Cocaine- And Amphetamine-regulated Transcript Levels Research Articles

Comparison of orexigenic and anorexigenic neuropeptide levels in hyperemesis gravidarum patients with normal pregnant women: A prospective cohort study.

The aim of this study was to determine whether orexigenic neuropeptides, orexin and galanin, and anorexigenic neuropeptides, alpha-melanocyte-stimulating hormone (α-MSH) and cocaine- and amphetamine-regulated transcript (CART), are implicated in hyperemesis gravidarum (HG). Fifty pregnant women who had been diagnosed with HG between April 2022 and February 2023 at the Siirt University Faculty of Medicine Training and Research Hospital (tertiary center) were recruited for this study. An equal number of pregnant women without an HG diagnosis were included in the study as the control group. Participants' age, pregnancy history, medical history, thyroid function test results, complete blood count results, and electrolyte levels were recorded, and their orexin, galanin, α-MSH, and CART serum levels were analyzed using an enzyme-linked immunosorbent assay. No statistically significant differences in orexigenic neuropeptides (orexin and galanin) were observed between the HG and control groups. A statistical difference was found between an anorexigenic neuropeptide (α-MSH) and the control group (P = .012). Based on a receiver operating characteristic analysis, the α-MSH parameter was statistically significant for distinguishing between participants with an HG diagnosis and those without, with a sensitivity of 63.6%, specificity of 65.9%, and cutoff value of 11769.3 pg/mL (P = .012, area under curve: 0.655). Based on the severity classification of ketonuria (ketonuria levels of +1 or +2 were classified as mild, whereas levels of +3 or +4 were classified as moderate to severe), the anorexigenic CART neuropeptide was found to be a statistically significant diagnostic indicator of severe ketonuria (P = .020). α-MSH and CART levels were found to be related in HG patients and in HG patients with severe ketonuria.

Decreased Serum Cocaine- and Amphetamine-Regulated Transcript Level in Internet Gaming Disorder.

Vulnerability to internet gaming disorder (IGD) has increased as internet gaming continues to grow. Cocaine- and amphetamine-regulated transcript (CART) is a hormone that plays a role in reward, anxiety, and stress. The purpose of this study was to identify the role of CART in the pathophysiology of IGD. The serum CART levels were measured by enzyme-linked immunosorbent assay, and the associations of the serum CART level with psychological variables were analyzed in patients with IGD (n=31) and healthy controls (HC) (n=42). The serum CART level was significantly lower in the IGD than HC group. The IGD group scored significantly higher than the HC group on the psychological domains of depression, anxiety, the reward response in the Behavioral Activation System and Behavioral Inhibition System. There were no significant correlations between serum CART level and other psychological variables in the IGD group. Our results indicate that a decrease in the expression of the serum CART level is associated with the vulnerability of developing IGD. This study supports the possibility that CART is a biomarker in the pathophysiology of IGD.

Are decreased cocaine- and amphetamine regulated transcript and Agouti- related peptide levels associated Eating behavior in medication-free children with attention deficit and hyperactivity disorder?

This study aimed to investigate plasma levels of cocaine- and amphetamine-regulated transcript (CART), agouti-related protein (AgRP), cholecystokinin (CCK) and peptide YY (PYY) and their relationship with eating behaviors among children with attention deficit hyperactivity disorder (ADHD) and healthy controls. A total of 94 medication-free children with ADHD and 82 controls aged 8–14 years were included in this study. The Plasma levels of CART, AgRP, CCK and PYY were measured using enzyme-linked immunosorbent assay kits. The Children's Eating Behavior Questionnaire (CEBQ) was used to assess eating behaviors in children. CART and AgRP levels were found to be significantly lower in the ADHD group than in the control group, while CCK levels were found to be significantly higher in the ADHD group than in the control group. However, there was no significant difference in PYY levels between the groups. Compared to controls, those with ADHD demonstrated significantly higher scores on the CEBQ subscales of food responsiveness, emotional overeating, desire to drink, enjoyment of food, and food fussiness, and significantly lower scores on the slowness of eating subscale. CART was significantly correlated with emotional overeating and enjoyment of food scores, while AgRP was significantly correlated with emotional undereating scores. Covariance analysis was performed by controlling potential confounders such as body mass index, age and sex, and the results were found to be unchanged. It was concluded that CART, AgRP, and CCK may play a potential role in the pathogenesis of ADHD.

