Central glucagon-like peptide-1 (GLP-1), secreted by a distinct population of nucleus tractus solitarius neurons, suppresses feeding but the exact mechanisms of action in the brain remain unclear. Here, we investigate a descending circuit formed by GLP-1 receptor (GLP-1R) neurons in the paraventricular hypothalamic nucleus (PVNGLP-1R) projecting to the dorsal vagal complex (DVC) of the brain stem in mice. PVNGLP-1R→DVC synapses release glutamate and are augmented by GLP-1. Chemogenetic activation of PVNGLP-1R→DVC suppresses feeding. Under an energy deficit (that is, hunger) state, synaptic strength is weaker but is more profoundly augmented by GLP-1R activation than under energy-replete state. In an obese condition, the dynamic synaptic changes in this circuit are disrupted. Optogenetic activation of PVNGLP-1R→DVC projections suppresses food intake energy state dependently, and blocking its synaptic release or ablating GLP-1Rs in the presynaptic neurons impairs metabolic health. These findings indicate that the state-dependent synaptic regulation by GLP-1 in PVNGLP-1R→DVC descending circuit is important for energy homeostasis.

Housing conditions, which have a major impact on the welfare of laboratory animals, are an important issue in experimental research. Individually ventilated cage (IVC) and open-top cage (OTC) systems are widely used for housing laboratory mice.

This study aimed to comprehensively investigate the effects of OTC and IVC housing conditions on the behavior, metabolism, and pain responses of laboratory mice from an animal welfare perspective.

We measured body temperature, body weight, anxiety levels (using the elevated plus maze and open field test), and thermal nociceptive responses (using the hot-plate and tail-flick tests) in male albino BALB/c mice. At the end of these procedures, the mice were sacrificed, and the serum levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT), ghrelin, and leptin were determined by ELISA, and the weight of the adrenal glands was measured.

The results showed that there were significant differences in body weight, body temperature, anxiety-related behaviors, pain latency, and hormonal parameters between the OTC group and the IVC group. Compared to OTC, IVC had lower levels of leptin, especially under stress conditions, where a significant interaction between housing and stress was observed, and higher levels of ghrelin, ACTH, and CORT. IVC group also had increased body weight, adrenal gland weight, and body temperature. In the hot-plate test, the IVC group showed increased latency of hind limb responses compared to the OTC group, but not in the tail-flick test. IVC group exhibited more anxiety-related behaviors in the OFT, while no differences were observed in the EPM.

According to the results of this study, housing mice in IVCs appears to compromise welfare, altering behavioral, hormonal, and pain responses. This suggests that the IVC system can induce physiological and behavioral stress, potentially acting as a systemic confounding factor in mouse research.

Appetite regulation is a complex process that is critical for maintaining energy balance and is governed by intricate molecular and cellular mechanisms in the hypothalamus. RNA-binding proteins play vital roles in the post-transcriptional regulation of mRNA and influence feeding behavior and energy metabolism. This study explored the role of cold-inducible RNA-binding protein (Cirbp) in hypothalamic neurons under metabolic stress conditions, such as fasting and cold exposure. Next-generation sequencing (NGS) of the hypothalami from fasted mice identified 67 differentially expressed RNA-binding proteins, with Cirbp and RNA-binding motif protein 3 (Rbm3) being significantly upregulated. Immunohistochemical analysis confirmed increased Cirbp expression in the arcuate nucleus (ARC) and dorsomedial hypothalamus during fasting, indicating responsiveness to metabolic cues. Ribo-Tag analysis of agouti-related protein (AgRP) neurons demonstrated elevated Cirbp expression levels in response to fasting, linking it to hunger-regulating pathways. Intracerebroventricular injection of Cirbp antisense oligodeoxynucleotides (AS ODN) reduced Cirbp expression, leading to a decrease in food intake and a reduction in body weight, highlighting the functional role of Cirbp in appetite regulation. Cold exposure also induced Cirbp expression in the ARC, which correlated with an increase in food intake. Blockade of Cirbp by AS ODN treatment attenuated cold-induced food intake, indicating that Cirbp plays a specific role in regulating feeding behavior during cold stress. This suggests that Cirbp is a key mediator in hypothalamic responses to metabolic stress, influencing feeding behavior through its regulatory functions in AgRP neurons. Further exploration of Cirbp mechanisms may offer insights into therapeutic strategies for energy balance disorders, such as obesity and anorexia.

Estrogen is synthesized throughout various tissues in the body, and its production is regulated by the rate-limiting enzyme aromatase (encoded by the Cyp19a1 gene). Notably, aromatase is also expressed in central nervous system cells, allowing for localized estrogen synthesis in regions such as the hypothalamus. Estrogens produced within these neurons are referred to as neuroestrogens. In this study, we investigated the role of neuroestrogens in the regulation of appetite through modulation of hypothalamic pathways in OVX, ArKO, and aromatase-restored mice. Estrogen suppresses appetite by influencing the expression of appetite-regulating peptides, including POMC and NPY, via MC4R. We explored the direct effects of neuroestrogens, independent from ovarian estrogen, on appetite suppression and the underlying molecular mechanisms. We monitored body weight and food intake and evaluated the expression of Cyp19a1, Mc4r, and other appetite-related genes. Our findings indicate that OVX and ArKO mice exhibited increased body weight and food consumption, which correlated with altered expression of Mc4r and Cyp19a1. Conversely, restoration of Cyp19a1 expression in a neuron specific manner significantly decreased food intake and increased Mc4r expression in the hypothalamus. Furthermore, neuroestrogens enhanced leptin responsiveness. Our results imply that neuroestrogens likely contribute to appetite regulation and may be relevant for body weight reduction.

