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ObjectiveThe central melanocortin system is essential for the regulation of food intake and body weight. Agouti-related protein (AgRP) is the sole orexigenic component of the central melanocortin system and is conserved across mammalian species. AgRP is currently known to be expressed exclusively in the mediobasal hypothalamus, and hypothalamic AgRP-expressing neurons are essential for feeding. Here we characterized a previously unknown population of AgRP cells in the mouse hindbrain.MethodsExpression of AgRP in the hindbrain was investigated using gene expression analysis, single-cell RNA sequencing, immunofluorescent analysis and multiple transgenic mice with reporter expressions. Activation of AgRP neurons was achieved by Designer Receptors Exclusively Activated by Designer Drugs (DREADD) and by transcranial focal photo-stimulation using a step-function opsin with ultra-high light sensitivity (SOUL).ResultsAgRP expressing cells were present in the area postrema (AP) and the adjacent subpostrema area (SubP) and commissural nucleus of the solitary tract (cNTS) of the mouse hindbrain (termed AgRPHind herein). AgRPHind cells consisted of locally projecting neurons as well as tanycyte-like cells. Food deprivation stimulated hindbrain Agrp expression as well as neuronal activity of subsets of AgRPHind cells. In adult mice that lacked hypothalamic AgRP neurons, chemogenetic activation of AgRP neurons resulted in hyperphagia and weight gain. In addition, transcranial focal photo-stimulation of hindbrain AgRP cells increased food intake in adult mice with or without hypothalamic AgRP neurons.ConclusionsOur study indicates that the central melanocortin system in the hindbrain possesses an orexigenic component, and that AgRPHind neurons stimulate feeding independently of hypothalamic AgRP neurons.

Opioids are generally known to promote hedonic food consumption. Although much of the existing evidence is primarily based on studies of the mesolimbic pathway, endogenous opioids and their receptors are widely expressed in hypothalamic appetite circuits as well; however, their role in homeostatic feeding remains unclear. Using a fluorescent opioid sensor, deltaLight, here we report that mediobasal hypothalamic opioid levels increase by feeding, which directly and indirectly inhibits agouti-related protein (AgRP)-expressing neurons through the μ-opioid receptor (MOR). AgRP-specific MOR expression increases by energy surfeit and contributes to opioid-induced suppression of appetite. Conversely, its antagonists diminish suppression of AgRP neuron activity by food and satiety hormones. Mice with AgRP neuron-specific ablation of MOR expression have increased fat preference without increased motivation. These results suggest that post-ingestion release of endogenous opioids contributes to AgRP neuron inhibition to shape food choice through MOR signaling.

Introduction: Glucose homeostasis is a physiological process mediated by a variety of hormones. Fibroblast growth factor (FGF) 21 is a protein expressed in the liver, adipose tissue, muscle and pancreas and exerts actions in multiple targets including adipose, liver, pancreas and hypothalamus. The aim of this study was to examine the possible involvement of FGF21 in pancreatic and central control of glucose by measuring reflective changes in the release of insulin and glucagon. Methods: Thirty adult male Wistar Albino rats were divided; Control, PD + aCSF, PD + FGF21 groups (n = 10). Effects of intracerebroventricular (icv) FGF21 administration to pancreatic denervated (PD) rats. Agouti-related protein (AgRP), Pro-opiomelanocortin (POMC) levels and blood glucose homeostasis were investigated. Results: Administration of FGF21 to 3rd ventricle increased food consumption but body weight didn't change significantly. AgRP level increased, pancreatic insulin levels increased, and glucagon level decreased. Conclusion: Central FGF21 administration is effective in regulating blood glucose homeostasis by increasing the amount and efficiency of insulin and changing glucose use. [ABSTRACT FROM AUTHOR]

