Similar Datasets
Project description:Obesity is associated with insulin resistance, glucose intolerance, inflammation, and altered neuronal activity in brain regions controlling metabolic functions including food intake, energy expenditure, and glucose homeostasis, such as the hypothalamus. In this study, we tested the hypothesis that inhibiting inflammation with minocycline could reduce adverse metabolic consequences associated with high-fat diet (HFD)-induced obesity in mice and sought to determine if metabolic improvements were associated with reduced hypothalamic microglia activity. Male C57Bl/6J mice were placed on 60% HFD for 12 weeks, with minocycline (40 mg/kg, p.o.) or normal tap water given during the last 6 weeks of diet. Age-matched mice maintained on control diet were used as an additional comparator group. Metabolic function was assessed during the last week of treatment. Ramified (resting) and non-ramified (active) microglia were quantified in the hypothalamus following immunohistochemical staining of ionized calcium-binding adaptor 1 (Iba-1) and further assessed by RNAseq. In HFD fed mice, minocycline attenuated body mass and adiposity without altering food intake suggesting enhanced energy expenditure. Minocycline also attenuated hyperinsulinemia and improved insulin sensitivity in HFD mice. Increased microglial activation and autophagy gene network changes were observed in the paraventricular nucleus (PVN) of the hypothalamus of HFD mice, which was prevented by minocycline treatment. Contrary to PVN findings, there were no significant effects of either HFD or minocycline on microglia activation in the hypothalamic arcuate nucleus or central amygdala. Together, these findings suggest that minocycline improves HFD-induced weight gain and insulin resistance in part by reducing inflammatory processes in the PVN, a key hypothalamic region regulating metabolic function.
| S-EPMC9244633 | biostudies-literature
Project description:Hypothalamic Microglia Activation is Associated with High Fat Diet-Induced Obesity and Metabolic Dysfunction in Mice
| PRJNA815307 | ENA
Project description:A number of studies have proposed that excess food intake, particularly of high fat diets arise due dysregulation of homeostatic mechanisms regulating neuroendocrine control of appetite and energy balance. Current dogma suggests high fat diets invoke hypothalamic inflammation which reduces hypothalamic sensitivity to metabolic and hormonal cues of conveying peripheral status of energy balance, such as leptin and insulin. A hypothesis for the mechanism leading to hypothalamic inflammation is based on high fat diet mediated changes in gut microbiota which are then proposed to increase circulating levels of lipopolysaccharide (LPS). This in turn activates a hypothalamic inflammatory response via the toll-like receptor (TLR4) and CD14. The aim of this study was to determine hypothalamic gene expression in response to long term feeding of a high fat diet, taking into account the importance of using a control diet with a similar composition and balanced for sucrose content.
2018-10-23 | E-MTAB-6929 | biostudies-arrayexpress
Project description:Oxytocin-expressing paraventricular hypothalamic neurons (PVN^OT neurons) integrate afferent signals from the gut including cholecystokinin (CCK) to adjust whole-body energy homeostasis. However, the molecular underpinnings by which PVN^OT neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective ablation of PVNOT neurons fail to reduce food intake in response to CCK and develop hyperphagic obesity on chow diet. Notably, exposing wildtype mice to a high-fat/high-sugar (HFHS) diet recapitulates this insensitivity towards CCK, which is linked to diet-induced transcriptional and electrophysiological aberrations specifically in PVNOT neurons. Restoring OT pathways in DIO mice via chemogenetics or polypharmacology sufficiently re-establishes CCK?s anorexigenic effects. Lastly, by single-cell profiling, we identify a specialized PVN^OT neuronal subpopulation with increased ?-opioid signaling under HFHS diet, which restrains their CCK-evoked activation. In sum, we here document a novel (patho)mechanism by which PVN^OT signaling uncouples a gut-brain satiation pathway under obesogenic conditions.