Stress, an evolutionarily adaptive mechanism, has become a pervasive challenge in modern life, significantly impacting feeding-relevant circuits that play a role in the development and pathogenesis of eating disorders (EDs). Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, disrupts specific neural circuits, and dysregulates key brain regions, including the hypothalamus, hippocampus, and lateral septum. These particular structures are interconnected and key in integrating stress and feeding signals, modulating hunger, satiety, cognition, and emotional coping behaviors. Here we discuss the interplay between genetic predispositions and environmental factors that may exacerbate ED vulnerability. We also highlight the most commonly used animal models to study the mechanisms driving EDs and recent rodent studies that emphasize the discovery of novel cellular and molecular mechanisms integrating stress and feeding signals within the hippocampus-lateral septum-hypothalamus axis. In this review, we discuss the role of gut microbiome, an emerging area of research in the field of EDs and unanswered questions that persist and hinder the scientific progress, such as why some individuals remain resilient to stress while others become at high risk for the development of EDs. We finally discuss the need for future research delineating the impact of specific stressors on neural circuits, clarifying the relevance and functionality of hippocampal-septal-hypothalamic connectivity, and investigating the role of key neuropeptides such as CRH, oxytocin, and GLP-1 in human ED pathogenesis. Emerging tools like single-cell sequencing and advanced human imaging could uncover cellular and circuit-level changes in brain areas relevant for feeding in ED patients. Ultimately, by integrating basic and clinical research, science offers promising avenues for developing personalized, mechanism-based treatments targeting maladaptive eating behavior for patients suffering from EDs.

Neuronal growth regulator 1 (NEGR1) is a synaptic plasma membrane localized cell adhesion molecule implicated in a wide spectrum of psychiatric disorders. By RNAseq analysis of the transcriptomic changes in the brain of NEGR1-deficient mice, we found that NEGR1 deficiency affects the expression of the Gad2 gene. We show that glutamic acid decarboxylase 65 (GAD65), the Gad2 - encoded enzyme synthesizing the inhibitory neurotransmitter GABA on synaptic vesicles, accumulates non-synaptically in brains of NEGR1-deficient mice. The density of non-synaptic GAD65 accumulations is also increased in NEGR1 deficient cultured hypothalamic neurons, and this effect is rescued by re-expression of NEGR1. By using a novel biosensor of the plasma membrane attachment of GAD65, we demonstrate that GAD65 attaches to the plasma membrane. NEGR1 promotes palmitoylation-dependent clearance of GAD65 from the plasma membrane and targeting of GAD65 to plasma membrane-derived endocytic vesicles. In NEGR1 deficient cultured hypothalamic neurons, the synaptic and extrasynaptic levels of the plasma membrane attached GAD65 are increased, and the synaptic levels of GABA are reduced. NEGR1-deficient mice are characterized by reduced body weight, lower GABAergic synapse densities in the arcuate nucleus, and blunted responsiveness to the reinforcing effects of food rewards. Our results indicate that abnormalities in synaptic GABA synthesis can contribute to brain disorders associated with abnormal expression of NEGR1 in humans.

The cloning of leptin 30 years ago in 1994 was an important milestone in obesity research. Prior to the discovery of leptin, obesity was stigmatized as a condition caused by lack of character and self-control. Mutations in either leptin or its receptor were the first single gene mutations found to cause severe obesity, and it is now recognized that obesity is caused mostly by a dysregulation of central neuronal circuits. Since the discovery of the leptin-deficient obese mouse (ob/ob) the cloning of leptin (ob aka lep) and leptin receptor (db aka lepr) genes, we have learned much about leptin and its action in the central nervous system. The first hope that leptin would cure obesity was quickly dampened because humans with obesity have increased leptin levels and develop leptin resistance. Nevertheless, leptin target sites in the brain represent an excellent blueprint to understand how neuronal circuits control energy homeostasis. Our expanding understanding of leptin function, interconnection of leptin signaling with other systems and impact on distinct physiological functions continues to guide and improve the development of safe and effective interventions to treat metabolic illnesses. This review highlights past concepts and current emerging concepts of the hormone leptin, leptin receptor signaling pathways and central targets to mediate distinct physiological functions.

The brain coordinates the homeostatic defense of multiple metabolic variables, including blood glucose levels, in the context of ever-changing external and internal environments. The biologically defended level of glycemia (BDLG) is the net result of brain modulation of insulin-dependent mechanisms in cooperation with the islet, and insulin-independent mechanisms through direct innervation and neuroendocrine control of glucose effector tissues. In this article, we highlight evidence from animal and human studies to develop a framework for the brain's core homeostatic functions-sensory/afferent, integration/processing, and motor/efferent-that contribute to the normal BDLG in health and its elevation in diabetes.