Abstract Background The CTNS gene mutation causes infantile nephropathic cystinosis (INC). Patients with INC develop Fanconi syndrome and chronic kidney disease (CKD) with significant bone deformations. C57BL/6 Ctns−/− mice are an animal model for studying INC. Hyperleptinaemia results from the kidney's inability to eliminate the hormone leptin in CKD. Ctns−/− mice have elevated serum leptin concentrations. Leptin regulates bone metabolism through its receptor that signals further via the hypothalamic melanocortin 4 receptor (MC4R). Leptin signalling may affect bone health in Ctns−/− mice. Methods We first defined the time course of bone abnormalities in Ctns−/− mice between 1 and 12 months of age. We used both genetic and pharmacological approaches to investigate leptin signalling in Ctns−/− mice. We generated Ctns−/−Mc4r−/− double knockout mice. Bone phenotype of Ctns−/−Mc4r−/− mice, Ctns−/− mice and wild type (WT) mice at 1, 4, and 9 months of age were compared. We then treated 12‐month‐old Ctns−/− mice and WT mice with a pegylated leptin receptor antagonist (PLA) (7 mg/kg/day, IP), a MC4R antagonist agouti‐related peptide (AgRP) (2 nmol, intracranial infusion on days 0, 3, 6, 9, 12, 15, 18, 21, 24, and 27), or vehicle (normal saline), respectively, for 28 days. Whole‐body (BMC/BMD, bone area) and femoral bone phenotype (BMC/BMD, bone area, length and failure load) of mice were measured by DXA and femoral shaft biochemical test. We also measured lean mass content by EchoMRI and muscle function (grip strength and rotarod activity) in mice. Femur protein content of JAK2 and STAT3 was measured by ELISA kits, respectively. Results Bone defects are present in Ctns−/− mice throughout its first year of life. The deletion of the Mc4r gene attenuated bone disorder in Ctns−/− mice. Femoral BMD, bone area, length, and strength (failure load) were significantly increased in 9‐month‐old Ctns−/−Mc4r−/− mice than in age‐matched Ctns−/− mice. PLA and AgRP treatment significantly increased femoral bone density (BMC/BMD) and mechanical strength in 12‐month‐old Ctns−/− mice. We adopted the pair‐feeding approach for this study to show that the protective effects of PLA or AgRP on bone phenotype are independent of their potent orexigenic effect. Furthermore, an increase in lean mass and in vivo muscle function (grip strength and rotarod activity) are associated with improvements in bone phenotype (femoral BMC/BMD and mechanical strength) in Ctns−/− mice, suggesting a muscle‐bone interplay. Decreased femur protein content of JAK2 and STAT3 was evident in Ctns−/− mice. PLA or AgRP treatment attenuated femur STAT3 content in Ctns−/− mice. Conclusions Our findings suggest a significant role for dysregulated leptin signalling in INC‐related bone disorder, either directly or potentially involving a muscle‐bone interplay. Leptin signalling blockade may represent a novel approach to treating bone disease as well as muscle wasting in INC.

Abstract Within the brain, the connections between neurons are constantly changing in response to environmental stimuli. A prime environmental regulator of neuronal activity is diet, and previous work has highlighted changes in hypothalamic connections in response to diets high in dietary fat and elevated sucrose. We sought to determine if the change in hypothalamic neuronal connections was driven primarily by an elevation in dietary fat alone. Analysis was performed in both male and female animals. We measured Agouti-related peptide (AgRP) neuropeptide and Synaptophysin markers in the paraventricular nucleus of the hypothalamus (PVH) in response to an acute 48 h high fat diet challenge. Using two image analysis methods described in previous studies, an effect of a high fat diet on AgRP neuronal projections in the PVH of male or female mice was not identified. These results suggest that it may not be dietary fat alone that is responsible for the previously published alterations in hypothalamic connections. Future work should focus on deciphering the role of individual macronutrients on neuroanatomical and functional changes.

