Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity.

ABSTRACT: The neuronal circuits involved in the regulation of feeding behavior and energy expenditure are soft-wired, reflecting the relative activity of the postsynaptic neuronal system, including the anorexigenic proopiomelanocortin (POMC)-expressing cells of the arcuate nucleus. We analyzed the synaptic input organization of the melanocortin system in lean rats that were vulnerable (DIO) or resistant (DR) to diet-induced obesity. We found a distinct difference in the quantitative and qualitative synaptology of POMC cells between DIO and DR animals, with a significantly greater number of inhibitory inputs in the POMC neurons in DIO rats compared with DR rats. When exposed to a high-fat diet (HFD), the POMC cells of DIO animals lost synapses, whereas those of DR rats recruited connections. In both DIO rats and mice, the HFD-triggered loss of synapses on POMC neurons was associated with increased glial ensheathment of the POMC perikarya. The altered synaptic organization of HFD-fed animals promoted increased POMC tone and a decrease in the stimulatory connections onto the neighboring neuropeptide Y (NPY) cells. Exposure to HFD was associated with reactive gliosis, and this affected the structure of the blood-brain barrier such that the POMC and NPY cell bodies and dendrites became less accessible to blood vessels. Taken together, these data suggest that consumption of an HFD has a major impact on the cytoarchitecture of the arcuate nucleus in vulnerable subjects, with changes that might be irreversible due to reactive gliosis.

SUBMITTER: Horvath TL

PROVIDER: S-EPMC2930476 | biostudies-other | 2010 Aug

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity.

Project description:Previous studies have proposed roles for hypothalamic reactive oxygen species (ROS) in the modulation of circuit activity of the melanocortin system. Here we show that suppression of ROS diminishes pro-opiomelanocortin (POMC) cell activation and promotes the activity of neuropeptide Y (NPY)- and agouti-related peptide (AgRP)-co-producing (NPY/AgRP) neurons and feeding, whereas ROS-activates POMC neurons and reduces feeding. The levels of ROS in POMC neurons were positively correlated with those of leptin in lean and ob/ob mice, a relationship that was diminished in diet-induced obese (DIO) mice. High-fat feeding resulted in proliferation of peroxisomes and elevated peroxisome proliferator-activated receptor ? (PPAR-?) mRNA levels within the hypothalamus. The proliferation of peroxisomes in POMC neurons induced by the PPAR-? agonist rosiglitazone decreased ROS levels and increased food intake in lean mice on high-fat diet. Conversely, the suppression of peroxisome proliferation by the PPAR antagonist GW9662 increased ROS concentrations and c-fos expression in POMC neurons. Also, it reversed high-fat feeding-triggered elevated NPY/AgRP and low POMC neuronal firing, and resulted in decreased feeding of DIO mice. Finally, central administration of ROS alone increased c-fos and phosphorylated signal transducer and activator of transcription 3 (pStat3) expression in POMC neurons and reduced feeding of DIO mice. These observations unmask a previously unknown hypothalamic cellular process associated with peroxisomes and ROS in the central regulation of energy metabolism in states of leptin resistance.

| S-EPMC3388795 | biostudies-literature

Early-life exposure to testosterone programs the hypothalamic melanocortin system.

Project description:In mammals, males consume more food, which is considered a masculinized behavior, but the underlying mechanism of this sex-specific feeding behavior is unknown. In mice, neonatal testosterone (NT) is critical to masculinize the developing brain, leading to sex differences in reproductive physiology. The proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus (ARC) are critical to suppress energy intake and POMC innervation of hypothalamic feeding circuits develops to a large extent neonatally. We hypothesized that NT programs the masculinization of energy intake by programming POMC neurons. We tested this hypothesis by comparing control females and control males (CMs) with female mice neonatally androgenized with testosterone (NTFs). We show that increased food intake in CMs is associated with reduced POMC expression and decreased intensity of neuronal projections from POMC neurons within the ARC compared with control females. We found that NTFs display a masculinized energy intake and ARC POMC expression and innervation as observed in CMs, which can be mimicked by neonatal exposure to the androgen receptor agonist dihydrotestosterone (DHT). NTFs also exhibit hyperleptinemia and a decreased ability of leptin to up-regulate POMC, suppress food intake, and prevent adipose tissue accumulation, independent of signal transducer and activator of transcription 3. However, this leptin resistance is specific to NTFs, is not a consequence of masculinization, and is reproduced by neonatal exposure to estrogen but not DHT. Thus, NT programs a sexual differentiation of POMC neurons in female mice via DHT but also predisposes to leptin resistance and obesity in an estrogen-dependent manner.

| S-EPMC3060636 | biostudies-literature

The central melanocortin system and human obesity.

