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Background: "Western" style dietary patterns are characterized by a high proportion of highly processed foods rich in fat and low in fiber. This diet pattern is associated with a myriad of metabolic dysfunctions, including neuroinflammation and cognitive impairment. β-glucan, the major soluble fiber in oat and barley grains, is fermented in the lower gastrointestinal tract, potentially impacting the microbial ecosystem and thus may improve elements of cognition and brain function via the gut-brain axis. The present study aimed to evaluate the effect of β-glucan on the microbiota gut-brain axis and cognitive function in an obese mouse model induced by a high-fat and fiber-deficient diet (HFFD)., Results: After long-term supplementation for 15 weeks, β-glucan prevented HFFD-induced cognitive impairment assessed behaviorally by object location, novel object recognition, and nesting building tests. In the hippocampus, β-glucan countered the HFFD-induced microglia activation and its engulfment of synaptic puncta, and upregulation of proinflammatory cytokine (TNF-α, IL-1β, and IL-6) mRNA expression. Also, in the hippocampus, β-glucan significantly promoted PTP1B-IRS-pAKT-pGSK3β-pTau signaling for synaptogenesis, improved the synaptic ultrastructure examined by transmission electron microscopy, and increased both pre- and postsynaptic protein levels compared to the HFFD-treated group. In the colon, β-glucan reversed HFFD-induced gut barrier dysfunction increased the thickness of colonic mucus (Alcian blue and mucin-2 glycoprotein immunofluorescence staining), increased the levels of tight junction proteins occludin and zonula occludens-1, and attenuated bacterial endotoxin translocation. The HFFD resulted in microbiota alteration, effects abrogated by long-term β-glucan supplementation, with the β-glucan effects on Bacteroidetes and its lower taxa particularly striking. Importantly, the study of short-term β-glucan supplementation for 7 days demonstrated pronounced, rapid differentiating microbiota changes before the cognitive improvement, suggesting the possible causality of gut microbiota profile on cognition. In support, broad-spectrum antibiotic intervention abrogated β-glucan's effects on improving cognition, highlighting the role of gut microbiota to mediate cognitive behavior., Conclusion: This study provides the first evidence that β-glucan improves indices of cognition and brain function with major beneficial effects all along the gut microbiota-brain axis. Our data suggest that elevating consumption of β-glucan-rich foods is an easily implementable nutritional strategy to alleviate detrimental features of gut-brain dysregulation and prevent neurodegenerative diseases associated with Westernized dietary patterns. Video Abstract.

Background: Western pattern diets induce neuroinflammation and impair cognitive behavior in humans and animals. Neuroinflammation and cognitive impairment have been associated with microbiota dysbiosis, through the gut-brain axis. Furthermore, microbiota-accessible carbohydrates (MACs) found in dietary fiber are important in shaping the microbial ecosystem and have the potential to improve the gut-brain-axis. However, the effects of MACs on neuroinflammation and cognition in an obese condition have not yet been investigated. The present study aimed to evaluate the effect of MACs on the microbiota-gut-brain axis and cognitive function in obese mice induced by a high-fat and fiber deficient (HF-FD) diet., Methods: C57Bl/6 J male mice were fed with either a control HF-FD or a HF-MAC diet for 15 weeks. Moreover, an additional group was fed with the HF-MAC diet in combination with an antibiotic cocktail (HF-MAC + AB). Following the 15-week treatment, cognitive behavior was investigated; blood, cecum content, colon, and brain samples were collected to determine metabolic parameters, endotoxin, gut microbiota, colon, and brain pathology., Results: We report MACs supplementation prevented HF-FD-induced cognitive impairment in nesting building and temporal order memory tests. MACs prevented gut microbiota dysbiosis, including increasing richness, α-diversity and composition shift, especially in Bacteroidetes and its lower taxa. Furthermore, MACs increased colonic mucus thickness, tight junction protein expression, reduced endotoxemia, and decreased colonic and systemic inflammation. In the hippocampus, MACs suppressed HF-FD-induced neuroglia activation and inflammation, improved insulin IRS-pAKT-pGSK3β-pTau synapse signaling, in addition to the synaptic ultrastructure and associated proteins. Furthermore, MACs' effects on improving colon-cognitive parameters were eliminated by wide spectrum antibiotic microbiota ablation., Conclusions: These results suggest that MACs improve cognitive impairments via the gut microbiota-brain axis induced by the consumption of an HF-FD. Supplemental MACs to combat obesity-related gut and brain dysfunction offer a promising approach to prevent neurodegenerative diseases associated with Westernized dietary patterns and obesity.