A potential role for GPR160 and its ligand, CART, in the modulation of feeding behavior in Prader-Willi Syndrome

Hyperphagia is a hallmark of Prader-Willi syndrome (PWS). Managing the extreme hunger and insatiability associated with PWS remains a considerable challenge to PWS patients and their caregivers. Appetite and feeding behavior are governed by numerous neural circuits, several of which are potentially disrupted when some or all of the Prader-Willi critical region on chromosome 15 is lost. Previous research has focused on well-established feeding circuits in an effort to uncover the physiology underlying PWS hyperphagic behavior; however, due to the complex interplay between these circuits, much is left to be explored. We have previously demonstrated that interactions between GPR160 and its ligand cocaine and amphetamine regulated transcript (CART) are important in the control of feeding behavior. Several groups have reported that CART exerts anorexigenic properties when injected into areas of the brain that are important to feeding behavior, including regions of the brainstem and hypothalamus. The prohormone convertase PSCK1, which is responsible for post-translational processing of the CART prohormone, appears to be reduced in PWS patients, suggesting that CART could play a role in the pathophysiology of PWS. Using a rat model of PWS supplied by the Foundation for Prader-Willi Research (Magel2- deficient), we seek to investigate this potential role of CART and GPR160 in PWS-associated hyperphagia. Through the use of continuous monitoring of food and water intake, we were able to define meal patterning differences between wild type and paternally Magel2-deficient rats. In addition to evaluating baseline meal patterning, we also administered CART centrally and recorded CART-induced changes in feeding behavior. Lastly, we determined physiologic changes in levels of GPR160, CART, and PSCK1 in the pituitary, hypothalamus, amygdala, and brainstem from WT and paternally-deficient Magel2 rats in the setting of metabolic stress (fasting). Although additional studies must be performed to better define the role of CART and GPR160 in the feeding behavior of PWS patients, we anticipate that this ligand-receptor pair has the potential to serve as a novel therapeutic target for the treatment of PWS-associated hyperphagia. Foundation for Prader-Willi Research This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Reproductive phase related variations in the expression of neuropeptide, cocaine- and amphetamine- regulated transcript (CART) in the brain and pituitary gland of adult male Microhyla ornata

Cocaine- and amphetamine-regulated transcript (CART) peptide is a multifaceted neuropeptide involved in several physiological functions including appetite and reproduction. While studies in mammals, aves and fishes suggest evolutionary conserved role of CART, the information in amphibian is scanty. We have investigated the reproductive phase related variations of CART in the brain of adult male Microhyla ornata. Seasonal changes in the expression of CART peptide were noticed in the brain and pituitary of M. ornata. Significant differences were observed in the nucleus infundibularis ventralis (NIV), epiphysis (E), anteroventral tegmental region (AV), raphe nucleus (Ra) of the brain and pars intermedia (PI), pars distalis (PD) of the pituitary. Compared to the pre-breeding and post-breeding seasons, increase in CART immunoreactivity was seen in E, NIV, AV, Ra of brain and PI, PD of pituitary gland of animals collected during breeding season. Similarly, highest mRNA levels of CART were also observed in the breeding season in the middle region of brain that includes hypothalamus and pituitary gland. Variation in the levels of CART peptide and mRNA in the brain of M. ornata suggests its conserved role in seasonal control of appetite and reproduction.