Obesity, a prevalent disorder, predisposes individuals to metabolic syndrome, type 2 diabetes mellitus, and high blood pressure. Obesity has been investigated in various organisms that display genetic, high-fat, and high-carbohydrate diet (HFCD)-induced obesity. Recent studies have found that both male and female Zucker rats, which are genetically obese, exhibit alterations in dendritic arborization of neurons in certain structures of the central nervous system. Therefore, the present study aimed to analyze dendritic arborization and dendritic spine density of pyramidal neurons in the medial prefrontal cortex (mPFC) of obese adult male Zucker rats using the Golgi-Cox method and Sholl analysis. Obese male Zucker rats exhibit increased body weight and high concentrations of glucose, triglycerides, and cholesterol. Analysis of mPFC pyramidal neurons in these rats revealed basilar dendritic retraction at a medium distance from the soma, in addition to a reduction in total basilar dendritic length, without any changes in dendritic spine density. These findings are consistent with previous reports, indicating that changes in dendritic retraction may occur as a result of the leptin receptor mutation itself, in addition to the reduction in dendritic arborization observed in other regions of the central nervous system in rats. Furthermore, we suggest the possibility that biological processes modulated by the mPFC, such as foraging and social behavior, are also affected.

The expression of BDNF in both neuronal and non-neuronal cells is influenced by various stimuli, including prenatal developmental factors and postnatal conditions such as estrogens, dietary habits, and lifestyle factors like obesity, blood pressure, and aging. Central BDNF plays a crucial role in modulating how target tissues respond to these stimuli, influencing the pathogenesis of hypertension, mitigating obesity, and protecting neurons from aging. Thus, BDNF serves as a dynamic mediator of environmental influences, reflecting an individual's unique history of exposure. Estrogens, on the other hand, regulate various processes to maintain overall physiological well-being. Through nuclear estrogen receptors (ERα, ERβ) and the membrane estrogen receptor (GPER1), estrogens modulate transcriptional processes and signaling events that regulate the expression of target genes, such as ERα, components of the renin-angiotensin system (RAS), and hormone-sensitive lipase. Estrogens are instrumental in maintaining the set point for blood pressure and energy balance. BDNF and estrogens work cooperatively to prevent obesity by favoring lipolysis, and counteractively regulate blood pressure to adapt to the environment. Estrogen deficiency leads to menopause in women with low central BDNF level. This review delves into the complex mechanisms involving BDNF and estrogen, especially in the context of hypertension and obesity, particularly among postmenopausal women. The insights gained aim to inform the development of comprehensive therapeutic strategies for these prevalent syndromes affecting approximately 68% of adults.

The paraventricular hypothalamus (PVH) is crucial for food intake control, yet the presynaptic mechanisms underlying PVH neurons remain unclear. Here, we show that RUVBL2 in the PVH is significantly reduced during energy deficit, and knockout (KO) of PVH RUVBL2 results in hyperphagic obesity in mice. RUVBL2-expressing neurons in the PVH (PVHRUVBL2) exert the anorexigenic effect by projecting to the arcuate hypothalamus, the dorsomedial hypothalamus, and the parabrachial complex. We further demonstrate that PVHRUVBL2 neurons form the synaptic connections with POMC and AgRP neurons in the ARC. PVH RUVBL2 KO impairs the excitatory synaptic transmission by reducing presynaptic boutons and synaptic vesicles near active zone. Finally, RUVBL2 overexpression in the PVH suppresses food intake and protects against diet induced obesity. Together, this study demonstrates an essential role for PVH RUVBL2 in food intake control, and suggests that modulation of synaptic plasticity could be an effective way to curb appetite and obesity.

Coordinated detection of changes in metabolic state by the nervous system is fundamental for survival. Hypothalamic pro-opiomelanocortin (POMC) neurons play a critical role in integrating metabolic signals, including leptin levels. They also coordinate adaptative responses and thus represent an important relay in the regulation of energy balance. Despite a plethora of work documenting the effects of individual hormones, nutrients, and neuropeptides on POMC neurons, the importance for crosstalk and additive effects between such signaling molecules is still underexplored. The ability of the metabolic state and the concentrations of nutrients, such as glucose, to influence leptin's effects on POMC neurons appears critical for understanding the function and complexity of this regulatory network. Here, we summarize the current knowledge on the effects of leptin on POMC neuron electrical excitability and discuss factors potentially contributing to variability in these effects, with a particular focus on the mouse models that have been developed and the importance of extracellular glucose levels. This review highlights the importance of the metabolic "environment" for determining hypothalamic neuronal responsiveness to metabolic cues and for determining the fundamental effects of leptin on the activity of hypothalamic POMC neurons.

In April 2023, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), in partnership with the National Institute of Child Health and Human Development, the National Institute on Aging, and the Office of Behavioral and Social Sciences Research, hosted a 2-day online workshop to discuss neural plasticity in energy homeostasis and obesity. The goal was to provide a broad view of current knowledge while identifying research questions and challenges regarding neural systems that control food intake and energy balance. This review includes highlights from the meeting and is intended both to introduce unfamiliar audiences with concepts central to energy homeostasis, feeding, and obesity and to highlight up-and-coming research in these areas that may be of special interest to those with a background in these fields. The overarching theme of this review addresses plasticity within the central and peripheral nervous systems that regulates and influences eating, emphasizing distinctions between healthy and disease states. This is by no means a comprehensive review because this is a broad and rapidly developing area. However, we have pointed out relevant reviews and primary articles throughout, as well as gaps in current understanding and opportunities for developments in the field.