Obesity is underpinned by both genetic and environmental factors, including a high-saturated-fat diet. Some mice develop diet-induced obesity (DIO), but others remain diet resistant (DR) despite intake of the same high-saturated-fat diet, a phenomenon that mimics characteristics of the human obese phenotype. Microbiota-colon-brain axis regulation is important for energy metabolism and cognition. Using DIO and DR mouse models, this study aimed to examine gut microbiota, colonic inflammation and cognitive function to elucidate the role of microbiota-gut-brain regulation in DIO. C57Bl6/J mice fed a chronic saturated-palmitic-acid diet for 22 weeks showed significant body weight gain differences, with the top one third gaining 48% heavier body weight than the lower one third. There was significant reduction in gut microbiota richness and diversity in DIO mice but not in DR mice. At the phylum level, DIO mice had increased abundance of Firmicutes and Antinobacteria, and decreased abundance of Bacterioides and Proteobacteria in gut microbiota. DIO mice exhibited reduced tight junction proteins, increased plasma endotoxin lipopolysaccharide (LPS) and increased inflammation in the colon and liver. Recognition memory and spatial memory were impaired in DIO mice, associated with decreased Bacteroidetes. Further examination showed that hippocampal brain-derived neurotrophic factor was significantly decreased in DIO mice (vs. DR). Conversely, DR mice showed no changes in the above parameters measured. Therefore, gut microbiota, colon inflammation and circulating LPS may play a major role in the development of the obese phenotype and cognitive decline associated with a chronic high-saturated-palmitic-acid diet., (Copyright © 2018. Published by Elsevier Inc.)

Antipsychotic pharmacotherapy is strongly obesogenic and is associated with increased oxidative stress in patients with schizophrenia. However, whether these changes reflect psychopathology, antipsychotic efficacy, or some other factor is not known. Our study aims to investigate the degree of oxidative stress in different BMI categories and to identify clinical symptomatology that may be paired with increased oxidative stress in a schizophrenia population. To this end, we performed a cross-sectional study and recruited 89 long-term inpatients with schizophrenia and collected the following variables: plasma malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), routine biochemical analysis, and psychopathology through the Positive and Negative Syndrome Scale (PANSS). The results indicate that the levels of the lipid peroxidation product, MDA, were significantly higher in the high BMI group than the low (normal) BMI group. As expected, high BMI was associated with an atherogenic lipid profile; however, it was also associated with fewer psychopathological symptoms. Multiple regression analysis found that MDA levels, the PANSS general psychopathology subscore, and triglyceride levels (all p < 0.05) were independent contributors to the BMI in patients. These results suggested that oxidative stress may play an important role in antipsychotic-induced weight gain. Further investigations using the longitudinal design in first-episode schizophrenia patients are needed to explore the beneficial effect of antioxidants on the abnormal lipid metabolism mediated by antipsychotic treatment.