The anorexigenic effect of beta-melanocyte-stimulating hormone involves corticotrophin-releasing factor and mesotocin in birds

Beta-melanocyte-stimulating hormone (β-MSH), when centrally injected, induces anorexigenic effects in rodents and chickens but its mechanism remains unclear. Thus, the primary goal of this research was to elucidate the hypothalamic mechanism using chickens. Intracerebroventricular injection of 0.3, 1.0 and 3.0 nmol of β-MSH decreased food intake for 540 min. Expression of hypothalamic mRNAs were affected by β-MSH injection, including corticotrophin-releasing factor (CRF) and its receptor subtype 1 (CRFR1), mesotocin (MT) and its receptor (MTR), pro-opiomelanocortin, cocaine- and amphetamine-regulated transcript (CART), growth hormone secretagogue receptor (GHSR) and neuropeptide Y (NPY) receptor subtype 5 (NPYR5). Within the arcuate nucleus, expressions of NPY, agouti-related peptide, MT and MTR were increased by β-MSH injection. β-MSH-treated chicks had more CRF, CRFR1, CRF receptor subtype 2, GHSR, NPY receptor subtype 1 (NPYR1) and NPYR5 mRNA but lower levels of CART and ghrelin, in the paraventricular nucleus. Greater amounts of mRNA for MTR, GHSR, NPYR1 and NPYR5 and less CRF expression were observed in the ventromedial hypothalamus. In conclusion, central injection of β-MSH potently reduced food intake and was associated with changes in mRNA expression of some anorexigenic factors in a hypothalamic nucleus-specific manner.

Regulation of Pituitary Cocaine- and Amphetamine-Regulated Transcript Expression and Secretion by Hypothalamic Gonadotropin-Releasing Hormone in Chickens.

There is increasing evidence that cocaine- and amphetamine-regulated transcript (CART) peptide is abundantly expressed in the anterior pituitary of birds and mammals, suggesting that CART peptide may be a novel pituitary hormone and its expression and secretion is likely controlled by the hypothalamic factor(s). To substantiate this hypothesis, using chicken as an animal model, we examined the effects of gonadotropin-releasing hormone (GnRH) on pituitary CART secretion and expression and investigated whether GnRH could modulate plasma CART levels. The results showed that: (1) chicken GnRH (GnRH1 and GnRH2) could potently stimulate CART peptide secretion in intact pituitaries incubated in vitro, as detected by Western blot; (2) GnRH could also stimulate CART mRNA expression in cultured pituitary cells, as revealed by quantitative real-time polymerase chain reaction (qPCR) assay; (3) GnRH actions on pituitary CART expression and secretion are likely mediated by GnRH receptor coupled to the intracellular Ca2+, MEK/ERK, and cAMP/PKA signaling pathways; and (4) plasma CART levels are high in chickens at various developmental stages (1.2–3.5 ng/ml) and show an increasing trend towards sexual maturity, as detected by enzyme-linked immunosorbent assay (ELISA). Moreover, plasma CART levels could be significantly induced by intraperitoneal administration of GnRH in chicks. Taken together, our data provide the first collective evidence that CART peptide is a novel pituitary hormone and its expression and secretion are tightly controlled by hypothalamic GnRH, thus likely being an active player in the hypothalamic-pituitary-gonadal (HPG) axis.

Hypothalamic Energy Regulatory Peptides in Chronic Kidney Disease.

Loss of appetite affects one-third of patients with CKD and is the leading cause of malnutrition in this population. Orexigenic Agouti-related peptide (AgRP) with neuropeptide-Y (NPY) and anorexigenic melanocyte-stimulating hormone-α (MSH-α) with cocaine- and amphetamine-regulated transcript (CART) are known to regulate appetite. In this study, we aimed to evaluate the levels of these peptides in CKD patients compared to healthy subjects and demonstrate the effects of dialysis treatment and erythropoiesis-stimulating agent (ESA) therapy. The cross-sectional study is composed of consecutive inclusion of 20 healthy individuals, 20 predialysis CKD patients, 20 HD, and 20 peritoneal dialysis (PD) patients. Exclusion criteria were an active infection, history of malignancy, hypo- or hyperthyroidism, and diabetes. Patients on dialysis had targeted Kt/Vs. Demographic features and BMIs of the four groups were similar. Levels of AgRP, NPY, AMSH, and CART were significantly different between groups. Nondialysis CKD patients had significantly lower hypothalamic hormones compared to healthy individuals, HD and PD patients (P = 0.02, P = 0.03, and P = 0.07 for AgRP; P = 0.02, P = 0.01, and P = 0.09 for NPY; P = 0.02, P = 0.02, and P = 0.03 for AMSH; P = 0.02, P = 0.005, and P = 0.030 for CART). Dialysis patients with or without ESA treatment had similar hormone levels (P = 0.13 for AgRP; P = 0.11 for NPY; P = 0.23 for AMSH, and P = 019 for CART). Predialysis CKD patients have lower orexigenic and presumably indirectly lower anorexigenic peptides compared to healthy subjects and dialysis patients. ESA treatment does not affect these hypothalamic peptides in dialysis patients.

