treatment options is thus substantial and is the goal of preclinical studies unraveling neurobiological mechanisms underlying AUD. Although these neurobiological processes are complex and numerous, one system gaining recent attention is the gut-brain axis. Peptides of the gut-brain axis include anorexigenic peptide like glucagon-like peptide-1 (GLP-1) and amylin as well as the orexigenic peptide ghrelin. In animal models, agonists of the GLP-1 or amylin receptor and ghrelin receptor (GHSR) antagonists reduce alcohol drinking, relapse drinking, and alcohol-seeking. Moreover, these three gut-brain peptides modulate alcohol-related responses (behavioral and neurochemical) in rodents, suggesting that the alcohol reduction may involve a suppression of alcohol's rewarding properties. Brain areas participating in the ability of these gut-brain peptides to reduce alcohol-mediated behaviors/neurochemistry involve those important for reward. Human studies support these preclinical studies as polymorphisms of the genes encoding for GLP-1 receptor or the ghrelin pathway are associated with AUD. Moreover, a GLP-1 receptor agonist decreases alcohol drinking in overweight patients with AUD and an inverse GHSR agonist reduces alcohol craving. Although preclinical and clinical studies reveal an interaction between the gut-brain axis and AUD, additional studies should explore this in more detail.

Intraperitoneal administration of nesfatin‑1 stimulates glucagon‑like peptide‑1 secretion in fasted mice.

Increasing endogenous secretion of glucagon‑like peptide (GLP)‑1 is considered a promising therapeutic approach for type 2 diabetes because decreased GLP‑1 plasma concentrations have been observed in patients with this condition. Nesfatin‑1, which is a central and peripheral anorexigenic peptide, has been reported to release GLP‑1 from enteroendocrine STC‑1 cells, although whether nesfatin‑1 stimulates GLP‑1 secretion invivo remains to be elucidated. Previous studies have indicated that nesfatin‑1 has glucose‑lowering and insulinotropic effects in mice and rats; however, the invivo mechanism remains unclear. The present study aimed to investigate whether peripheral administration of nesfatin‑1 increased blood concentrations of GLP‑1 and insulin in food‑deprived mice. Nesfatin‑1 was administered intraperitoneally to 18‑h fasted mice. Plasma GLP‑1 and insulin concentrations in the mice administered 2.5µmol/kg nesfatin‑1 were higher than those in saline‑treated mice. Blood glucose concentrations in mice treated with 1.25 and 2.5µmol/kg nesfatin‑1 were lower than those in saline‑treated mice. The mRNA expression of preproglucagon in mouse ilea after treatment with 1.25µmol/kg nesfatin‑1 was higher than that in saline‑treated mice. The administration of 1.25µmol/kg nesfatin‑1 raised GLP‑1 concentrations at 30 and 60min and insulin concentrations at 30 and 60min after injection. Furthermore, the higher level of nesfatin‑1‑induced insulin was diminished by pre‑administration of anti‑GLP‑1 antiserum. Intraperitoneally administered nesfatin‑1 increased insulin concentrations by accelerating GLP‑1 secretion. The results are the first invivo demonstration of promotion of GLP‑1 secretion by nesfatin‑1 in the mouse, suggesting the developmental potential of nesfatin‑1 for GLP‑1 release.

Prolyl Carboxypeptidase Activity Is Present in Human Adipose Tissue and Is Elevated in Serum of Obese Men with Type 2 Diabetes

Prolyl carboxypeptidase (PRCP) is involved in metabolic disorders by hydrolyzing anorexigenic peptides. A link between serum PRCP activity and obesity has been reported, but its origin/source is still unclear. Previously proven correlations between human serum PRCP activity and the amount of adipose tissue may suggest that adipose tissue is an important source of circulating PRCP. We investigated PRCP activity in visceral, subcutaneous adipose tissue (VAT and SCAT), skeletal muscle tissue and serum of lean and obese men with or without type 2 diabetes (T2D). Correlations between PRCP activity, metabolic and biochemical parameters and immune cell populations were assessed. PRCP activity was the highest in VAT, compared to SCAT, and was very low in skeletal muscle tissue in the overall group. Serum PRCP activity was significantly higher in T2-diabetic obese men, compared to lean and obese non-diabetic men, and was positively correlated with glycemic control. A positive correlation was observed between serum PRCP activity and VAT immune cell populations, which might indicate that circulating PRCP activity is deriving rather from the immune fraction than from adipocytes. In conclusion, PRCP activity was observed in human adipose tissue for the first time and serum PRCP activity is correlated with T2D in obese men.

