AgRP Levels Research Articles

Identifying novel proteins underlying bipolar disorder via integrating pQTLs of the plasma, CSF, and brain with GWAS summary data

Bipolar disorder (BD) presents a significant challenge due to its chronic and relapsing nature, with its underlying pathogenesis remaining elusive. This study employs Mendelian randomization (MR), a widely recognized genetic approach, to unveil intricate causal associations between proteins and BD, leveraging protein quantitative trait loci (pQTL) as key exposures. We integrate pQTL data from brain, cerebrospinal fluid (CSF), and plasma with genome-wide association study (GWAS) findings of BD within a comprehensive systems analysis framework. Our analyses, including two-sample MR, Steiger filtering, and Bayesian colocalization, reveal noteworthy associations. Elevated levels of AGRP, FRZB, and IL36A in CSF exhibit significant associations with increased BD_ALL risk, while heightened levels of CTSF and LRP8 in CSF, and FLRT3 in plasma, correlate with decreased BD_ALL risk. Specifically for Bipolar I disorder (BD_I), increased CSF AGRP levels are significantly linked to heightened BD_I risk, whereas elevated CSF levels of CTSF and LRP8, and plasma FLRT3, are associated with reduced BD_I risk. Notably, genes linked to BD-related proteins demonstrate substantial enrichment in functional pathways such as “antigen processing and presentation,” “metabolic regulation,” and “regulation of myeloid cell differentiation.” In conclusion, our findings provide beneficial evidence to support the potential causal relationship between IL36A, AGRP, FRZB, LRP8 in cerebrospinal fluid, and FLRT3 in plasma, and BD and BD_I, providing insights for future mechanistic studies and therapeutic development.

The Relationship Between Eating-Attitudes and Clinical Characteristics, Agouti-Related Peptide, and Other Biochemical Markers in Adult-Attention Deficit Hyperactivity Disorder

Objective: In our study, we aimed to evaluate eating-attitudes in adult-ADHD, and to examine its relationship with sociodemographic, clinical, AgRP, and biochemical parameters. Method: The study included 70 adult-patients and 47 healthy-controls. The DIVA2.0, SCID-1 was administered to the participants. Eating-Attitudes Test (EAT), Night-Eating Questionnaire (NEQ), Barratt Impulsivity Scale (BIS-11) were filled by the participants. Results: We found that psychological state affect eating-attitudes in adult-ADHD (p = .013), emotional eating is more common, nocturnal chronotype is dominant (p < .001), NES is more frequent (p < .001), waist circumference measurement is higher (p = .030), and lipid profile is deteriorated (p < .001). AgRP levels were significantly lower in patients treated with methylphenidate (p = .021). Those who received methylphenidate treatment had less NES than those who did not. Deterioration in eating-attitudes and symptom severity of night eating in ADHD, it was positively correlated with clinical severity of ADHD and impulsivity. In addition, age and increase in night eating symptoms were predictors of deterioration in eating attitudes in adult-ADHD. We found that impaired eating-attitudes and impulsivity severity were also predictors of NES (p = .006, p = .034). Conclusion: The necessity of adult-ADHD treatment has been demonstrated by the deterioration in eating-attitudes and cardiometabolic risk dimensions and the underlying mechanisms.

A review: Effects of estrogen and estrogen receptor modulators on leptin resistance: Mechanisms and pathway

Obesity is characterized by an increase in food intake and a decrease in energy expenditure, which causes the accumulation of fat in the body, resulting in various disorders such as type 2 diabetes and cancer. Adipocytes secrete the hormone leptin, and leptin signaling plays an essential role in regulating energy balance. Leptin reduces food intake and increases energy expenditure by binding to its receptors in the hypothalamus and regulating appetite-regulating neurons. Accumulation of excess fat along with increased blood levels of leptin impairs the passage of leptin across the blood-brain barrier and induces leptin resistance. Estrogen also plays an important role in regulating energy balance due to the expression of its receptors in the hypothalamus, and its deficiency is associated with increased food intake and body weight, and estrogen therapy is able to partially mimic the effects of leptin. In this review, we get familiar with the concept of leptin resistance and its mechanisms, and finally, we examine the role of estrogen by emphasizing the mechanisms of energy balance regulation. • Increased inflammation and high levels of leptin in obesity lead to leptin resistance. • Estrogen via ERα increases p-STAT3 signaling in the ARC of hypothalamus and reduces leptin resistance. • Estrogen via ERα reduces inflammation, NPY, and AgRP levels and increases α-MSH. • Tamoxifen as a SERM, reduces leptin resistance by reducing inflammation and modulating brain neuropeptides. • Aging is an influential factor contributing to leptin responsiveness in presence of estrogen, which reduces the effects of estrogen.