Cold exposure is considered to be a form of stress and has various adverse effects on the body. The present study aimed to investigate the effects of chronic daily cold exposure on food intake, body weight, serum glucose levels and the central energy balance regulatory pathway in mice fed with a high‑fat diet (HFD). C57BL/6 mice were divided into two groups, which were fed with a standard chow or with a HFD. Half of the mice in each group were exposed to ice‑cold water for 1 h/day for 7 weeks, while the controls were exposed to room temperature. Chronic daily cold exposure significantly increased energy intake, body weight and serum glucose levels in HFD‑fed mice compared with the control group. In addition, 1 h after the final cold exposure, c‑fos immunoreactivity was significantly increased in the central amygdala of HFD‑fed mice compared with HFD‑fed mice without cold exposure, indicating neuronal activation in this brain region. Notably, 61% of these c‑fos neurons co‑expressed the neuropeptide Y (NPY), and the orexigenic peptide levels were significantly increased in the central amygdala of cold‑exposed mice compared with control mice. Notably, cold exposure significantly decreased the anorexigenic brain‑derived neurotropic factor (BDNF) messenger RNA (mRNA) levels in the ventromedial hypothalamic nucleus and increased growth hormone releasing hormone (GHRH) mRNA in the paraventricular nucleus. NPY‑ergic neurons in the central amygdala were activated by chronic cold exposure in mice on HFD via neuronal pathways to decrease BDNF and increase GHRH mRNA expression, possibly contributing to the development of obesity and impairment of glucose homeostasis.

Aim: Obesity impairs leptin-induced regulation of brain-derived neurotrophic factor (BDNF) expression and synaptogenesis, which has been considered to be associated with the incidence of neuronal degenerative diseases, cognitive decline, and depression. Ginsenoside Rb1 (Rb1), a major bioactive component of ginseng, is known to have an antiobesity effect and improve cognition. This study examined whether Rb1 can improve central leptin effects on BDNF expression and synaptogenesis in the prefrontal cortex during obesity using an in vivo and an in vitro model., Result: Ginsenoside Rb1 (Rb1) chronic treatment improved central leptin sensitivity, leptin-JAK2-STAT3 signaling, and leptin-induced regulation of BDNF expression in the prefrontal cortex of high-fat diet-induced obese mice. In cultured prefrontal cortical neurons, palmitic acid, the saturated fat, impaired leptin-induced BDNF expression, reduced the immunoreactivity and mRNA expression of synaptic proteins, and impaired leptin-induced neurite outgrowth and synaptogenesis. Importantly, Rb1 significantly prevented these pernicious effects induced by palmitic acid., Conclusion: These results indicate that Rb1 reverses central leptin resistance and improves leptin-BDNF-neurite outgrowth and synaptogenesis in the prefrontal cortical neurons. Thus, Rb1 supplementation may be a beneficial avenue to treat obesity-associated neurodegenerative disorders., (© 2017 John Wiley & Sons Ltd.)

Antipsychotic treatment, particularly olanzapine and clozapine, induces severe obesity. The Histamine H1 receptor is considered to be an important contributor to olanzapine-induced obesity, however how olanzapine modulates the histaminergic system is not sufficiently understood. This study examined the effect of olanzapine on key molecules of the histaminergic system, including histidine decarboxylase (HDC), H1 receptor (H1R) and H3 receptor (H3R), in the brain at different stages of olanzapine-induced obesity. During short-term treatment (8-day), olanzapine increased hypothalamic HDC mRNA expression and H1R binding in the arcuate nucleus (Arc) and ventromedial hypothalamus (VMH), without changing H3R binding density. HDC mRNA and Arc H1R binding were positively correlated with increased food intake, feeding efficiency and weight gain. When the treatment was extended to 16 and 36 days, H1R binding was increased not only in the hypothalamic Arc and VMH but also in the brainstem dorsal vagal complex (DVC). The H1R bindings in the Arc, VMH and DVC were positively correlated with weight gain induced by olanzapine treatment. However, the expression of HDC and H3R mRNA was not increased. These results suggest that olanzapine time-dependently modulates histamine neurotransmission, which suggested the different neuronal mechanisms underlying different stages of weight gain development. Treatment targeting the H1R may be effective for both short- and long-term olanzapine-induced weight gain., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A high-fat (HF) diet alters gut microbiota and promotes obesity related inflammation and cognitive impairment. Teasaponin is the major active component of tea, and has been associated with anti-inflammatory effects and improved microbiota composition. However, the potential protective effects of teasaponin, against HF diet-induced obesity and its associated alteration of gut microbiota, inflammation and cognitive decline have not been studied. In this study, obesity was induced in C57BL/6 J male mice by feeding a HF diet for 8 weeks, followed by treatment with oral teasaponin (0.5%) mixed in HF diet for a further 6 weeks. Teasaponin treatment prevented the HF diet-induced recognition memory impairment and improved neuroinflammation, gliosis and brain-derived neurotrophic factor (BDNF) deficits in the hippocampus. Furthermore, teasaponin attenuated the HF diet-induced endotoxemia, pro-inflammatory macrophage accumulation in the colon and gut microbiota alterations. Teasaponin also improved glucose tolerance and reduced body weight gain in HF diet-induced obese mice. The behavioral and neurochemical improvements suggest that teasaponin could limit unfavorable gut microbiota alterations and cognitive decline in HF diet-induced obesity.