Novel pituitary actions of GnRH in teleost: The link between reproduction and feeding regulation.

Gonadotropin-releasing hormone (GnRH), as a vital hypothalamic neuropeptide, was a key regulator for pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the vertebrate. However, little is known about the other pituitary actions of GnRH in teleost. In the present study, two GnRH variants (namely, GnRH2 and GnRH3) and four GnRH receptors (namely, GnRHR1, GnRHR2, GnRHR3, and GnRHR4) had been isolated from grass carp. Tissue distribution displayed that GnRHR4 was more highly detected in the pituitary than the other three GnRHRs. Interestingly, ligand–receptor selectivity showed that GnRHR4 displayed a similar and high binding affinity for grass carp GnRH2 and GnRH3. Using primary culture grass carp pituitary cells as model, we found that both GnRH2 and GnRH3 could not only significantly induce pituitary reproductive hormone gene (GtHα, LHβ, FSHβ, INHBa, secretogranin-2) mRNA expression mediated by AC/PKA, PLC/IP3/PKC, and Ca2+/CaM/CaMK-II pathways but also reduce dopamine receptor 2 (DRD2) mRNA expression via the Ca2+/CaM/CaMK-II pathway. Interestingly, GnRH2 and GnRH3 could also stimulate anorexigenic peptide (POMCb, CART2, UTS1, NMBa, and NMBb) mRNA expression via AC/PKA, PLC/IP3/PKC, and Ca2+/CaM/CaMK-II pathways in grass carp pituitary cells. In addition, food intake could significantly induce brain GnRH2 mRNA expression. These results indicated that GnRH should be the coupling factor to integrate the feeding metabolism and reproduction in teleost.

Recent advances in neuropeptide-related omics and gene editing: Spotlight on NPY and somatostatin and their roles in growth and food intake of fish.

Feeding and growth are two closely related and important physiological processes in living organisms. Studies in mammals have provided us with a series of characterizations of neuropeptides and their receptors as well as their roles in appetite control and growth. The central nervous system, especially the hypothalamus, plays an important role in the regulation of appetite. Based on their role in the regulation of feeding, neuropeptides can be classified as orexigenic peptide and anorexigenic peptide. To date, the regulation mechanism of neuropeptide on feeding and growth has been explored mainly from mammalian models, however, as a lower and diverse vertebrate, little is known in fish regarding the knowledge of regulatory roles of neuropeptides and their receptors. In recent years, the development of omics and gene editing technology has accelerated the speed and depth of research on neuropeptides and their receptors. These powerful techniques and tools allow a more precise and comprehensive perspective to explore the functional mechanisms of neuropeptides. This paper reviews the recent advance of omics and gene editing technologies in neuropeptides and receptors and their progresses in the regulation of feeding and growth of fish. The purpose of this review is to contribute to a comparative understanding of the functional mechanisms of neuropeptides in non-mammalians, especially fish.

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

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

Immunolocalization of Nesfatin-1 in the Gastrointestinal Tract of the Common Bottlenose Dolphin Tursiops truncatus.