The relationship of body condition indicators with the level of plasma cocaine and amphetamine regulated transcript and energy metabolism indicators in dairy cows

The factors affecting the course of lactation and intensity of milk secretion include the condition and body weight, as well as chewing time. A little researched factor is also the cocaine and amphetamine regulated transcript (CART) which has been suggested to have an anorexigenic function. This study sought to examine the dependent indicators of condition and chewing time on daily milk yield assessment in the context of the concentration of CART, glucose and ß-hydroxybutyrate (BHB) in blood. Higher CART levels contributed to shorter chewing time (min/day), lower body condition and lower body weight. Blood glucose concentration showed a stronger correlation with body weight and condition than with blood BHB concentration. An important practical aspect of the results is the relationship shown between CART and chewing time and the potential relation between daily milk production and chewing time. Importantly, the animals with lower daily milk production had relatively the highest concentration CART. This may suggest that this neuropeptide is indirectly involved in milk production, especially by shortening the chewing time. The obtained results help to better explain the mechanisms involved in milk secretion and the process of rumination and digestion. More research is required, but they also show important functions of other examined neuropeptides.

Central action of CART induces neuronal activation in the paraventricular and dorsomedial hypothalamus of diet-induced obese and lean mice

The cocaine- and amphetamine-regulated transcript (CART) is a peptide commonly studied in the feeding behavior, but it exerts an important role in the autonomic and cardiovascular control as well. It is known that exogenous administration of CART in the central nervous system can elicit increase in blood pressure of both conscious and anesthetized rodents, but little is known whether these central effects might differ between lean and obese animals. We have recently shown that diet-induced obese mice that developed hypertension presented an upregulation of CART levels in the dorsomedial nucleus of hypothalamus, while obese normotensive ones had not. Herein we investigate whether the central action of CART could activate differently the hypothalamic nuclei of diet-induced obese mice compared to the lean counterparts by using Fos protein expression, C57BL/6 mice were randomly assigned to two cohorts, one fed with a high-fat diet for 8 weeks (obese), and the other fed with regular rodent chow (lean). Both groups received an ICV injection of CART at the dose of 400μM, 1 mM or vehicle. Subsequently, the brains were processed for Fos protein immunohistochemical in order to identify hypothalamic neuronal activation. Significantly greater numbers of Fos-positive neurons were observed in the PVN and DMH of obese mice that received CART 1 mM, when compared to the lean control. These results indicate that the central action of CART induces neuronal activation in the hypothalamic nuclei of obese and lean mice, and this could be relevant to the different autonomic and cardiovascular adjustments that an organism exposed to different diet and metabolic condition.

Cocaine‑ and amphetamine‑regulated transcript (CART) is associated with dopamine and is protective against ischemic stroke.

Cocaine and amphetamine-regulated transcript (CART) is a neuropeptide that can protect brains against ischemic injury. The aim of the present study was to investigate the effects of the CART within ischemic stroke and it possible mechanism. The expression levels of dopamine (DA) and CART in ischemic brain tissues of mice were measured following middle cerebral artery occlusion (MCAO). After receiving the treatment of DA and CART, the infarct volume of brain was measured in mice with MCAO. In addition, the function and potential mechanism of CART in ischemic stroke were further investigated. DA and CART expression was significantly decreased in mice with MCAO compared with normal control mice. Treatment of mice with MCAO with exogenous CART significantly decreased the extent of brain injury compared with untreated mice with MCAO. Treatment with exogenous CART promoted the survival of ex vivo neurons following oxygen-glucose deprivation (OGD), while exogenous DA induced CART mRNA expression in a dose-dependent manner, which suggested an association between CART and DA. Apoptosis of ex vivo neurons was significantly increased following OGD, however treatment with exogenous CART significantly inhibited this effect. The potential mechanism of CART was determined to be associated with inflammatory cytokines and related apoptotic genes. CART therefore appears to be associated with DA in its effect on ischemic stroke and is protective against brain injury following ischemic stroke by reducing inflammation activation; it may provide a promising means to treat ischemic stroke patients.