Intake of High Fat Diet leads to Over‐expression of CD36, QRFP and QRFPr in the Gustatory Neural Circuit

Taste is a primary sensory modality that guides food preferences. Orosensory fat perception, which is mediated by lingual CD36, contributes to the intake and preference of dietary fat. Our previous studies indicate that feeding patterns differentially affect lingual CD36 mRNA expression and expression of homeostatic and hedonic markers in the brain. QRFP, an orexigenic peptide expressed primarily in the mediobasal hypothalamus (MBH), selectively increases the intake of high fat diet (HFD). The relationship between lingual CD36 and hypothalamic QRFP has yet to be investigated. Therefore, the goal of the current study was to conduct a time course analysis of continuous access to HFD on neural markers of food intake, including QRFP in the MBH and its receptor, QRFPr, in the nucleus accumbens (NAc). Male Sprague‐Dawley rats were fed a low fat diet (LFD, 10% kcal from fat) or HFD (55% kcal from fat) for 1 day, 3 days or 14 days. Body weight, food intake, and body adiposity were assessed. Real time PCR was used to determine the expression of CD36 mRNA on the circumvallate papillae of the tongue, expression of prepro‐QRFP, prepro‐NPY, and AgRP mRNA in the MBH, and dopamine receptor 1 (D1), 2 (D2) and QRFPr mRNA levels in the NAc. Rats fed HFD consumed more kilocalories than rats consuming the LFD, and gained more body adiposity, but not body weight, after 14 days of HFD intake. Lingual expression of CD36 mRNA was increased after 3 and 14 days of HFD intake. Intake of HFD increased hypothalamic expression of prepro‐QRFP mRNA but did not alter AgRP or prepro‐NPY mRNA levels. QRFPr expression in the NAc was significantly elevated by HFD intake, while D1 and D2 mRNA levels were differentially altered across days of HFD intake, with D1 levels decreasing after 14 days and D2 levels decreasing following 3 days access to HFD. Lingual CD36 mRNA was positively correlated with body weight gain and body adiposity and negatively correlated with AgRP mRNA levels. Hypothalamic prepro‐QRFP levels were positively correlated with kilocalorie intake. QRFPr mRNA levels in the NAc were positively correlated with body adiposity and negatively correlated with D1 and D2 mRNA levels. Prepro‐NPY and AgRP mRNA levels were negatively correlated with weight gain, body adiposity and QRFPr expression and AgRP levels were positively correlated with prepro‐NPY and D2 expression. Hypothalamic neuropeptides regulate food intake, particularly homeostatic eating. In this study, a time course analysis of HFD‐induced changes in gene expression suggest that while prepro‐NPY and AgRP levels were not altered, prepro‐QRFP mRNA levels were elevated. In the NAc, a brain region regulating hedonic eating, expression of D1 and D2, regulators of dopamine signaling, decreased, while QRFPr expression increased with HFD intake. These data, combined with the positive relationship between QRFP and kilocalories consumed and negative relationships between prepro‐NPY and AgRP and weight gain, suggest that CD36, QRFP and its receptor, QRFPr, may serve as positive regulators of caloric intake and weight gain by mediating the continued overconsumption of dietary fat.

Adult rats from undernourished dams show sex-dependent impaired expression in taste papillae and hypothalamus of genes responsible for sweet and fat detection and signalling

ABSTRACT Aim Individuals undernourished in utero or during early life are at high risk of developing obesity and metabolic disorders and show an increased preference for consuming sugary and fatty food. This study aimed at determining whether impaired taste detection and signalling in the lingual epithelium and the brain might contribute to this altered pattern of food intake. Methods The preference for feeding fat and sweet food and the expression in circumvallate papillae and hypothalamus of genes coding for sweet and fat receptors and transducing pathways were evaluated in adult rats born to control or calorie-restricted dams. Expression in the hypothalamus and the brain's reward system of genes involved in the homeostatic and hedonic control of food intake was also determined. Results Male and female undernourished animals exhibited increased expression in taste papillae and hypothalamus of T1R1, T1R2, CD36, gustducin, TRMP5 and PLC-β2 genes, all of which modulate sweet and fat detection and intracellular signalling. However, the severity of the effect was greater in females than in males. Moreover, male, but not female, undernourished rats consumed more standard and sweetened food than their control counterparts and presented increased hypothalamic AgRP and NPY mRNAs levels together with enhanced dopamine transporter and dopamine receptor D2 expression in the ventral tegmental area. Conclusions Maternal undernutrition induces sex-specific changes in food preferences and gene expression in taste papillae, hypothalamus and brain reward regions. The gene expression alterations in the male offspring are in line with their preference for consuming sugary and fatty food.