Neuroscience offers important insights into the pathogenesis and treatment of obesity by investigating neural circuits underpinning appetite and feeding. Gamma-aminobutyric acid (GABA), one of the most abundant neurotransmitters in the brain, and its associated receptors represent an array of pharmacologically targetable mediators of appetite signalling. Targeting the GABAergic system is therefore an increasingly investigated approach to obesity treatment. However, the many GABAergic projections that control feeding have yet to be collectively analysed. This review provides a comprehensive analysis of the relationship between GABAergic signalling and appetite by examining both foundational studies and the results of newly emerging chemogenetic/optogenetic experiments. A current snapshot of these efforts to map GABAergic projections influencing appetite is provided, and potential avenues for further investigation are provided.

Obesity is associated with hypogonadism in males, characterized by low testosterone and sperm number. Previous studies determined that these stem from dysregulation of hypothalamic circuitry that regulates reproduction, by unknown mechanisms. Herein, we used mice fed chronic high-fat diet, which mimics human obesity, to determine mechanisms of impairment at the level of the hypothalamus, in particular gonadotropin-releasing hormone (GnRH) neurons that regulate luteinizing hormone (LH), which then regulates testosterone. Consistent with obese humans, we demonstrated lower LH, and lower pulse frequency of LH secretion, but unchanged pituitary responsiveness to GnRH. LH pulse frequency is regulated by pulsatile GnRH secretion, which is controlled by kisspeptin. Peripheral and central kisspeptin injections, and DREADD-mediated activation of kisspeptin neurons, demonstrated that kisspeptin neurons were suppressed in obese mice. Thus, we investigated regulators of kisspeptin secretion. We determined that the LH response to NMDA was lower in obese mice, corresponding to fewer glutamate receptors in kisspeptin neurons, which may be critical for kisspeptin synchronization. Given that kisspeptin neurons also interact with anorexigenic POMC neurons, which are affected by obesity, we examined their cross talk, and determined that the LH response to either DREADD-mediated activation of POMC neurons or central injection of αMSH, a product of POMC, is abolished in obese mice. This was accompanied by diminished levels of αMSH receptor, MC4R, in kisspeptin neurons. Together, our studies determined that obesity leads to the downregulation of receptors that regulate kisspeptin neurons, which is associated with lower LH pulse frequency, leading to lower LH and hypogonadism.

Astrocytes are no longer considered as passive support cells. In the hypothalamus, these glial cells actively participate in the control of appetite, energy expenditure, and the processes leading to obesity and its secondary complications. Here we briefly review studies supporting this conclusion and the advances made in understanding the underlying mechanisms.

Ghrelin is a stomach-derived hormone that increases feeding and is elevated in response to chronic psychosocial stressors. The effects of ghrelin on feeding are mediated by the binding of ghrelin to the growth hormone secretagogue receptor (GHSR), a receptor located in hypothalamic and extrahypothalamic regions important for regulating food intake and metabolic rate. The ability of ghrelin to enter the brain, however, seems to be restricted to circumventricular organs like the median eminence and the brainstem area postrema, whereas ghrelin does not readily enter other GHSR-expressing regions like the ventral tegmental area (VTA). Interestingly, social stressors result in increased blood-brain barrier permeability, and this could therefore facilitate the entry of ghrelin into the brain. To investigate this, we exposed mice to social defeat stress for 21 d and then peripherally injected a Cy5-labelled biologically active ghrelin analog. The results demonstrate that chronically stressed mice exhibit higher Cy5-ghrelin fluorescence in several hypothalamic regions in addition to the ARC, including the hippocampus and midbrain. Furthermore, Cy5-ghrelin injections resulted in increased FOS expression in regions associated with the reward system in chronically stressed mice. Further histologic analyses identified a reduction in the branching of hypothalamic astrocytes in the ARC-median eminence junction, suggesting increased blood-brain barrier permeability. These data support the hypothesis that during metabolically challenging conditions like chronic stress, ghrelin may be more able to cross the blood-brain barrier and diffuse throughout the brain to target GHSR-expressing brain regions away from circumventricular organs.

Co-treatment with long acting PYY and the GLP-1 receptor agonists has potential as an efficient obesity treatment. This study investigates whether the mechanisms behind additive reduction of food intake and weight loss depends on complementary effects in brain areas regulating food intake and if restoration of leptin sensitivity is involved.

Diet-induced obese (DIO) mice were co-treated with PYY(3-36) and exendin-4 (Ex4, GLP-1R agonist) for 14 days using minipumps. Leptin responsiveness was evaluated by measuring food intake and body weight after leptin injection, and gene expression profile was investigated in various of brain regions and liver.

We show that weight loss associated with co-treatment of PYY(3-36) and Ex4 and Ex4 mono-treatment in DIO mice increased expression of several genes in area postrema (AP) known to be involved in appetite regulation and Cart, Pdyn, Bdnf and Klb were synergistically upregulated by the co-treatment. The upregulations were independent of weight loss, as shown by inclusion of a weight matched control. Moreover, PYY(3-36) and Ex4 co-treatment resulted in synergistically upregulated plasma concentrations of soluble leptin receptor (SLR) and improved sensitivity to exogenous leptin demonstrated by food intake lowering.

The study results suggest that synergistic upregulation of appetite-regulating genes in AP and improved leptin sensitivity are important mediators for the additive weight loss resulting from PYY and Ex4 co-treatment.