Project description:The prevalence of obesity and the associated comorbidities highlight the importance of understanding the regulation of energy homeostasis. The central melanocortin system plays a critical role in controlling body weight balance. Melanocortin neurons sense and integrate the neuronal and hormonal signals, and then send regulatory projections, releasing anorexigenic or orexigenic melanocortin neuropeptides, to downstream neurons to regulate the food intake and energy expenditure. This review summarizes the latest progress in our understanding of the role of the melanocortin pathway in energy homeostasis. We also review the advances in the identification of human genetic variants that cause obesity via mechanisms that affect the central melanocortin system, which have provided rational targets for treatment of genetically susceptible patients.

| S-EPMC7816681 | biostudies-literature

The functional organization of excitatory synaptic input to place cells.

Project description:Hippocampal place cells contribute to mammalian spatial navigation and memory formation. Numerous models have been proposed to explain the location-specific firing of this cognitive representation, but the pattern of excitatory synaptic input leading to place firing is unknown, leaving no synaptic-scale explanation of place coding. Here we used resonant scanning two-photon microscopy to establish the pattern of synaptic glutamate input received by CA1 place cells in behaving mice. During traversals of the somatic place field, we found increased excitatory dendritic input, mainly arising from inputs with spatial tuning overlapping the somatic field, and functional clustering of this input along the dendrites over ~10 µm. These results implicate increases in total excitatory input and co-activation of anatomically clustered synaptic input in place firing. Since they largely inherit their fields from upstream synaptic partners with similar fields, many CA1 place cells appear to be part of multi-brain-region cell assemblies forming representations of specific locations.

| S-EPMC8196201 | biostudies-literature

Semiquantitative analysis of hypothalamic damage on MRI predicts risk for hypothalamic obesity.

Project description:ObjectiveExcessive weight gain frequently occurs in patients with hypothalamic tumors and lesions leading to hypothalamic obesity (HO).MethodsDigital brain magnetic resonance imaging (MRI) and clinical outcomes were studied retrospectively in a single center, including 45 children with postoperative lesions in the sellar region (41 craniopharyngiomas, 4 with Rathke's cleft cysts), ?5 years post-surgery, mean age 13.9 years. Four standard sections covering hypothalamic areas critical to energy homeostasis were used to assess lesions and calculate a hypothalamic lesion score (HLS); the association with HO was examined.ResultsCompared to subjects who did not develop HO (n = 23), subjects with HO (n = 22) showed more frequently lesions affecting the third ventricular floor, mammillary bodies, and anterior, medial (all P?<?0.05), and most importantly posterior hypothalamus (P < 0.01). The HLS correlated significantly with BMI z-score changes 12 and 30 months post-surgery, even after adjusting for potential confounders of gender, age at surgery, surgery date, surgery BMI z-score, hydrocephalus, and residual hypothalamic tumor (r = 0.34, P = 0.03; r = 0.40, P = 0.02, respectively). Diabetes insipidus was found to be an endocrine marker for HO risk.ConclusionsThe extent of damage following surgery in the sellar region can be assessed by MRI using a novel scoring system for early HO risk assessment.

| S-EPMC5029599 | biostudies-literature

Silencing of hypothalamic FGF11 prevents diet-induced obesity.

Project description:Fibroblast growth factor 11 (FGF11) is a member of the intracellular fibroblast growth factor family. Here, we report the central role of FGF11 in the regulation of metabolism. Lentiviral injection of Fgf11 shRNA into the arcuate nucleus of the mouse hypothalamus decreased weight gain and fat mass, increased brown adipose tissue thermogenesis, and improved glucose and insulin intolerances under high-fat diet conditions. Fgf11 was expressed in the NPY-expressing neurons, and Fgf11 knockdown considerably decreased Npy expression and projection, leading to increased expression of tyrosine hydroxylase in the paraventricular nucleus. Mechanistically, FGF11 regulated Npy gene expression through the glycogen synthase kinase 3-cAMP response element-binding protein pathway. Our study defines the physiological significance of hypothalamic FGF11 in the regulation of metabolism in response to overnutrition such as high-fat diet.

| S-EPMC9447329 | biostudies-literature

Hypothalamic Ventromedial Lin28a Enhances Glucose Metabolism in Diet-Induced Obesity.