Low cocaine- and amphetamine-regulated transcript (CART) peptide levels in human cerebrospinal fluid of major depressive disorder (MDD) patients

BackgroundCocaine- and amphetamine-regulated transcript (CART) peptide is a candidate neuropeptide as a biomarker for major depressive disorder (MDD) because of its effects on emotion and distribution covering brain areas involved in the pathophysiology of MDD symptoms. However, it is unknown whether CART peptide levels are altered in the cerebrospinal fluid (CSF) of patients with MDD patients and are correlated with MDD symptoms. MethodsSubjects were 24 patients with MDD and 25 healthy controls matched for age, gender and ethnicity (Japanese). We measured CSF CART levels by a commercially available immunoassay kit and analyzed the relationships of the levels with antidepressant dose and symptoms assessed with the 21 item Hamilton Depression Rating Scale (HAMD-21). ResultsCSF CART levels were significantly decreased in the patients than in the controls (p < 0.05). In MDD patient group, the CART levels had a negative correlation with antidepressant dose (imipramine-equivalent dose) (ρ = −0.55, p < 0.01) and significantly decreased in antidepressant-treated group (AD-treated group) compared to controls (p < 0.05). CSF CART levels showed significant negative correlations with psychomotor retardation, somatic anxiety, and general somatic symptoms (all p < 0.05) and a positive correlation with obsessive and compulsive symptoms (p < 0.05). LimitationsIn our analysis, all classes of antidepressants were combined together and the effects of medication use in a longitudinal manner did not confirm. ConclusionsWe report for the first time that CSF CART peptide levels are reduced in patients with MDD compared with healthy controls. The CART levels showed negative correlations with antidepressant dose and some symptoms, supporting the possibility that CART peptide is involved in the development of depressive symptoms.

Increased cocaine and amphetamine-regulated transcript cord blood levels in the newborns exposed to crack cocaine in utero.

Cocaine and amphetamine-regulated transcript (CART) is an endogenous antioxidant present since the embryonic period. CART is activated by high levels of dopamine and might be of interested in understanding the changes in the REDOX system associated with crack/cocaine intake. The goal of this study was to determine whether exposure to crack in utero is associated with increased CART levels. In this cross-sectional study with consecutive sampling, we compared the umbilical cord blood (UCB) CART levels (μg/mL) of newborns exposed to crack/cocaine in utero (EN, n=57) to levels in non-exposed newborns (NEN, n=99). In addition, we compared serum CART levels between EN and NEN mothers, in the immediate postpartum period. Potential confounders, such as perinatal data (e.g., weight, Apgar, etc.), psychopathology (DSM-IV), and use of drugs other than crack (ASSIST) were assessed. According to general linear model analysis, the adjusted mean CART was significantly higher in EN (0.180, 95% CI 0.088-0.272) than in NEN (0.048, 95% CI 0.020-0.076; p<0.002; d=0.68). The difference in CART levels between EN and NEN mothers was not significant (p≥0.05). The increase in CART levels in EN UBC suggests a response to crack/cocaine-induced oxidative stress during gestational period, as a potential attempt of neuroprotection. In adult women in puerperium, however, this endogenous antioxidant recruitment does not seem to operate.