Within the brain, the connections between neurons are constantly changing in response to environmental stimuli. A prime environmental regulator of neuronal activity is diet, and previous work has highlighted changes in hypothalamic connections in response to diets high in dietary fat and elevated sucrose. We sought to determine if the change in hypothalamic neuronal connections was driven primarily by an elevation in dietary fat alone. Analysis was performed in both male and female animals. We measured Agouti-related peptide (AgRP) neuropeptide and Synaptophysin markers in the paraventricular nucleus of the hypothalamus (PVH) in response to an acute 48 h high fat diet challenge. Using two image analysis methods described in previous studies, an effect of a high fat diet on AgRP neuronal projections in the PVH of male or female mice was not identified. These results suggest that it may not be dietary fat alone that is responsible for the previously published alterations in hypothalamic connections. Future work should focus on deciphering the role of individual macronutrients on neuroanatomical and functional changes. [ABSTRACT FROM AUTHOR]

ABSTRACT: The parents of broiler (meat) chickens (ie, broiler breeders) are food-restricted until sexual maturity, ensuring good health and reproduction, but resulting in hunger. We investigated whether diets with added insoluble fiber promote satiety and reduce behavioral, motivational, and physiological signs of hunger. Ninety-six broiler breeders were fed 1 of 4 feed treatments (n = 24 per diet) from 6 to 12 wk of age: 1) a commercial diet fed to the recommended ration (R) or 2) ad libitum (AL), the same diet as R but mixed with oat hulls at 3) 20% (OH20%) or 4) 40% (OH40%). The R, OH20% and OH40% diets were approximately iso-energetic and resulted in mean 12 wk of age weights within 2.5% of each other (1.21 kg), while AL birds weighed 221% as much (2.67kg). At 12 wk of age, agouti-related protein (AGRP) expression, was, on average, more than 12 times lower in AL birds (P < 0.001) but did not differ between the fiber diet treatments and R. Pro-opiomelanocortin (POMC) expression, was, on average, over 1.5 times higher in AL birds, but was not statistically significantly affected by feed treatments (P = 0.33). In their home pens, AL birds stood/sat more, foraged less and fed more in total (P < 0.001) and OH40% birds spent longer feeding than R (P = 0.001). Motivation to forage tested by willingness to walk through water to access an area of wood shavings (without food) was not significantly affected by diet (P = 0.33). However, restricted birds were willing to cross in only 7.3% to 12.5% of tests. Mostly birds stayed on the start platform, where AL birds sat more than other treatments and OH40% birds reduced walking relative to R birds (P = 0.016). Across the behavioral and physiological measurements there was a dichotomy of effects in response to approximately iso-energetic diets differing in fiber. There were some potentially beneficial behavioral effects related to reduced foraging and walking. However, there was no evidence that these diets significantly improved physiological measures of satiety of broiler breeders.

Abstract Background SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) monogenic mutations or deficiency leads to excessive stereotypic behavior and impaired sociability, which frequently occur in autism cases. To date, the underlying mechanisms by which Shank3 mutation or deletion causes autism and the part of the brain in which Shank3 mutation leads to the autistic phenotypes are understudied. The hypothalamus is associated with stereotypic behavior and sociability. p38α, a mediator of inflammatory responses in the brain, has been postulated as a potential gene for certain cases of autism occurrence. However, it is unclear whether hypothalamus and p38α are involved in the development of autism caused by Shank3 mutations or deficiency. Methods Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and immunoblotting were used to assess alternated signaling pathways in the hypothalamus of Shank3 knockout (Shank3 −/− ) mice. Home-Cage real-time monitoring test was performed to record stereotypic behavior and three-chamber test was used to monitor the sociability of mice. Adeno-associated viruses 9 (AAV9) were used to express p38α in the arcuate nucleus (ARC) or agouti-related peptide (AgRP) neurons. D176A and F327S mutations expressed constitutively active p38α. T180A and Y182F mutations expressed inactive p38α. Results We found that Shank3 controls stereotypic behavior and sociability by regulating p38α activity in AgRP neurons. Phosphorylated p38 level in hypothalamus is significantly enhanced in Shank3 −/− mice. Consistently, overexpression of p38α in ARC or AgRP neurons elicits excessive stereotypic behavior and impairs sociability in wild-type (WT) mice. Notably, activated p38α in AgRP neurons increases stereotypic behavior and impairs sociability. Conversely, inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3 −/− mice. In contrast, activated p38α in pro-opiomelanocortin (POMC) neurons does not affect stereotypic behavior and sociability in mice. Limitations We demonstrated that SHANK3 regulates the phosphorylated p38 level in the hypothalamus and inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3 −/− mice. However, we did not clarify the biochemical mechanism of SHANK3 inhibiting p38α in AgRP neurons. Conclusions These results demonstrate that the Shank3 deficiency caused autistic-like behaviors by activating p38α signaling in AgRP neurons, suggesting that p38α signaling in AgRP neurons is a potential therapeutic target for Shank3 mutant-related autism.