Simple SummaryNesfatin-1 (Nesf-1) is a neuropeptide that plays important roles in regulating food intake, mainly related to its anorexigenic effect, and it is mainly distributed in the digestive systems of all vertebrates. With this study, we expand knowledge on the localization of Nesf-1 in the digestive tract of an aquatic mammalian species, the common bottlenose dolphin (Tursiops truncatus), allowing comparative study on terrestrial mammals. Dolphin tissue samples (three gastric chambers and intestine) were provided by the Mediterranean Marine Mammal Tissue Bank of the Department of Comparative Biomedicine and Food Science of the University of Padova (Italy).First identified as an anorexigenic peptide, in the last decades, several studies have suggested that Nesfatin-1 (Nesf-1) is a pleiotropic hormone implicated in numerous regulatory processes in peripheral organs and tissues. In vertebrates, Nesf-1 is indeed expressed in the central nervous system and peripheral organs. In this study, we characterized the pattern of Nesf-1 distribution within the digestive tract of the common bottlenose dolphin (Tursiops truncatus), composed of three gastric chambers and an intestine without a clear subdivision in the small and large intestine, also lacking a caecum. Our results indicated that Nesf-1 is widely distributed in cells of the mucosal epithelium of the gastric chambers. Most of the immunoreactivity was observed in the second chamber, compared to the first and third chambers. Immunopositivity was also found in nerve fibers and neurons, scattered or/and clustered in ganglion structures along all the examined gastrointestinal tracts. These observations add new data on the highly conserved role of Nesf-1 in the mammalian digestive system.

TRPV1-Mediated Sensing of Sodium and Osmotic Pressure in POMC Neurons in the Arcuate Nucleus of the Hypothalamus.

The central melanocortin system conducted by anorexigenic pro-opiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARC) not only regulates feeding behavior but also blood pressure. Excessive salt intake raises the Na+ concentration ([Na+]) in the cerebrospinal fluid (CSF) and worsens hypertension. The blood–brain barrier is immature in the ARC. Therefore, both AgRP and POMC neurons in the ARC have easy access to the electrolytes in the blood and can sense changes in their concentrations. However, the sensitivity of AgRP and POMC neurons to Na+ remains unclear. This study aimed to explore how the changes in the extracellular Na+ concentration ([Na+]) influence these neurons by measuring the cytosolic Ca2+ concentration ([Ca2+]i) in the single neurons isolated from the ARC that were subsequently immunocytochemically identified as AgRP or POMC neurons. Both AgRP and POMC neurons responded to increases in both [Na+] and osmolarity in C57BL/6 mice. In contrast, in transient receptor potential vanilloid 1 (TRPV1) knockout (KO) mice, POMC neurons failed to respond to increases in both [Na+] and osmolarity, while they responded to high glucose and angiotensin II levels with increases in [Ca2+]i. Moreover, in KO mice fed a high-salt diet, the expression of POMC was lower than that in wild-type mice. These results demonstrate that changes in [Na+] and osmolarity are sensed by the ARC POMC neurons via the TRPV1-dependent mechanism.

NUCB2/nesfatin-1 is associated with severity of eating disorder symptoms in female patients with obesity

BackgroundNesfatin-1 has been described as an anorexigenic peptide. Comprehensive evidence also points towards an involvement of nesfatin-1 in the modulation of emotional pathways with a sex-specific regulation of nesfatin-1 in association with anxiety. Although the implication of nesfatin-1 in the regulation of food intake is well-established in animals, data in humans are lacking. Therefore, we investigated a possible association of circulating NUCB2/nesfatin-1 with eating disorder symptoms in female and male patients displaying a wide range of body weight. MethodsWe enrolled 243 inpatients (177 female, 66 male) hospitalized due to anorexia nervosa (n = 66) or obesity (n = 144) or with normal weight and suffering from somatoform, adjustment, depressive or anxiety disorders (n = 33). Plasma samples (NUCB2/nesfatin-1 levels measured by ELISA) and measures of eating disorder symptoms (by EDI-2, range 0–100) were obtained within three days after admission. ResultsThe study population displayed a distinct prevalence of eating disorder symptoms with female patients with anorexia nervosa (+ 77.0%, p < 0.001) and obesity (+ 87.9%, p < 0.001) reported significantly higher EDI-2 scores than normal weight patients of the same sex. Accordingly, males with anorexia nervosa (+ 39.7%, p < 0.05) and obesity (+ 51.7%, p < 0.001) had significantly higher EDI-2 scores than males with normal weight. Within the same BMI group, women displayed significantly higher scores than men (+ 21.4%, p < 0.05 in patients with anorexia nervosa, + 18.8%, p < 0.001 in participants with obesity). We observed a positive correlation between NUCB2/nesfatin-1 levels and EDI-2 total scores in female patients with obesity (r = 0.285, p = 0.015), whereas no associations were found in other subgroups. A positive correlation between NUCB2/nesfatin-1 levels and BMI was only observed in the male study population (r = 0.315, p = 0.018). ConclusionsNUCB2/nesfatin-1 plasma levels were positively associated with EDI-2 total scores in women with obesity, while no association was observable in men. The lacking association of NUCB2/nesfatin-1 and EDI-2 total scores in female patients with anorexia nervosa might be due to already low NUCB2/nesfatin-1 plasma levels. Whether NUCB2/nesfatin-1 is selectively involved in eating behavior in women with obesity will have to be further investigated.