GPR88 is a critical regulator of feeding and body composition in mice

GPR88 is an orphan G-protein-coupled receptor with predominant expression in reward-related areas in the brain. While the lack of GPR88 has been demonstrated to induce behavioral deficits, the potential function of the receptor in the control of food intake and energy balance remains unexplored. In this work, the role of GPR88 in energy homeostasis was investigated in Gpr88−/− mice fed either standard chow or high fat diet (HFD). Gpr88−/− mice showed significantly reduced adiposity accompanied with suppressed spontaneous food intake, particularly pronounced under HFD treatment. While energy expenditure was likewise lower in Gpr88−/− mice, body weight gain remained unchanged. Furthermore, deregulation in glucose tolerance and insulin responsiveness in response to HFD was attenuated in Gpr88−/− mice. On the molecular level, distinct changes in the hypothalamic mRNA levels of cocaine-and amphetamine-regulated transcript (Cartpt), a neuropeptide involved in the control of feeding and reward, were observed in Gpr88−/− mice. In addition, GPR88 deficiency was associated with altered expressions of the anorectic Pomc and the orexigenic Npy in the arcuate nucleus, especially under HFD condition. Together, our results indicate that GPR88 signalling is not only important for reward processes, but also plays a role in the central regulatory circuits for energy homeostasis.

CART modulates beta-amyloid metabolism-associated enzymes and attenuates memory deficits in APP/PS1 mice

Introduction: Cocaine- and amphetamine-regulated transcript (CART) peptide has been demonstrated to exert neuroprotective effects in stroke and some neurodegeneration diseases. In current study, we investigated the protective effects and underlying mechanisms of CART in APP/PS1 mice.Methods: The protein levels of CART, soluble Aβ1–40 and Aβ1–42 were measured in the hippocampus of APP/PS1 mice by enzyme-linked immunosorbent assay. We determined the mRNA and protein levels of Aβ metabolism-associated enzymes including neprilysin (NEP), insulin-degrading enzyme (IDE), receptor for advanced glycation end products (RAGE), and low-density lipoprotein receptor-related protein 1 (LRP-1) in the hippocampus of APP/PS1 mice using real-time PCR and western blotting. Spatial memory was measured in APP/PS1 mice using the Morris water maze. The phosphorylation of AKT, ERK, p38, and JNK was determined using western blotting.Results: The levels of soluble Aβ1–40 and Aβ1–42 were significantly decreased in the hippocampus of APP/PS1 mice after CART treatment. CART modulated the levels of NEP, IDE, RAGE, and LRP-1. In addition, CART inhibited the MAPK pathways and activated the AKT pathway, whereas inhibition of the AKT pathway decreased the levels of IDE and LRP-1. Furthermore, CART attenuated spatial memory deficits in the APP/PS1 mice.Conclusion: CART decreases the levels of soluble Aβ in the hippocampus of APP/PS1 mice by modulating the expression of Aβ metabolism-associated enzymes, which may be associated with the MAPK and AKT pathways.

Adenovirus-mediated suppression of hypothalamic glucokinase affects feeding behavior

Glucokinase (GK), the hexokinase involved in glucosensing in pancreatic β-cells, is also expressed in arcuate nucleus (AN) neurons and hypothalamic tanycytes, the cells that surround the basal third ventricle (3V). Several lines of evidence suggest that tanycytes may be involved in the regulation of energy homeostasis. Tanycytes have extended cell processes that contact the feeding-regulating neurons in the AN, particularly, agouti-related protein (AgRP), neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC) neurons. In this study, we developed an adenovirus expressing GK shRNA to inhibit GK expression in vivo. When injected into the 3V of rats, this adenovirus preferentially transduced tanycytes. qRT-PCR and Western blot assays confirmed GK mRNA and protein levels were lower in GK knockdown animals compared to the controls. In response to an intracerebroventricular glucose injection, the mRNA levels of anorexigenic POMC and CART and orexigenic AgRP and NPY neuropeptides were altered in GK knockdown animals. Similarly, food intake, meal duration, frequency of eating events and the cumulative eating time were increased, whereas the intervals between meals were decreased in GK knockdown rats, suggesting a decrease in satiety. Thus, GK expression in the ventricular cells appears to play an important role in feeding behavior.