Hunger increases the motivation for calorie consumption, often at the expense of low‐taste appeal. However, the neural mechanisms integrating calorie‐sensing with increased motivation for calorie consumption remain unknown. Agouti‐related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus sense hunger, and the ingestion of caloric solutions promotes dopamine release in the absence of sweet taste perception. Therefore, we hypothesised that metabolic‐sensing of hunger by AgRP neurons would be essential to promote dopamine release in the nucleus accumbens in response to caloric, but not non‐caloric solutions. Moreover, we examined whether metabolic sensing in AgRP neurons affected taste preference for bitter solutions under conditions of energy need. Here we show that impaired metabolic sensing in AgRP neurons attenuated nucleus accumbens dopamine release in response to sucrose, but not saccharin, consumption. Furthermore, metabolic sensing in AgRP neurons was essential to distinguish nucleus accumbens dopamine response to sucrose consumption when compared with saccharin. Under conditions of hunger, metabolic sensing in AgRP neurons increased the preference for sucrose solutions laced with the bitter tastant, quinine, to ensure calorie consumption, whereas mice with impaired metabolic sensing in AgRP neurons maintained a strong aversion to sucrose/quinine solutions despite ongoing hunger. In conclusion, we demonstrate normal metabolic sensing in AgRP neurons drives the preference for calorie consumption, primarily when needed, by engaging dopamine release in the nucleus accumbens. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study aimed to elucidate the possible effects of the acute/long-term infusion of glucagon in the brain as the regulatory role on the endocrine secretions of the pancreas. MATERIALS AND METHODS: Ninety male Wistar albino rats were divided as Control, artificial Cerebrospinal Fluid (aCSF) (120 min), Glucagon (120 min), pancreatic denervation (PD)+aCSF (120 min), PD+Glucagon (120 min), aCSF (7 days), Glucagon (7 days), PD+aCSF (7 days) and PD+Glucagon (7 days). Glucagon and solvent (aCSF) were administered after pancreatic denervation (PD) by Hamilton syringe and osmotic mini pump (1 µg/10 µl/min) in the third ventricle of the brain. RESULTS: Acute intracerebroventricular (icv) administration of glucagon resulted in an elevation of glucagon levels and a concurrent reduction in blood glucose levels. Furthermore, in both the PD+aCSF (7 days) and PD+Glucagon (7 days) groups, there was a notable decrease in propiomelanocortin (POMC) and agouti-related protein (AgRP). Significant changes were observed in feed consumption and body weight, as well as pancreatic glucagon levels, with a simultaneous decrease in insulin levels in the PD (7 days), Glucagon (7 days), and PD+Glucagon (7 days) groups. These alterations were statistically significant when compared to the control group (p<0.05). CONCLUSIONS: The research outcomes established that pancreas-secreted glucagon functions as a neurohormone within the brain, activating central pathways linked to blood glucose regulation. The presence of glucagon led to a decrease in POMC levels. Surprisingly, this reduction in POMC resulted in the suppression of AgRP. Contrary to expectations, the suppression of AgRP led to an increase in food intake rather than a decrease. As already highlighted in the results section, it was emphasized that POMC may play a more significant role than AgRP in influencing feeding behavior. [ABSTRACT FROM AUTHOR]