Leptin irresponsiveness, which is often associated with obesity, can have significant impacts on the hypothalamic proteome of individuals, including those who are lean. While mounting evidence on leptin irresponsiveness has focused on obese individuals, understanding the early molecular and proteomic changes associated with deficient hypothalamic leptin signaling in lean individuals is essential for early intervention and prevention of metabolic disorders. Leptin receptor antagonists block the binding of leptin to its receptors, potentially reducing its effects and used in cases where excessive leptin activity might be harmful.

In this work, we blocked the central actions of leptin in lean male adult Wistar rat by chronically administering intracerebroventricularly the superactive leptin receptor antagonist (SLA) (D23L/L39A/D40A/F41A) and investigated its impact on the hypothalamic proteome using label-free sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) for quantitative proteomics.

Our results show an accumulation of proteins involved in mRNA processing, mRNA stability, and translation in the hypothalamus of SLA-treated rats. Conversely, hypothalamic leptin signaling deficiency reduces the representation of proteins implicated in energy metabolism, neural circuitry, and neurotransmitter release.

The alterations in the adult rat hypothalamic proteome contribute to dysregulate appetite, metabolism, and energy balance, which are key factors in the development and progression of obesity and related metabolic disorders. Additionally, using bioinformatic analysis, we identified a series of transcription factors that are potentially involved in the upstream regulatory mechanisms responsible for the observed signature.

The growth hormone secretagogue receptor (GHSR), primarily known as the receptor for the hunger hormone ghrelin, potently controls food intake, yet the specific Ghsr-expressing cells mediating the orexigenic effects of this receptor remain incompletely characterized. Since Ghsr is expressed in gamma-aminobutyric acid (GABA)-producing neurons, we sought to investigate whether the selective expression of Ghsr in a subset of GABA neurons is sufficient to mediate GHSR's effects on feeding. First, we crossed mice that express a tamoxifen-dependent Cre recombinase in the subset of GABA neurons that express glutamic acid decarboxylase 2 (Gad2) enzyme (Gad2-CreER mice) with reporter mice, and found that ghrelin mainly targets a subset of Gad2-expressing neurons located in the hypothalamic arcuate nucleus (ARH) and that is predominantly segregated from Agouti-related protein (AgRP)-expressing neurons. Analysis of various single-cell RNA-sequencing datasets further corroborated that the primary subset of cells coexpressing Gad2 and Ghsr in the mouse brain are non-AgRP ARH neurons. Next, we crossed Gad2-CreER mice with reactivable GHSR-deficient mice to generate mice expressing Ghsr only in Gad2-expressing neurons (Gad2-GHSR mice). We found that ghrelin treatment induced the expression of the marker of transcriptional activation c-Fos in the ARH of Gad2-GHSR mice, yet failed to induce food intake. In contrast, food deprivation-induced refeeding was higher in Gad2-GHSR mice than in GHSR-deficient mice and similar to wild-type mice, suggesting that ghrelin-independent roles of GHSR in a subset of GABA neurons is sufficient for eliciting full compensatory hyperphagia in mice.

Diets rich in saturated fats are more detrimental to health than those containing mono- or unsaturated fats. Fatty acids are an important source of energy, but they also relay information regarding nutritional status to hypothalamic metabolic circuits and when in excess can be detrimental to these circuits. Astrocytes are the main site of central fatty acid β-oxidation, and hypothalamic astrocytes participate in energy homeostasis, in part by modulating hormonal and nutritional signals reaching metabolic neurons, as well as in the inflammatory response to high-fat diets. Thus, we hypothesized that how hypothalamic astrocytes process-specific fatty acids participates in determining the differential metabolic response and that this is sex dependent as males and females respond differently to high-fat diets. Male and female primary hypothalamic astrocyte cultures were treated with oleic acid (OA) or palmitic acid (PA) for 24 h, and an untargeted metabolomics study was performed. A clear predictive model for PA exposure was obtained, while the metabolome after OA exposure was not different from controls. The observed modifications in metabolites, as well as the expression levels of key metabolic enzymes, indicate a reduction in the activity of the Krebs and glutamate/glutamine cycles in response to PA. In addition, there were specific differences between the response of astrocytes from male and female mice, as well as between hypothalamic and cerebral cortical astrocytes. Thus, the response of hypothalamic astrocytes to specific fatty acids could result in differential impacts on surrounding metabolic neurons and resulting in varied systemic metabolic outcomes.

The prevalence of obesity has increased over the past three decades. Proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (ARC) play a vital role in induction of satiety. Chronic consumption of high-fat diet is known to reduce hypothalamic neuronal sensitivity to hormones like leptin, thus contributing to the development and persistence of obesity. The functional and morphological effects of a high-calorie diet on POMC neurons and how these effects contribute to the development and maintenance of the obese phenotype are not fully understood. For this purpose, POMC-Cre transgenic mice model was exposed to high-fat diet (HFD) and at the end of a 3- and 6-month period, electrophysiological and morphological changes, and the role of POMC neurons in homeostatic nutrition and their response to leptin were thoroughly investigated.

Effects of HFD on POMC-satiety neurons in transgenic mice models exposed to chronic high-fat diet were investigated using electrophysiological (patch-clamp), chemogenetic and Cre recombinase advanced technological methods. Leptin, glucose and lipid profiles were determined and analyzed.