Influence of Nutritional Status and Leptin Action on Agrp and Pomc Co-Expression in Hypothalamic Melanocortin System Neurons

Objectives: The control of energy balance relies on the counterbalancing release of neuropeptides encoded by the pro-opiomelanocortin (Pomc) and agouti-related protein (Agrp) genes, expressed by 2 distinct neuronal populations of the arcuate (ARC) nucleus of the hypothalamus. Although largely segregated, single-cell resolution techniques demonstrate some degree of co-expression. We studied whether challenges to the control of energy balance influence the degree of Agrp and Pomc co-expression in ARC melanocortin neurons. Methods: We used fluorescence-activated cell sorting followed by quantitative polymerase chain reaction and fluorescent in situ hybridization to measure Pomc and Agrp gene co-expression in POMC or AGRP neurons in response to (1) acute or chronic calorie restriction, or (2) obesity due to loss of leptin receptor expression or chronic high-fat diet feeding in male mice. Results: Melanocortin ARC neurons of fed mice exhibited low, yet detectable, levels of Pomc and Agrp gene co-expression. Calorie restriction significantly increased and decreased total Agrp and Pomc expression, respectively, and reduced the expression of Pomc relative to Agrp in AGRP neurons. Leptin-deficient db/db mice showed increased total Agrp levels and decreased Pomc expression, as well as significantly increased Agrp expression relative to Pomc in POMC neurons. Expression or co-expression levels did not differ between diet-induced obese mice and lean controls. Conclusions: Changes in Agrp and Pomc co-expression within POMC and AGRP neurons following chronic calorie restriction or in db/db mice suggest an additional mechanism to further suppress the melanocortin signaling during conditions of severely reduced leptin action.

LEPR polymorphism may affect energy balance during weight loss among Brazilians obese adolescents

ObjectiveLeptin is an adipokine released mainly by adipose tissue, with many functions including regulation of energy balance. However, little is known about the effect of LEPR polymorphism on orexigenic and anorexigenic neuropeptides. Thus, the aim of the present study is to verify the influence of LEPR polymorphism (rs2767485) on serum orexigenic (NPY, MCH and AgRP) and anorexigenic (Leptin and α-MSH) neuropeptides levels among obese adolescents submitted to 1year of multicomponent weight loss therapy. MethodsSeventy-six adolescents with obesity were enrolled in 1year of weight loss therapy including clinical, nutritional, psychological and exercise-related. Blood samples were collected to analyze neuropeptides (NPY, MCH, AgRP and leptin) and LEPR genotyping. Visceral fat was measured by ultrasound and body composition was measured by plethysmography. The parameters were measured at baseline and after one year. Adolescents were grouped according to genotype (TT or CT+CC group). Effect of the weight loss therapy was analyzed through ANOVA and Wilcox, according to normality. Statistic value was set at <0.05. ResultsC-allele carriers have the orexigenic neuropeptides (NPY, AgRP and MCH) levels statistically higher when compared with TT group, at baseline. Furthermore, TT group seems to respond better to the therapy by a greater delta on BMI. Indeed, the data suggest a concomitant increased of AgRP levels in CT+CC genotypes, after weight loss therapy. ConclusionBoth groups responded to the weight loss intervention, however wildtypes (TT) appear to respond to the intervention most optimally with C carries, where post intervention reduction in BMI was significantly greater in wildtypes. The leptin receptor polymorphism seems to affect neuroendocrine regulation of energy balance among adolescents with obesity.

Aerobic training (AT) is more effective than aerobic plus resistance training (AT + RT) to improve anorexigenic/orexigenic factors in obese adolescents

Background: The regulation of energy balance is influenced by physical exercise. Although some studies show a stimulation of hormones related to food intake, others show that exercise provides satiety. Aim: The aim of this study was to compare the effects of aerobic training (AT) and aerobic plus resistance training (AT+RT) on anorexigenic and orexigenic factors in obese adolescents undergoing interdisciplinary weight loss therapy. Methods: A total of 26 obese adolescents, aged 15–19years with BMI⩾P95 were submitted to 12months of interdisciplinary intervention (clinical support, nutrition, psychology and physical exercise) and divided into two groups, aerobic training (AT) (n=13) or aerobic plus resistance training (AT+RT) (n=13), which were matched according to gender and body mass. Blood samples were collected to analyze orexigenic factors (AgRP, NPY, MCH) and the anorexigenic factor alpha-MSH. Results: The AT and AT+RT groups significantly reduced body mass, body mass index and body fat mass (kg) during the therapy. The AT group showed no significant changes in body lean mass (kg), whereas the AT+RT group showed an increase in body lean mass (kg) during the interdisciplinary intervention. There was an increase in AgRP levels (ng/ml) only in the AT+RT group after 6months of interdisciplinary intervention compared with baseline condition. Conversely, α-MSH levels (ng/ml) increased only in the AT group after 12months of interdisciplinary intervention compared with baseline condition. Conclusion: Aerobic training (AT) as part of an interdisciplinary therapy is more effective than aerobic plus resistance training (AT+RT) to improve secretion of anorexigenic/orexigenic factors in obese adolescents.