High-fat (HF) diet modulates gut microbiota and increases plasma concentration of lipopolysaccharide (LPS) which is associated with obesity and its related low-grade inflammation and cognitive decline. Rhein is the main ingredient of the rhubarb plant which has been used as an anti-inflammatory agent for several millennia. However, the potential effects of rhein against HF diet-induced obesity and its associated alteration of gut microbiota, inflammation and cognitive decline have not been studied. In this study, C57BL/6J male mice were fed an HF diet for 8 weeks to induce obesity, and then treated with oral rhein (120 mg/kg body weight/day in HF diet) for a further 6 weeks. Chronic rhein treatment prevented the HF diet-induced recognition memory impairment assessed by the novel object recognition test, neuroinflammation and brain-derived neurotrophic factor (BDNF) deficits in the perirhinal cortex. Furthermore, rhein inhibited the HF diet-induced increased plasma LPS level and the proinflammatory macrophage accumulation in the colon and alteration of microbiota, including decreasing Bacteroides-Prevotella spp. and Desulfovibrios spp. DNA and increasing Bifidobacterium spp. and Lactobacillus spp. DNA. Moreover, rhein also reduced body weight and improved glucose tolerance in HF diet-induced obese mice. In conclusion, rhein improved recognition memory and prevented obesity in mice on a chronic HF diet. These beneficial effects occur via the modulation of microbiota, hypoendotoxinemia, inhibition of macrophage accumulation, anti-neuroinflammation and the improvement of BDNF expression. Therefore, supplementation with rhein-enriched food or herbal medicine could be beneficial as a preventive strategy for chronic HF diet-induced cognitive decline, microbiota alteration and neuroinflammation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