In mice exposed to a high-fat diet for 6 months, no significant changes in POMC dendritic spine number or projection density from POMC neurons to the paraventricular hypothalamus (PVN), lateral hypothalamus (LH), and bed nucleus stria terminalis (BNST) were observed. It was revealed that leptin hormone did not change the electrophysiological activities of POMC neurons in mice fed with HFD for 6 months. In addition, chemogenetic stimulation of POMC neurons increased HFD consumption. In the 3-month HFD-fed group, POMC activation induced an orexigenic response in mice, whereas switching to a standard diet was found to abolish orexigenic behavior in POMC mice.

Chronic high fat consumption disrupts the regulation of POMC neuron activation by leptin. Altered POMC neuron activation abolished the neuron's characteristic behavioral anorexigenic response. Change in nutritional content contributes to the reorganization of developing maladaptations.

Neural circuits in the brain, primarily in the hypothalamus, are paramount to the homeostatic control of feeding and energy utilization. They integrate hunger, satiety, and body adiposity cues from the periphery and mediate the appropriate behavioral and physiological responses to satisfy the energy demands of the animal. Notably, perturbations in central homeostatic circuits have been linked to the etiology of excessive feeding and obesity. Considering the ever-changing energy requirements of the animal and required adaptations, it is not surprising that brain-feeding circuits remain plastic in adulthood and are subject to changes in synaptic strength as a consequence of nutritional status. Indeed, synapse density, probability of presynaptic transmitter release, and postsynaptic responses in hypothalamic energy balance centers are tailored to behavioral and physiological responses required to sustain survival. Mounting evidence supports key roles of astrocytes facilitating some of this plasticity. Here we discuss these synaptic plasticity mechanisms and the emerging roles of astrocytes influencing energy and glucose balance control in health and disease. This article is categorized under: Cancer > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology.

This study furthers the investigation of how pituitary adenylate cyclase activating polypeptide (PACAP) and the PAC1 receptor (PAC1R) regulate the homeostatic energy balance circuitry. We hypothesized that apoptotic ablation of PACAP neurones in the hypothalamic ventromedial nucleus (VMN) would affect both energy intake and energy expenditure. We also hypothesized that selective PAC1R knockdown would impair the PACAP-induced excitation in anorexigenic proopiomelanocortin (POMC) neurones and inhibition of orexigenic neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurones in the hypothalamic arcuate nucleus (ARC). The results show CASPASE-3-induced ablation of VMN PACAP neurones leads to increased energy intake and meal frequency as well as decreased energy expenditure in lean animals. The effects were more robust in obese males, whereas we saw the opposite effects in obese females. We then utilized visualized whole-cell patch clamp recordings in hypothalamic slices. PAC1R knockdown in POMC neurones diminishes the PACAP-induced depolarization, increase in firing, decreases in energy intake and meal size, as well as increases in CO2 production and O2 consumption. Similarly, the lack of expression of the PAC1R in NPY/AgRP neurones greatly attenuates the PACAP-induced hyperpolarization, suppression of firing, decreases in energy intake and meal frequency, as well as increases in energy expenditure. The PACAP response in NPY/AgRP neurones switched from predominantly inhibitory to excitatory in fasted animals. Finally, the anorexigenic effect of PACAP was potentiated when oestradiol was injected into the ARC in ovariectomized females. This study demonstrates the critical role of anorexigenic VMN PACAP neurones and the PAC1R in exciting POMC and inhibiting NPY/AgRP neurons to control homeostatic feeding.

The development and diversity of neuronal subtypes in the human hypothalamus has been insufficiently characterized. To address this, we integrated transcriptomic data from 241,096 cells (126,840 newly generated) in the prenatal and adult human hypothalamus to reveal a temporal trajectory from proliferative stem cell populations to mature hypothalamic cell types. Iterative clustering of the adult neurons identified 108 robust transcriptionally distinct neuronal subtypes representing 10 hypothalamic nuclei. Pseudotime trajectories provided insights into the genes driving formation of these nuclei. Comparisons to single-cell transcriptomic data from the mouse hypothalamus suggested extensive conservation of neuronal subtypes despite certain differences in species-enriched gene expression. The uniqueness of hypothalamic neuronal lineages was examined developmentally by comparing excitatory lineages present in cortex and inhibitory lineages in ganglionic eminence, revealing both distinct and shared drivers of neuronal maturation across the human forebrain. These results provide a comprehensive transcriptomic view of human hypothalamus development through gestation and adulthood at cellular resolution.

Overeating disorders (ODs), usually stemming from dieting history and stress, remain a pervasive issue in contemporary society, with the pathological mechanisms largely unresolved. Here, we show that alterations in intestinal microbiota are responsible for the excessive intake of palatable foods in OD mice and patients with bulimia nervosa (BN). Stress combined with a history of dieting causes significant changes in the microbiota and the intestinal metabolism, which disinhibit the vagus nerve terminals in the gut and thereby lead to a subsequent hyperactivation of the gut-brain axis passing through the vagus, the solitary tract nucleus, and the paraventricular nucleus of the thalamus. The transplantation of a probiotic Faecalibacterium prausnitzii or dietary supplement of key metabolites restores the activity of the gut-to-brain pathway and thereby alleviates the OD symptoms. Thus, our study delineates how the microbiota-gut-brain axis mediates energy balance, unveils the underlying pathogenesis of the OD, and provides potential therapeutic strategies.