Objective: The central melanocortin system is essential for the regulation of food intake and body weight. Agouti-related protein (AgRP) is the sole orexigenic component of the central melanocortin system and is conserved across mammalian species. AgRP is currently known to be expressed exclusively in the mediobasal hypothalamus, and hypothalamic AgRP-expressing neurons are essential for feeding. Here we characterized a previously unknown population of AgRP cells in the mouse hindbrain. Methods: Expression of AgRP in the hindbrain was investigated using gene expression analysis, single-cell RNA sequencing, immunofluorescent analysis and multiple transgenic mice with reporter expressions. Activation of AgRP neurons was achieved by Designer Receptors Exclusively Activated by Designer Drugs (DREADD) and by transcranial focal photo-stimulation using a step-function opsin with ultra-high light sensitivity (SOUL). Results: AgRP expressing cells were present in the area postrema (AP) and the adjacent subpostrema area (SubP) and commissural nucleus of the solitary tract (cNTS) of the mouse hindbrain (termed AgRPHind herein). AgRPHind cells consisted of locally projecting neurons as well as tanycyte-like cells. Food deprivation stimulated hindbrain Agrp expression as well as neuronal activity of subsets of AgRPHind cells. In adult mice that lacked hypothalamic AgRP neurons, chemogenetic activation of AgRP neurons resulted in hyperphagia and weight gain. In addition, transcranial focal photo-stimulation of hindbrain AgRP cells increased food intake in adult mice with or without hypothalamic AgRP neurons. Conclusions: Our study indicates that the central melanocortin system in the hindbrain possesses an orexigenic component, and that AgRPHind neurons stimulate feeding independently of hypothalamic AgRP neurons.

The molecular mechanisms underlying neuronal leptin and insulin resistance in obesity and diabetes are not fully understood. In this study, we show that induction of the unfolded protein response transcription factor, spliced X-box binding protein 1 (Xbp1s), in Agouti-Related Peptide (AgRP) neurons alone, is sufficient to not only protect against but also significantly reverse diet-induced obesity (DIO) as well as improve leptin and insulin sensitivity, despite activation of endoplasmic reticulum stress. We also demonstrate that constitutive expression of Xbp1s in AgRP neurons contributes to improved insulin sensitivity and glucose tolerance. Together, our results identify critical molecular mechanisms linking ER stress in arcuate AgRP neurons to acute leptin and insulin resistance as well as liver glucose metabolism in DIO and diabetes. • Deficiency of Xbp1 in AgRP neurons exacerbates the metabolic outcomes associated with diet-induced obesity. • Upregulation of Xbp1 in AgRP neurons prevents and reverses diet-induced obesity and improves glucose homeostasis. • Xbp1 deficiency accelerates, while its upregulation protects against ER stress-induced leptin resistance in AgRP neurons. • Constitutive activation of Xbp1s mimics the effects of exercise. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: The CTNS gene mutation causes infantile nephropathic cystinosis (INC). Patients with INC develop Fanconi syndrome and chronic kidney disease (CKD) with significant bone deformations. C57BL/6 Ctns -/- mice are an animal model for studying INC. Hyperleptinaemia results from the kidney's inability to eliminate the hormone leptin in CKD. Ctns -/- mice have elevated serum leptin concentrations. Leptin regulates bone metabolism through its receptor that signals further via the hypothalamic melanocortin 4 receptor (MC4R). Leptin signalling may affect bone health in Ctns -/- mice., Methods: We first defined the time course of bone abnormalities in Ctns -/- mice between 1 and 12 months of age. We used both genetic and pharmacological approaches to investigate leptin signalling in Ctns -/- mice. We generated Ctns -/- Mc4r -/- double knockout mice. Bone phenotype of Ctns -/- Mc4r -/- mice, Ctns -/- mice and wild type (WT) mice at 1, 4, and 9 months of age were compared. We then treated 12-month-old Ctns -/- mice and WT mice with a pegylated leptin receptor antagonist (PLA) (7 mg/kg/day, IP), a MC4R antagonist agouti-related peptide (AgRP) (2 nmol, intracranial infusion on days 0, 3, 6, 9, 12, 15, 18, 21, 24, and 27), or vehicle (normal saline), respectively, for 28 days. Whole-body (BMC/BMD, bone area) and femoral bone phenotype (BMC/BMD, bone area, length and failure load) of mice were measured by DXA and femoral shaft biochemical test. We also measured lean mass content by EchoMRI and muscle function (grip strength and rotarod activity) in mice. Femur protein content of JAK2 and STAT3 was measured by ELISA kits, respectively., Results: Bone defects are present in Ctns -/- mice throughout its first year of life. The deletion of the Mc4r gene attenuated bone disorder in Ctns -/- mice. Femoral BMD, bone area, length, and strength (failure load) were significantly increased in 9-month-old Ctns -/- Mc4r -/- mice than in age-matched Ctns -/- mice. PLA and AgRP treatment significantly increased femoral bone density (BMC/BMD) and mechanical strength in 12-month-old Ctns -/- mice. We adopted the pair-feeding approach for this study to show that the protective effects of PLA or AgRP on bone phenotype are independent of their potent orexigenic effect. Furthermore, an increase in lean mass and in vivo muscle function (grip strength and rotarod activity) are associated with improvements in bone phenotype (femoral BMC/BMD and mechanical strength) in Ctns -/- mice, suggesting a muscle-bone interplay. Decreased femur protein content of JAK2 and STAT3 was evident in Ctns -/- mice. PLA or AgRP treatment attenuated femur STAT3 content in Ctns -/- mice., Conclusions: Our findings suggest a significant role for dysregulated leptin signalling in INC-related bone disorder, either directly or potentially involving a muscle-bone interplay. Leptin signalling blockade may represent a novel approach to treating bone disease as well as muscle wasting in INC., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