High-fat (HF) diet-induced obesity is associated with hypothalamic leptin resistance and low grade chronic inflammation, which largely impairs the neuroregulation of negative energy balance. Neuroregulation of negative energy balance is largely controlled by the mediobasal and paraventricular nuclei regions of the hypothalamus via leptin signal transduction. Recently, a derivative of oleanolic acid, bardoxolone methyl (BM), has been shown to have anti-inflammatory effects. We tested the hypothesis that BM would prevent HF diet-induced obesity, hypothalamic leptin resistance, and inflammation in mice fed a HF diet. Oral administration of BM via drinking water (10 mg/kg daily) for 21 weeks significantly prevented an increase in body weight, energy intake, hyperleptinemia, and peripheral fat accumulation in mice fed a HF diet. Furthermore, BM treatment prevented HF diet-induced decreases in the anorexigenic effects of peripheral leptin administration. In the mediobasal and paraventricular nuclei regions of the hypothalamus, BM administration prevented HF diet-induced impairments of the downstream protein kinase b (Akt) pathway of hypothalamic leptin signalling. BM treatment also prevented an increase in inflammatory cytokines, tumour necrosis factor alpha (TNFα) and interleukin 6 (IL-6) in these two hypothalamic regions. These results identify a potential novel neuropharmacological application for BM in preventing HF diet-induced obesity, hypothalamic leptin resistance, and inflammation., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Scope: Obesity impairs cognition, and the leptin-induced increase of brain-derived neurotrophic factor (BDNF) and neurogenesis. Tea consumption improves cognition and increases brain activation in the prefrontal cortex., Methods and Results: This study examined whether teasaponin, an active ingredient in tea, could improve memory and central leptin effects on neurogenesis in the prefrontal cortex of obese mice, and in vitro in cultured prefrontal cortical neurons. Teasaponin (10 mg/kg, intraperitoneal) for 21 days improved downstream leptin signaling (JAK2 and STAT3), and leptin's effect on BDNF, in the prefrontal cortex of high-fat diet (HFD) fed mice. Prefrontal cortical neurons were cultured with teasaponin and palmitic acid (the most abundant dietary saturated fatty acid) to examine their effects on neurogenesis and BDNF expression in response to leptin. Palmitic acid decreased leptin's effect on neurite outgrowth, postsynaptic density protein 95, and BDNF expression in cultured cortical neurons, which was reversed by teasaponin., Conclusion: Teasaponin improved the leptin sensitivity of prefrontal cortical neurons in obese mice or when treated by palmitic acid. This in turn increased BDNF expression and neurite growth. Therefore, teasaponin supplementation may be used to prevent obesity-associated neurodegeneration and improve cognitive function., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Key features of diet-induced obesity are visceral fat deposition, macrophage infiltration and inflammation that can lead to metabolic disorders. This study examined the effects of bardoxolone methyl (BARD) in preventing obesity and inflammation in the visceral fat of mice fed high-fat diet. Male C57BL/6J mice were fed a high-fat diet (HFD), a low-fat diet (LFD, i.e., lab chow diet) or a high-fat diet supplemented with BARD (HFD/BARD) for 21weeks. BARD at a dosage of 10mg/kg body weight was administered orally in drinking water. Histology, immunohistochemistry and Western blot were used for the analysis of epididymal adipose tissue. Morphological results demonstrated that HFD fed mice treated with BARD had smaller adipocytes and fewer macrophages present in epididymal adipose tissue than the HFD group. Furthermore, BARD administration reduced the inflammatory profile in this tissue by increasing the expression of nuclear factor of kappa-light-polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α) protein and decreasing the protein expression of tumour necrosis factor alpha (TNF-α). BARD also prevented oxidative stress reflected by a reduction in stress activated proteins, including signal transducer and activator of transcription 3 (STAT3), protein kinase B (Akt), extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). BARD administration activated the sympathetic nervous system in epididymal adipose tissue assessed by the increased synthesis of tyrosine hydroxylase (TH) and uncoupling protein 2 (UCP2). The expression of inflammatory and sympathetic nervous system proteins in BARD mice fed a HFD was equivalent to that of the LFD control mice, indicating the anti-inflammatory and anti-obesity properties of this drug. In conclusion, the oral administration of BARD in HFD mice prevented fat deposition, inflammation and oxidative stress, and improved sympathetic activity in visceral fat. This study suggests a potential therapeutic role of BARD in preventing the development of obesity., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Mesenteric fat belongs to visceral fat. An increased deposition of mesenteric fat contributes to obesity associated complications such as type 2 diabetes and cardiovascular diseases. We have investigated the therapeutic effects of bardoxolone methyl (BARD) on mesenteric adipose tissue of mice fed a high-fat diet (HFD). Male C57BL/6J mice were administered oral BARD during HFD feeding (HFD/BARD), only fed a high-fat diet (HFD), or fed low-fat diet (LFD) for 21 weeks. Histology and immunohistochemistry were used to analyse mesenteric morphology and macrophages, while Western blot was used to assess the expression of inflammatory, oxidative stress, and energy expenditure proteins. Supplementation of drinking water with BARD prevented mesenteric fat deposition, as determined by a reduction in large adipocytes. BARD prevented inflammation as there were fewer inflammatory macrophages and reduced proinflammatory cytokines (interleukin-1 beta and tumour necrosis factor alpha). BARD reduced the activation of extracellular signal-regulated kinase (ERK) and Akt, suggesting an antioxidative stress effect. BARD upregulates energy expenditure proteins, judged by the increased activity of tyrosine hydroxylase (TH) and AMP-activated protein kinase (AMPK) and increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and uncoupling protein 2 (UCP2) proteins. Overall, BARD induces preventive effect in HFD mice through regulation of mesenteric adipose tissue.