Overeating disorders largely contribute to worldwide incidences of obesity. Available treatments are limited. Here, we discovered that long-term chemogenetic activation of ventrolateral periaqueductal gray (vlPAG) GABAergic cells rescue obesity of high-fat diet-induced obesity (DIO) mice. This was associated with the recovery of enhanced mIPSCs, decreased food intake, increased energy expenditure, and inguinal white adipose tissue (iWAT) browning. In vivo calcium imaging confirmed vlPAG GABAergic suppression for DIO mice, with corresponding reduction in intrinsic excitability. Single-nucleus RNA sequencing identified transcriptional expression changes in GABAergic cell subtypes in DIO mice, highlighting Cacna2d1 as of potential importance. Overexpressing CACNA2D1 in vlPAG GABAergic cells of DIO mice rescued enhanced mIPSCs and calcium response, reversed obesity, and therefore presented here as a potential target for obesity treatment.

Leptin plays a critical role in regulating appetite, energy expenditure and body weight, making it a key factor in maintaining a healthy balance. Despite numerous efforts to develop therapeutic interventions targeting leptin signaling, their effectiveness has been limited, underscoring the importance of gaining a better understanding of the mechanisms through which leptin exerts its functions. While the hypothalamus is widely recognized as the primary site responsible for the appetite-suppressing and weight-reducing effects of leptin, other brain regions have also been increasingly investigated for their involvement in mediating leptin's action. In this review, we summarize leptin signaling pathways and the neural networks that mediate the effects of leptin, with a specific emphasis on energy homeostasis.

Pro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus (ARC) are considered a major site of leptin action. Due to increasing evidence that POMC neurons are highly heterogeneous and indications that the conventional molecular tools to study their functions have important limitations, a reassessment of leptin's effects on definitive POMC neurons is needed. POMC neurons are also expressed in the retrochiasmatic area (RCA), where their function is poorly understood. Furthermore, the response of POMC neurons to leptin in females is largely unknown. Therefore, the present study aimed to determine the differences in leptin responsiveness of POMC neurons in the ARC and the RCA using a mouse model allowing adult-inducible fluorescent labeling. We performed whole-cell patch clamp electrophysiology on 154 POMC neurons from male and female mice. We confirmed and extended the model by which leptin depolarizes POMC neurons, in both the ARC and the RCA. Furthermore, we characterized the electrophysiological properties of an underappreciated subpopulation representing ∼10% of hypothalamic POMC neurons that are inhibited by leptin. We also provide evidence that sex does not appear to be a major determinant of basal properties and leptin responsiveness of POMC neurons, but that females are overall less responsive to leptin compared to males.

The potential of neural stem cells (NSCs) for neurological disorders the treatment has relied in large part upon identifying the NSCs fate decision. The hormone leptin has been reported to be a crucial regulator of brain development, able to influence the glial and neural development, yet, the underlying mechanism of leptin acting on NSCs' biological characteristics is still poorly understood. This study aims to investigate the role of leptin in the biological properties of NSCs. In this study, we investigate the possibility that leptin may regulate the NSCs' fate decision, which may promote the proliferation and neuronal differentiation of NSCs and thus act positively in neurological disorders. NSCs from the embryonic cerebral cortex were used in this study. We used CCK-8 assay, ki67 immunostaining, and FACS analysis to confirm that 25-100 ng/mL leptin promotes the proliferation of NSCs in a concentration-dependent pattern. This change was accompanied by the upregulation of p-AKT and p-ERK1/2, which are the classical downstream signaling pathways of leptin receptors b (LepRb). Inhibition of PI3K/AKT or MAPK/ERK signaling pathways both abolished the effect of leptin-induced proliferation. Moreover, leptin also enhanced the directed neuronal differentiation of NSCs. A blockade of the PI3K/AKT pathway reversed leptin-stimulated neurogenesis, while a blockade of JAK2/STAT3 had no effect on it. Taken together, our results support a role for leptin in regulating the fate of NSCs differentiation and promoting NSCs proliferation, which could be a promising approach for brain repair via regulating the biological characteristics of NSCs.

Eating behaviours are determined by the integration of interoceptive and environmental inputs. During pregnancy, numerous physiological adaptations take place in the maternal organism to provide an adequate environment for embryonic growth. Among them, whole-body physiological remodelling directly influences eating patterns, commonly causing notable taste perception alterations, food aversions and cravings. Recurrent food cravings for and compulsive eating of highly palatable food can contribute to the development and maintenance of gestational overweight and obesity with potential adverse health consequences for the offspring. Although much is known about how maternal eating habits influence offspring health, the mechanisms that underlie changes in taste perception and food preference during pregnancy (which guide and promote feeding) are only just starting to be elucidated. Given the limited and diffuse understanding of the neurobiology of gestational eating patterns, the aim of this Review is to compile, integrate and discuss the research conducted on this topic in both experimental models and humans. This article sheds light on the mechanisms that drive changes in female feeding behaviours during distinct physiological states. Understanding these processes is crucial to improve gestational parent health and decrease the burden of metabolic and food-related diseases in future generations.