Project description:The Lin28a/Let-7 axis has been studied in peripheral tissues for its role in metabolism regulation. However, its central function remains unclear. Here we found that Lin28a is highly expressed in the hypothalamus compared with peripheral tissues. Its expression is positively correlated with positive energy balance, suggesting a potential central role for Lin28a in metabolism regulation. Thus, we targeted the hypothalamic ventromedial nucleus (VMH) to selectively overexpress (Lin28aKIVMH ) or downregulate (Lin28aKDVMH ) Lin28a expression in mice. With mice on a standard chow diet, body weight and glucose homeostasis were not affected in Lin28aKIVMH or Lin28aKDVMH mice. On a high-fat diet, although no differences in body weight and composition were observed, Lin28aKIVMH mice showed improved glucose tolerance and insulin sensitivity compared with controls. Conversely, Lin28aKDVMH mice displayed glucose intolerance and insulin resistance. Changes in VMH AKT activation of diet-induced obese Lin28aKIVMH or Lin28aKDVMH mice were not associated with alterations in Let-7 levels or insulin receptor activation. Rather, we observed altered expression of TANK-binding kinase-1 (TBK-1), which was found to be a direct Lin28a target mRNA. VMH-specific inhibition of TBK-1 in mice with diet-induced obesity impaired glucose metabolism and AKT activation. Altogether, our data show a TBK-1-dependent role for central Lin28a in glucose homeostasis.

| S-EPMC5521863 | biostudies-other

Disrupted Hypothalamic CRH Neuron Responsiveness Contributes to Diet-induced Obesity

Project description:The current obesity epidemic mainly results from high-fat high-caloric diet (HFD) feeding and may also be contributed to by chronic stress; however, the neural basis underlying stress-related diet-induced obesity remains unknown. Corticotropin releasing hormone (CRH) neurons in the paraventricular hypothalamus (PVH), a known body weight-regulating region, represent one key group of stress-responsive neurons. Here we show that HFD feeding blunts PVH CRH neuron responses to nutritional challenges as well as stress stimuli and dexamathesone, which normally produce rapid activation and inhibition of these neurons, respectively. We generated mouse models with the activity of these neurons clamped at high or low levels, both of which show HFD-mimicking, blunted PVH CRH neuron responsiveness. Strikingly, both models develop rapid HFD-induced obesity, associated with HFD-mimicking, reduced diurnal rythmicity in feeding and energy expenditure. Thus, blunted responsiveness of PVH CRH neurons, but not their absolute activity levels, underlies HFD-induced obesity, and may contribute to stress-induced obesity.

| S-SCDT-EMBOR-2019-49210V1 | biostudies-other

Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity.

Project description:BackgroundIn experimental models, hypothalamic inflammation is an early and determining factor in the installation and progression of obesity. Pharmacological and gene-based approaches have proven efficient in restraining inflammation and correcting the obese phenotypes. However, the role of nutrients in the modulation of hypothalamic inflammation is unknown.Methodology/principal findingsHere we show that, in a mouse model of diet-induced obesity, partial substitution of the fatty acid component of the diet by flax seed oil (rich in C18:3) or olive oil (rich in C18:1) corrects hypothalamic inflammation, hypothalamic and whole body insulin resistance, and body adiposity. In addition, upon icv injection in obese rats, both ?3 and ?9 pure fatty acids reduce spontaneous food intake and body mass gain. These effects are accompanied by the reversal of functional and molecular hypothalamic resistance to leptin/insulin and increased POMC and CART expressions. In addition, both, ?3 and ?9 fatty acids inhibit the AMPK/ACC pathway and increase CPT1 and SCD1 expression in the hypothalamus. Finally, acute hypothalamic injection of ?3 and ?9 fatty acids activate signal transduction through the recently identified GPR120 unsaturated fatty acid receptor.Conclusions/significanceUnsaturated fatty acids can act either as nutrients or directly in the hypothalamus, reverting diet-induced inflammation and reducing body adiposity. These data show that, in addition to pharmacological and genetic approaches, nutrients can also be attractive candidates for controlling hypothalamic inflammation in obesity.

| S-EPMC3261210 | biostudies-literature

Disrupted hypothalamic CRH neuron responsiveness contributes to diet-induced obesity.

Project description:The current obesity epidemic mainly results from high-fat high-caloric diet (HFD) feeding and may also be contributed by chronic stress; however, the neural basis underlying stress-related diet-induced obesity remains unknown. Corticotropin-releasing hormone (CRH) neurons in the paraventricular hypothalamus (PVH), a known body weight-regulating region, represent one key group of stress-responsive neurons. Here, we found that HFD feeding blunted PVH CRH neuron response to nutritional challenges as well as stress stimuli and dexamethesone, which normally produce rapid activation and inhibition on these neurons, respectively. We generated mouse models with the activity of these neurons clamped at high or low levels, both of which showed HFD-mimicking, blunted PVH CRH neuron responsiveness. Strikingly, both models developed rapid HFD-induced obesity, associated with HFD-mimicking, reduced diurnal rhythmicity in feeding and energy expenditure. Thus, blunted responsiveness of PVH CRH neurons, but not their absolute activity levels, underlies HFD-induced obesity and may also contribute to stress-induced obesity.

| S-EPMC7332802 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data