Leptin inhibits hypothalamic Npy and Agrp gene expression via a mechanism that requires phosphatidylinositol 3-OH-kinase signaling

Phosphatidylinositol 3-OH-kinase (PI3K) and STAT3 are signal transduction molecules activated by leptin in brain areas controlling food intake. To investigate their role in leptin-mediated inhibition of hypothalamic neuropeptide Y (Npy) and agouti-related peptide (Agrp) gene expression, male Sprague-Dawley rats (n = 5/group) were either fed ad libitum or subjected to a 52-h fast. At 12-h intervals, the PI3K inhibitor LY-294002 (LY, 1 nmol) or vehicle was injected intracerebroventricularly (ICV) as a pretreatment, followed 1 h later by leptin (3 microg icv) or vehicle. Fasting increased hypothalamic Npy and Agrp mRNA levels (P < 0.05), and ICV leptin administration prevented this increase. As predicted, LY pretreatment blocked this inhibitory effect of leptin, such that Npy and Agrp levels in LY-leptin-treated animals were similar to fasted controls. By comparison, leptin-mediated activation of hypothalamic STAT3 signaling, as measured by induction of both phospho-STAT3 immunohistochemistry and suppressor of cytokine signaling-3 (Socs3) mRNA, was not significantly attenuated by ICV LY pretreatment. Because NPY/AgRP neurons project to the hypothalamic paraventricular nucleus (PVN), we next investigated whether leptin activation of PVN neurons is similarly PI3K dependent. Compared with vehicle, leptin increased the number of c-Fos positive cells within the parvocellular PVN (P = 0.001), and LY pretreatment attenuated this effect by 35% (P = 0.043). We conclude that leptin requires intact PI3K signaling both to inhibit hypothalamic Npy and Agrp gene expression and activate neurons within the PVN. In addition, these data suggest that leptin activation of STAT3 is insufficient to inhibit expression of Npy or Agrp in the absence of PI3K signaling.

Leptin regulation of Agrp and Npy mRNA in the rat hypothalamus.

Agouti-related protein (AGRP) is synthesized in the same neurones in the arcuate nucleus as neuropeptide Y (NPY), another potent orexigenic peptide. AGRP antagonizes the action of alpha-melanocyte stimulating hormone, a derivative of pro-opiomelanocortin (POMC) at the hypothalamic MC4 receptor to increase food intake. Although leptin has been shown to regulate Agrp/Npy and Pomc-expressing neurones, there are differences with respect to Agrp regulation in leptin receptor-deficient mice and rats. Unlike the obese leptin receptor-deficient db/db mouse, which exhibits upregulation of Agrp mRNA expression in the medial basal hypothalamus (MBH) compared to lean controls, the obese leptin receptor-deficient (faf; Koletsky) rat does not exhibit upregulation of Agrp expression. To determine whether this represents a general difference between leptin receptor-deficient mice and rats, neuropeptide gene expression was analysed in the MBH of lean and obese rats segregating for a different leptin receptor mutation, Leprfa (Zucker). Fasting in lean rats (+/fa) for 72 h significantly increased Agrp and Npy mRNA expression, and decreased Pomc mRNA expression as detected by a sensitive solution hybridization/S1 nuclease protection assay. Npy mRNA levels were significantly increased in fed obese fa/fa compared to lean rats, and further increased in the obese animals after fasting. In contrast, Agrp mRNA levels did not differ between fed lean and fed obese rats, and fasting did not significantly change Agrp levels in obese rats. To determine whether the change in Agrp expression that occurs with food deprivation in lean rats could be prevented by leptin replacement, Sprague-Dawley rats were fasted and infused via subcutaneous osmotic micropumps for 48 h with either saline or recombinant mouse leptin. Fasting significantly increased Agrp and Npy, and decreased Pomc mRNA levels. Leptin infusion almost completely reversed these changes such that there was no significant difference between the levels in the fasted rats and those that were fed ad libitum. Thus, in fasted lean rats, Agrp and Npy are upregulated in parallel when leptin levels fall and are downregulated by leptin infusion. By contrast, the absence of a functional leptin receptor results in the upregulation of Npy but not Agrp mRNA.