Systemic metabolism has to be constantly adjusted to the variance of food intake and even be prepared for anticipated changes in nutrient availability. Therefore, the brain integrates multiple homeostatic signals with numerous cues that predict future deviations in energy supply. Recently, our understanding of the neural pathways underlying these regulatory principles-as well as their convergence in the hypothalamus as the key coordinator of food intake, energy expenditure, and glucose metabolism-have been revealed. These advances have changed our view of brain-dependent control of metabolic physiology. In this Review, we discuss new concepts about how alterations in these pathways contribute to the development of prevalent metabolic diseases such as obesity and type 2 diabetes mellitus and how this emerging knowledge may provide new targets for their treatment.

Adipokines are protein hormones secreted by adipose tissue in response to disruptions in physiological homeostasis within the body's systems. The regulatory functions of adipokines within the central nervous system (CNS) are multifaceted and intricate, and they have been identified in a number of pathologies. Therefore, specific adipokines have the potential to be used as biomarkers for screening purposes in neurological dysfunctions. The systematic review presented herein focuses on the analysis of the functions of various adipokines in the pathogenesis of CNS diseases. Thirteen proteins were selected for analysis through scientific databases. It was found that these proteins can be identified within the cerebrospinal fluid either by their ability to modify their molecular complex and cross the blood-brain barrier or by being endogenously produced within the CNS itself. As a result, this can correlate with their measurability during pathological processes, including Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, depression, or brain tumors.

It is well-established that the hypothalamic-pituitary-gonadal (HPG) axis is suppressed due to negative energy balance. However, less information is available on whether kisspeptin neuronal activity contributes to fasting-induced responses. In the present study, female and male mice were fasted for 24 hours or provided food ad libitum (fed group) to determine whether acute fasting is sufficient to modulate kisspeptin neuronal activity. In female mice, fasting attenuated luteinizing hormone (LH) and prolactin (PRL) serum levels and increased follicle-stimulating hormone levels compared with the fed group. In contrast, fasting did not affect gonadotropin or PRL secretion in male mice. By measuring genes related to LH pulse generation in micropunches obtained from the arcuate nucleus of the hypothalamus (ARH), we observed that fasting reduced Kiss1 mRNA levels in female and male mice. In contrast, Pdyn expression was upregulated only in fasted female mice, whereas no changes in the Tac2 mRNA levels were observed in both sexes. Interestingly, the frequency and amplitude of the GABAergic postsynaptic currents recorded from ARH kisspeptin neurons (ARHKisspeptin) were reduced in 24-hour fasted female mice but not in males. Additionally, neuropeptide Y induced a hyperpolarization in the resting membrane potential of ARHKisspeptin neurons of fed female mice but not in males. Thus, the response of ARHKisspeptin neurons to fasting is sexually dependent with a female bias, associated with changes in gonadotropins and PRL secretion. Our findings suggest that GABAergic transmission to ARHKisspeptin neurons modulates the activity of the HPG axis during situations of negative energy balance.

Neuroplasticity refers to the brain's ability to undergo functional and structural changes in response to diverse challenges. Converging evidence supports the notion that exercise serves as a metabolic challenge, triggering the release of multiple factors both in the periphery and within the brain. These factors actively contribute to plasticity in the brain, and in turn, regulate energy and glucose metabolism.

The primary focus of this review is to explore the impact of exercise-induced plasticity in the brain on metabolic homeostasis, with an emphasis on the role of the hypothalamus in this process. Additionally, the review provides an overview of various factors induced by exercise that contribute to energy balance and glucose metabolism. Notably, these factors exert their effects, at least in part, through actions within the hypothalamus and more broadly in the central nervous system.

Exercise elicits both transient and sustained changes in metabolism, accompanied by changes in neural activity within specific brain regions. Importantly, the contribution of exercise-induced plasticity and the underlying mechanisms by which neuroplasticity influences the effects of exercise are not well understood. Recent work has begun to overcome this gap in knowledge by examining the complex interactions of exercise-induced factors which alter neural circuit properties to influence metabolism.

Matrix metalloproteinases (MMPs) are a family of zinc-activated peptidases that can be classified into six major classes, including gelatinases, collagenases, stromelysins, matrilysins, membrane type metalloproteinases, and other unclassified MMPs. The activity of MMPs is regulated by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). MMPs are involved in a wide range of biological processes, both in normal physiological conditions and pathological states. While some of these functions occur during development, others occur in postnatal life. Although the roles of several MMPs have been extensively studied in cancer and inflammation, their function in metabolism and metabolic diseases have only recently begun to be uncovered, particularly over the last two decades. This review aims to summarize the current knowledge regarding the metabolic roles of metalloproteinases in physiology, with a strong emphasis on adipose tissue homeostasis, and to highlight the consequences of impaired or exacerbated MMP actions in the development of metabolic disorders such as obesity, fatty liver disease, and type 2 diabetes.

Dopamine neurons of the ventral tegmental area (VTA DA ) respond to food and social stimuli and contribute to both forms of motivation. However, it is unclear if the same or different VTA DA neurons encode these different stimuli. To address this question, we performed 2-photon calcium imaging in mice presented with food and conspecifics, and found statistically significant overlap in the populations responsive to both stimuli. Both hunger and opposite-sex social experience further increased the proportion of neurons that respond to both stimuli, implying that modifying motivation for one stimulus affects responses to both stimuli. In addition, single-nucleus RNA sequencing revealed significant co-expression of feeding- and social-hormone related genes in individual VTA DA neurons. Taken together, our functional and transcriptional data suggest overlapping VTA DA populations underlie food and social motivation.