Dysregulation of hypothalamic modulation in olanzapine treated male rats

The mechanism of weight gain through application of olanzapine, a serotonin and dopamine receptor antagonist has not been fully understood. Weight gain and food intake are under the control of various neurohormones; POMC (proopiomelanocortin), CART (cocaine and amphetamine regulated transcript), AgRP (Agouti-related peptide) and NPY (neuropeptide Y) that are majorly synthesized and secreted from the arcuate nucleus (ARC) of hypothalamus. In this study, the alteration of the ARC neurohormone levels in rats were determined as one of the weight gain mechanisms. To understand the underlying mechanism of olanzapine-induced weight gain, the drug was orally administrated to healthy male Wistar rats for analysis of both the hypothalamic gene expression and peripheral levels of those candidate neuropeptides. In rats hypothalamic mRNA levels of NPY, AgRP and POMC decreased while CART levels did not show any alteration. Consistently, circulating levels of NPY, AgRP and α-MSH decreased significantly yet CART levels were also reduced. In conclusion, it may be presumed that the antagonistic effect of olanzapine on the ARC neurons might be the onset for a dysregulation of the neurohormones secretion which may cause weight gain during treatment.

High-fat diet-induced hypertension and autonomic imbalance are associated with an upregulation of CART in the dorsomedial hypothalamus of mice.

We evaluated herein whether diet‐induced obesity alters sympathovagal balance, blood pressure, and neuropeptides levels at the hypothalamus and brainstem of mice. Male C57BL6J mice fed with a high‐fat (HFD) or a high‐fat high‐sucrose (HFHSu), or a regular chow diet (C) for 8 weeks were evaluated for metabolic parameters and blood pressure, the latter being performed in conscious freely moving mice. Spectral analysis from the records of systolic blood pressure (SBP) and cardiac pulse intervals (PI) was performed to analyse the autonomic balance in the cardiovascular system. HFD‐fed mice developed two distinct hemodynamic phenotypes: hypertensive mice (HFD‐H) with high systolic and diastolic BP levels and hypertension‐resistant mice (HFD‐R) whose BP levels were similar to C group. Spectral analysis of SBP and PI variabilities indicate that the low‐frequency (LF)/high‐frequency (HF) ratio, which is an index of sympathovagal balance, is higher in HFD‐H compared to HFD‐R. Along with hypertension and higher LF/HF ratio, HFD‐H mice presented increased hypothalamic mRNA levels of cocaine‐ and amphetamine‐regulated transcript (CART), and increased CART‐positive neurones in the dorsomedial hypothalamus (DMH) by high‐fat diet when compared to C group. Despite developing obesity to similar levels than HFD feeding, intake of a HFHSu was not associated with hypertension in mice neither CART levels increase. Collectively, our main findings indicate that high‐fat diet induced‐hypertension and autonomic imbalance are associated to an upregulation of CART levels in the DMH of mice.

Transgenic n-3 PUFAs enrichment leads to weight loss via modulating neuropeptides in hypothalamus

Body weight is related to fat mass, which is associated with obesity. Our study explored the effect of fat-1 gene on body weight in fat-1 transgenic mice. In present study, we observed that the weight/length ratio of fat-1 transgenic mice was lower than that of wild-type mice. The serum levels of triglycerides (TG), cholesterol (CT), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) and blood glucose (BG) in fat-1 transgenic mice were all decreased. The weights of peri-bowels fat, perirenal fat and peri-testicular fat in fat-1 transgenic mice were reduced. We hypothesized that increase of n-3 PUFAs might alter the expression of hypothalamic neuropeptide genes and lead to loss of body weight in fat-1 transgenic mice. Therefore, we measured mRNA levels of appetite neuropeptides, Neuropeptide Y (NPY), Agouti-related peptides (AgRP), Proopiomelanocortin (POMC), Cocaine and amphetamine regulated transcript (CART), ghrelin and nesfatin-1 in hypothalamus by real-time PCR. Compared with wild-type mice, the mRNA levels of CART, POMC and ghrelin were higher, while the mRNA levels of NPY, AgRP and nesfatin-1 were lower in fat-1 transgenic mice. The results indicate that fat-1 gene or n-3 PUFAs participates in regulation of body weight, and the mechanism of this phenomenon involves the expression of appetite neuropeptides and lipoproteins in fat-1 transgenic mice.

Involvement of oxidative stress in the regulation of NPY/CART-mediated appetite control in amphetamine-treated rats

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.