The lactational period is associated with profound hyperphagia to accommodate the energy demands of nursing. These changes are important for the long-term metabolic health of the mother and children as altered feeding during lactation increases the risk of mothers and offspring developing metabolic disorders later in life. However, the specific behavioral mechanisms and neural circuitry mediating the hyperphagia of lactation are incompletely understood. Here, we utilized home cage feeding devices to characterize the dynamics of feeding behavior in lactating mice. A combination of pharmacological and behavioral assays were utilized to determine how lactation alters meal structure, circadian aspects of feeding, hedonic feeding, and sensitivity to hunger and satiety signals in lactating mice. Finally, we utilized chemogenetic, immunohistochemical, and in vivo imaging approaches to characterize the role of hypothalamic agouti-related peptide (AgRP) neurons in lactational-hyperphagia. The lactational period is associated with increased meal size, altered circadian patterns of feeding, reduced sensitivity to gut-brain satiety signals, and enhanced sensitivity to negative energy balance. Hypothalamic AgRP neurons display increased sensitivity to negative energy balance and altered in vivo activity during the lactational state. Further, using in vivo imaging approaches we demonstrate that AgRP neurons are directly activated by lactation. Chemogenetic inhibition of AgRP neurons acutely reduces feeding in lactating mice, demonstrating an important role for these neurons in lactational-hyperphagia. Together, these results show that lactation collectively alters multiple components of feeding behavior and position AgRP neurons as an important cellular substrate mediating the hyperphagia of lactation. • Lactation increases meal size and alters circadian feeding patterns in mice. • Lactating mice exhibit increased sensitivity to hunger signals. • Lactating mice have an attenuated response to satiety signals. • AgRP neurons are activated by nursing in lactating mice. • AgRP neurons are required for lactational hyperphagia. [ABSTRACT FROM AUTHOR]