2023-09-07 | GSE242245 | GEO
Project description:BACKGROUND/OBJECTIVES:The current obesity epidemic has spurred exploration of the developmental origin of adult heath and disease. A mother's dietary choices and health can affect both the early wellbeing and lifelong disease-risk of the offspring. SUBJECTS/METHODS:To determine if changes in the mother's diet and adiposity have long-term effects on the baby's metabolism, independently from a prenatal insult, we utilized a mouse model of diet-induced-obesity and cross-fostering. All pups were born to lean dams fed a low fat diet but were fostered onto lean or obese dams fed a high fat diet. This study design allowed us to discern the effects of a poor diet from those of mother's adiposity and metabolism. The weaned offspring were placed on a high fat diet to test their metabolic function. RESULTS:In this feeding challenge, all male (but not female) offspring developed metabolic dysfunction. We saw increased weight gain in the pups nursed on an obesity-resistant dam fed a high fat diet, and increased pathogenesis including liver steatosis and adipose tissue inflammation, when compared to pups nursed on either obesity-prone dams on a high fat diet or lean dams on a low fat diet. CONCLUSION:Exposure to maternal over-nutrition, through the milk, is sufficient to shape offspring health outcomes in a sex- and organ-specific manner, and milk from a mother who is obesity-prone may partially protect the offspring from the insult of a poor diet.
| S-EPMC5916951 | biostudies-literature
Project description:Adipose tissue plays an important role in storing excess nutrients and preventing ectopic lipid accumulation in other organs. Obesity leads to excess lipid storage in adipocytes, resulting in the generation of stress signals and the derangement of metabolic functions. SIRT1 is an important regulatory sensor of nutrient availability in many metabolic tissues. Here we report that SIRT1 functions in adipose tissue to protect from the development of inflammation and obesity under normal feeding conditions, and the progression to metabolic dysfunction under dietary stress. Genetic ablation of SIRT1 from adipose tissue leads to gene expression changes that highly overlap with changes induced by high fat diet in wild type mice, suggesting that dietary stress signals inhibit the activity of SIRT1. Indeed, we show that high fat diet induces the cleavage of SIRT1 in adipose tissue by the inflammation-activated caspase-1, providing a link between dietary stress and predisposition to metabolic dysfunction. Four replicates from four different biological conditions: 1) SIRT1 wild-type fed low fat diet, 2) SIRT1 wild-type fed high fat diet, 3) SIRT1 knock-out fed low fat diet, 4) SIRT1 knock-out fed high fat diet
2012-12-21 | E-GEOD-30247 | biostudies-arrayexpress
Project description:Background: Plasminogen activator inhibitor (PAI)-1 levels and activity are known to increase during metabolic syndrome and obesity. In addition, previous studies have implicated PAI-1 in adipose tissue (AT) expansion while also contributing to insulin resistance. As inflammation is also known to occur in AT during obesity, we hypothesized that in a high-fat diet (HFD)-induced obese mouse model PAI-1 contributes to macrophage-mediated inflammation and metabolic dysfunction. Methods: Four- to five-weeks-old male C57B6/6J mice were fed a HFD (45%) for 14 weeks, while age-matched control mice were fed a standard laboratory chow diet (10% fat). Additional studies were performed in PAI-1 knockout mice and wild type mice treated with an inhibitor (PAI-039) of PAI-1. Macrophage polarization were measured by real time PCR. Results: HFD mice showed increased expression of PAI-1 in visceral white AT (WAT) that also displayed increased macrophage numbers. PAI-1 deficient mice exhibited increased numbers of anti-inflammatory macrophages in WAT and were resistant to HFD-induced obesity. Similarly, pharmacological inhibition of PAI-1 using PAI-039 significantly decreased macrophage infiltration in WAT and improved metabolic status in HFD-induced wild-type mice. Importantly, the numbers of M1 macrophages appeared to be increased by the HFD and decreased by either genetic PAI-1 depletion or PAI-039 treatment. Conclusions: Collectively, our findings provide support for PAI-1 contributing to the development of inflammation in adipose tissue and explain the mechanism of inflammation modulated by PAI-1 in the disordered metabolism in HFD-induced obesity.