Effects of Modified Electroconvulsive Therapy on Serum Cortisol, Nesfatin-1, and Pro-inflammatory Cytokine Levels in Elderly Patients With Treatment-Resistant Depression.

AimModified electroconvulsive therapy (MECT) is an effective strategy for treatment-resistant depression (TRD); however, the mechanism underlying effects of MECT remains unclear. Accumulating evidence suggests that TRD is closely associated with dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, anorexigenic peptides, and pro-inflammatory cytokines. However, MECT effects on the HPA axis, anorexigenic peptides, and pro-inflammatory cytokines in elderly patients with TRD remain unclear. In this study, we investigated whether the HPA axis (cortisol), anorexigenic peptides (nesfatin-1), and pro-inflammatory cytokines (C-reactive protein, tumor necrosis factor-α, and interleukin-6, and interleukin-1β) are involved in the mechanism underlying MECT effects in elderly patients with TRD.MethodsElderly patients with TRD were enrolled in this study between December 2019 and October 2021; all patients underwent MECT after physical examination. Serum cortisol, nesfatin-1, and pro-inflammatory cytokine levels were measured before and after the first, third, and sixth MECT sessions. The Hamilton Depression Rating Scale-24 (HAMD-24) and the Mini-Mental State Examination (MMSE) were used to evaluate depression and cognitive impairment, respectively. We compared pre- and post-MECT serum cortisol, nesfatin-1, and pro-inflammatory cytokine levels to confirm the short-term effects of MECT on these serum indices. We compared these serum indices across three time points (before the first, third, and sixth MECT sessions) to determine the long-term effects of MECT on serum cortisol, nesfatin-1, and pro-inflammatory cytokine levels.ResultsWe observed no statistically significant changes in the pre- and post-MECT serum cortisol, nesfatin-1, or pro-inflammatory cytokine levels. No significant changes in serum cortisol, nesfatin-1, and pro-inflammatory cytokine levels were observed across the aforementioned time points. Moreover, there were no statistically significant sex-based differences in the aforementioned serum indices. Furthermore, the serum cortisol level was negatively correlated with the serum IL-6 level before and after the first MECT session in patients with high cortisol levels (> the 50th percentile value of all samples). Additionally, the post-MECT HAMD-24 and MMSE scores were significantly lower.ConclusionsMECT reduced depressive symptoms despite an adverse effect on cognition and had no significant effect on the serum cortisol, nesfatin-1, and pro-inflammatory cytokine levels in elderly patients with TRD.

Nesfatin-1 protects against diabetic cardiomyopathy in the streptozotocin-induced diabetic mouse model via the p38-MAPK pathway