Lipids are essential for neuron development and physiology. Yet, the central hubs that coordinate lipid supply and demand in neurons remain unclear. Here, we combine invertebrate and vertebrate models to establish the presence and functional significance of neuronal lipid droplets (LD) in vivo . We find that LD are normally present in neurons in a non-uniform distribution across the brain, and demonstrate triglyceride metabolism enzymes and lipid droplet-associated proteins control neuronal LD formation through both canonical and recently-discovered pathways. Appropriate LD regulation in neurons has conserved and male-biased effects on whole-body energy homeostasis across flies and mice, specifically neurons that couple environmental cues with energy homeostasis. Mechanistically, LD-derived lipids support neuron function by providing phospholipids to sustain mitochondrial and endoplasmic reticulum homeostasis. Together, our work identifies a conserved role for LD as the organelle that coordinates lipid management in neurons, with implications for our understanding of mechanisms that preserve neuronal lipid homeostasis and function in health and disease., Competing Interests: DECLARATION OF COMPETING INTERESTS The authors declare no competing interests.

The parents of broiler (meat) chickens (ie, broiler breeders) are food-restricted until sexual maturity, ensuring good health and reproduction, but resulting in hunger. We investigated whether diets with added insoluble fiber promote satiety and reduce behavioral, motivational, and physiological signs of hunger. Ninety-six broiler breeders were fed 1 of 4 feed treatments (n = 24 per diet) from 6 to 12 wk of age: 1) a commercial diet fed to the recommended ration (R) or 2) ad libitum (AL), the same diet as R but mixed with oat hulls at 3) 20% (OH20%) or 4) 40% (OH40%). The R, OH20% and OH40% diets were approximately iso-energetic and resulted in mean 12 wk of age weights within 2.5% of each other (1.21 kg), while AL birds weighed 221% as much (2.67kg). At 12 wk of age, agouti-related protein (AGRP) expression, was, on average, more than 12 times lower in AL birds (P < 0.001) but did not differ between the fiber diet treatments and R. Pro-opiomelanocortin (POMC) expression, was, on average, over 1.5 times higher in AL birds, but was not statistically significantly affected by feed treatments (P = 0.33). In their home pens, AL birds stood/sat more, foraged less and fed more in total (P < 0.001) and OH40% birds spent longer feeding than R (P = 0.001). Motivation to forage tested by willingness to walk through water to access an area of wood shavings (without food) was not significantly affected by diet (P = 0.33). However, restricted birds were willing to cross in only 7.3% to 12.5% of tests. Mostly birds stayed on the start platform, where AL birds sat more than other treatments and OH40% birds reduced walking relative to R birds (P = 0.016). Across the behavioral and physiological measurements there was a dichotomy of effects in response to approximately iso-energetic diets differing in fiber. There were some potentially beneficial behavioral effects related to reduced foraging and walking. However, there was no evidence that these diets significantly improved physiological measures of satiety of broiler breeders., Competing Interests: DISCLOSURES The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Laura Dixon reports financial support was provided by Biotechnology and Biological Sciences Research Council. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