| S-EPMC6169321 | biostudies-literature
Project description:Analysis of GPR120 which play roles for the fatty acid sensor in adipose tissue. Results provide insight into the transcriptional effects caused by the loss of the GPR120 proteins and provide further insight into their functions. GPR120 KO mice and the corresponding wild-type with normal diet(ND) or high fat diet(HFD), were subjected to Affymetrix Mus musculus microarrays. Epididymal adipose tissue and liver were analyzed in triplicates.
2012-02-22 | E-GEOD-32095 | biostudies-arrayexpress
Project description:BackgroundAssociations have been made between obesity and reduced intestinal numbers of members of the phylum Bacteroidetes, but there is no direct evidence of the role these bacteria play in obesity. Herein, the effects of Bacteroides uniformis CECT 7771 on obesity-related metabolic and immune alterations have been evaluated.Methods and findingsAdult (6-8 week) male wild-type C57BL-6 mice were fed a standard diet or a high-fat-diet HFD to induce obesity, supplemented or not with B. uniformis CECT 7771 for seven weeks. Animal weight was monitored and histologic, biochemical, immunocompetent cell functions, and features of the faecal microbiota were analysed after intervention. The oral administration of B. uniformis CECT 7771 reduced body weight gain, liver steatosis and liver cholesterol and triglyceride concentrations and increased small adipocyte numbers in HFD-fed mice. The strain also reduced serum cholesterol, triglyceride, glucose, insulin and leptin levels, and improved oral tolerance to glucose in HFD fed mice. The bacterial strain also reduced dietary fat absorption, as indicated by the reduced number of fat micelles detected in enterocytes. Moreover, B. uniformis CECT 7771 improved immune defence mechanisms, impaired in obesity. HFD-induced obesity led to a decrease in TNF-α production by peritoneal macrophages stimulated with LPS, conversely, the administration of B. uniformis CECT 7771 increased TNF-α production and phagocytosis. Administering this strain also increased TNF-α production by dendritic cells (DCs) in response to LPS stimulation, which was significantly reduced by HFD. B. uniformis CECT 7771 also restored the capacity of DCs to induce a T-cell proliferation response, which was impaired in obese mice. HFD induced marked changes in gut microbiota composition, which were partially restored by the intervention.ConclusionsAltogether, the findings indicate that administration of B. uniformis CECT 7771 ameliorates HFD-induced metabolic and immune dysfunction associated with intestinal dysbiosis in obese mice.
| S-EPMC3406031 | biostudies-literature
Project description:Energy restriction is a first therapy in the treatment of obesity, but the underlying biological mechanisms have not been completely clarified. We analyzed the effects of restriction of high-fat diet (HFD) on weight loss, circulating gut hormone levels and expression of hypothalamic neuropeptides. Ten-week-old male Wistar rats (n = 40) were randomly distributed into four groups: two fed ad libitum a normal diet (ND) (N group) or a HFD (H group) and two subjected to a 25% caloric restriction of ND (NR group) or HFD (HR group) for 9 weeks. A 25% restriction of HFD over 9 weeks leads to a 36% weight loss with regard to the group fed HFD ad libitum accompanied by normal values in adiposity index and food efficiency ratio (FER). This restriction also carried the normalization of NPY, AgRP and POMC hypothalamic mRNA expression, without changes in CART. Caloric restriction did not succeed in improving glucose homeostasis but reduced HFD-induced hyperinsulinemia. In conclusion, 25% restriction of HFD reduced adiposity and improved metabolism in experimental obesity, without changes in glycemia. Restriction of the HFD triggered the normalization of hypothalamic NPY, AgRP and POMC expression, as well as ghrelin and leptin levels.
| S-EPMC8308389 | biostudies-literature