ABSTRACT Nesfatin-1 is a novel anorexigenic peptide that possesses antihyperglycemic and cardiovascular effects. We hypothesized that nesfatin-1 has a beneficial protective effect against diabetic cardiomyopathy (DC). We investigated the therapeutic effect of nesfatin-1 on diabetes-associated cardiac dysfunction in the high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mouse model. We found that the cardiac nesfatin-1 level was lower in diabetic mice than in normal mice. Nesfatin-1 treatment (180 mg/kg/day for two weeks) improved insulin sensitivity and mitigated diabetic dyslipidemia. Nesfatin-1 ameliorated the diabetes-related myocardial hypertrophy and heart dysfunction, as revealed by the reduced hypertrophy index, heart rate, mean arterial pressure (MAP), creatine kinase (CK)-MB, and aspartate aminotransferase (AST) levels. Nesfatin-1 exerted antioxidant and anti-inflammatory activity in diabetic mice, as shown by decreased reactive oxygen species (ROS), oxidative lipid product malondialdehyde (MDA) levels, increased superoxide dismutase (SOD) and glutathione (GSH), decreased cardiac and plasma interleukin-1 β (IL-1β) and tumor necrosis factor-α (TNF-α) levels. Mechanistically, we found that nesfatin-1 inhibited the cardiac p38-MAPK pathway activation and subsequent glucagon-like peptide-1 (GLP-1) level. Collectively, our data shows nesfatin-1 exerted protective effects against diabetic cardiomyopathy. Our study suggests that nesfatin-1 therapy has therapeutic implications against diabetic cardiomyopathy.

ANGT_HUMAN[448-462], an Anorexigenic Peptide Identified Using Plasma Peptidomics.

The discovery of bioactive peptides is an important research target that enables the elucidation of the pathophysiology of human diseases and provides seeds for drug discovery. Using a large number of native peptides previously identified using plasma peptidomics technology, we sequentially synthesized selected sequences and subjected them to functional screening using human cultured cells. A 15-amino-acid residue proangiotensinogen-derived peptide, designated ANGT_HUMAN[448–462], elicited cellular responses and bound to cultured human cells. Synthetic fluorescent-labeled and biotinylated ANGT_HUMAN[448–462] peptides were rendered to bind to cell- and tissue-derived proteins and peptide-cell protein complexes were retrieved and analyzed using liquid chromatography–tandem mass spectrometry, revealing the β-subunit of ATP synthase as its cell-surface binding protein. Because ATP synthase mediates the effects of anorexigenic peptides, the ability of ANGT_HUMAN[448–462] to modulate eating behavior in mice was investigated. Both intraperitoneal and intracerebroventricular injections of low doses of ANGT_HUMAN[448–462] suppressed spontaneous food and water intake throughout the dark phase of the diurnal cycle without affecting locomotor activity. Immunoreactive ANGT_HUMAN[448–462], distributed throughout human tissues and in human-derived cells, is mostly co-localized with angiotensin II and is occasionally present separately from angiotensin II. In this study, an anorexigenic peptide, ANGT_HUMAN[448–462], was identified by exploring cell surface target proteins of the human native peptides identified using plasma peptidomics.

A discrete parasubthalamic nucleus subpopulation plays a critical role in appetite suppression.

Food intake behavior is regulated by a network of appetite-inducing and appetite-suppressing neuronal populations throughout the brain. The parasubthalamic nucleus (PSTN), a relatively unexplored population of neurons in the posterior hypothalamus, has been hypothesized to regulate appetite due to its connectivity with other anorexigenic neuronal populations and because these neurons express Fos, a marker of neuronal activation, following a meal. However, the individual cell types that make up the PSTN are not well characterized, nor are their functional roles in food intake behavior. Here, we identify and distinguish between two discrete PSTN subpopulations, those that express tachykinin-1 (PSTNTac1 neurons) and those that express corticotropin-releasing hormone (PSTNCRH neurons), and use a panel of genetically encoded tools in mice to show that PSTNTac1 neurons play an important role in appetite suppression. Both subpopulations increase activity following a meal and in response to administration of the anorexigenic hormones amylin, cholecystokinin (CCK), and peptide YY (PYY). Interestingly, chemogenetic inhibition of PSTNTac1, but not PSTNCRH neurons, reduces the appetite-suppressing effects of these hormones. Consistently, optogenetic and chemogenetic stimulation of PSTNTac1 neurons, but not PSTNCRH neurons, reduces food intake in hungry mice. PSTNTac1 and PSTNCRH neurons project to distinct downstream brain regions, and stimulation of PSTNTac1 projections to individual anorexigenic populations reduces food consumption. Taken together, these results reveal the functional properties and projection patterns of distinct PSTN cell types and demonstrate an anorexigenic role for PSTNTac1 neurons in the hormonal and central regulation of appetite.