• Jinkui Shenqi pills (JSP) has a regulatory effect on glucose homeostasis. • JSP ameliorates diabetes through regulating the POMC/AgRP expression and activity, and improving insulin resistance in the hypothalamus. • It underscores the potential of JSP as a multifaceted therapeutic agent in the management of diabetes-related metabolic dysfunctions. Research on the imbalance of proopiomelanocortin (POMC)/agouti-related protein (AgRP) neurons in the hypothalamus holds potential insights into the pathophysiology of diabetes. Jinkui Shenqi pills (JSP), a prevalent traditional Chinese medicine, regulate hypothalamic function and treat diabetes. To investigate the hypoglycemic effect of JSP and explore the probable mechanism in treating diabetes. A type 2 diabetes mouse model was used to investigate the pharmacodynamics of JSP. The glucose-lowering efficacy of JSP was assessed through various metrics including body weight, food consumption, fasting blood glucose (FBG), serum insulin levels, and an oral glucose tolerance test (OGTT). To elucidate the modulatory effects of JSP on hypothalamic mechanisms, we quantified the expression and activity of POMC and AgRP and assessed the insulin-mediated phosphoinositide 3-kinase (PI3K)/protein kinase A (AKT)/forkhead box O1 (FOXO1) pathway in diabetic mice via western blotting and immunohistochemistry. Additionally, primary hypothalamic neurons were exposed to high glucose and palmitic acid levels to induce insulin resistance, and the influence of JSP on POMC/AgRP protein expression and activation was evaluated by PI3K protein inhibition using western blotting and immunofluorescence. Medium- and high-dose JSP treatment effectively inhibited appetite, resulting in a steady declining trend in body weight, FBG, and OGTT results in diabetic mice (p < 0.05). These JSP groups also had significantly increased insulin levels (p < 0.05). Importantly, the medium-dose group exhibited notable protection of hypothalamic neuronal and synaptic structures, leading to augmentation of dendritic length and branching (p < 0.05). Furthermore, low-, medium-, and high-dose JSP groups exhibited increased phosphorylated (p) INSR, PI3K, pPI3K, AKT, and pAKT expression, as well as decreased FOXO1 and increased pFOXO1 expression, indicating improved hypothalamic insulin resistance in diabetic mice (p < 0.05). Treatment with 10% JSP-enriched serum produced a marked elevation of both expression and activation of POMC (p < 0.05), with a concurrent reduction in AgRP expression and activation within primary hypothalamic neurons (p < 0.05). Intriguingly, these effects could be attributed to the regulatory dynamics of PI3K activity. Our findings suggest that JSP can ameliorate diabetes by regulating POMC/AgRP expression and activity. The insulin-mediated PI3K/AKT/FOXO1 pathway plays an important regulatory role in this intricate process. [Display omitted] [ABSTRACT FROM AUTHOR]

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. • Children with ADHD had lower plasma CART and AgRP levels than controls. • Children with ADHD had higher plasma CCK levels than controls. • There was no significant change in plasma Peptide YY levels in children with ADHD. • CART was significantly correlated with emotional overeating and enjoyment of food scores. • AgRP was significantly correlated with emotional undereating scores. [ABSTRACT FROM AUTHOR]

The central melanocortin system is essential for the regulation of food intake and body weight. Agouti-related protein (AgRP) is the sole orexigenic component of the central melanocortin system and is conserved across mammalian species. AgRP is currently known to be expressed exclusively in the mediobasal hypothalamus, and hypothalamic AgRP-expressing neurons are essential for feeding. Here we characterized a previously unknown population of AgRP cells in the mouse hindbrain. Expression of AgRP in the hindbrain was investigated using gene expression analysis, single-cell RNA sequencing, immunofluorescent analysis and multiple transgenic mice with reporter expressions. Activation of AgRP neurons was achieved by Designer Receptors Exclusively Activated by Designer Drugs (DREADD) and by transcranial focal photo-stimulation using a step-function opsin with ultra-high light sensitivity (SOUL). AgRP expressing cells were present in the area postrema (AP) and the adjacent subpostrema area (SubP) and commissural nucleus of the solitary tract (cNTS) of the mouse hindbrain (termed AgRPHind herein). AgRPHind cells consisted of locally projecting neurons as well as tanycyte-like cells. Food deprivation stimulated hindbrain Agrp expression as well as neuronal activity of subsets of AgRPHind cells. In adult mice that lacked hypothalamic AgRP neurons, chemogenetic activation of AgRP neurons resulted in hyperphagia and weight gain. In addition, transcranial focal photo-stimulation of hindbrain AgRP cells increased food intake in adult mice with or without hypothalamic AgRP neurons. Our study indicates that the central melanocortin system in the hindbrain possesses an orexigenic component, and that AgRPHind neurons stimulate feeding independently of hypothalamic AgRP neurons. [Display omitted] • AgRP is expressed in the dorsal vagal complex of the mouse hindbrain. • Food deprivation increases expression of AgRP in the hindbrain and neuronal activity of hindbrain AgRP cells. • Activation of hindbrain AgRP cells stimulates feeding, and this action is independent of hypothalamic AgRP neurons. [ABSTRACT FROM AUTHOR]