Weight gain and its related metabolic disorders are major side effects associated with second generation antipsychotic drug treatment. The dorsal vagal complex (DVC) and AMP-activated protein kinase (AMPK) are implicated in the regulation of food intake and body weight. Blocking the histamine H1 receptor contributes to antipsychotic-induced weight gain. The present study investigated the time-dependent effect of olanzapine treatment (8, 16, and 36 d) on DVC AMPK signaling in olanzapine-induced weight gain and whether these changes are associated with olanzapine-induced H1 receptor antagonism. During the 8-day olanzapine treatment, the rats were hyperphagic and rapidly gained weight. The phosphorylation of AMPK (pAMPK) (activated AMPK) as well as its directly downstream phospho-acetyl-coenzyme A carboxylase was significantly increased. The pAMPK/AMPK ratio, an indicator of AMPK activity, was significantly positively correlated with feeding efficiency and weight gain. As treatment was prolonged (16 and 36 d of olanzapine treatment), the rats were no longer hyperphagic, and there were no longer any changes in DVC AMPK signaling. Although the DVC H1 receptor protein expression was not significantly altered by olanzapine, the pAMPK expression was significantly positively correlated with the H1 receptor level after the 8-, 16-, and 36-day olanzapine treatments. Moreover, we showed that an H1 receptor agonist, 2-(3-trifluoromethylphenyl) histamine, significantly inhibited the olanzapine-induced hyperphagia and DVC AMPK activation in a dose-dependent manner. These results suggest a time-dependent role of DVC AMPK in olanzapine-induced obesity. Thus, olanzapine-induced DVC AMPK activation may be at least partially related to olanzapine's antagonistic effect on the H1 receptor.

BACKGROUND: Brown rice contains nutrients that significantly reduce the incidence of obesity. This study aimed to investigate the effect of brown rice as a functional food on the reduction of obesity incidence through the pathways of gut microbiota dysbiosis. METHODS: In this study, we used white rats (Rattus norvegicus albus), which were divided into five groups, i.e., Normal, High fructose feed diet (HFFD), HFFD + Brown rice (BR) I, HFFD + BR II, HFFD + BR III. The parameters were SCFA concentration, FFAR3 expression, and Firmicutes– Bacteroidetes ratio. RESULTS: The rats fed HFFD + BR III diet with a high intake of brown rice resulted in a greater reduction in abdominal circumference. The group of rats fed the HFFD had a higher BFI than the other rats. The brown rice intervention reduced the Lee index, a higher concentration of short-chain fatty acid (SCFA), and led to a higher reduction in Firmicutes– Bacteroidetes ratio. The brown rice intervention also increased the FFAR3 expression in the rat ileal L cells. CONCLUSIONS: Brown rice has significant benefits for reducing obesity, as evidenced by the improvement in the abdominal circumference, Lee index, and BFI through the improvement of intestinal dysbiosis and increase in SCFA concentration and FFAR3 expression. [ABSTRACT FROM AUTHOR]

Background and aims: A novel non–insulin-based metabolic score for insulin resistance (METS‐IR) index has been proposed as a simple and reliable alternative insulin resistance (IR) marker, but its the predictive value in asymptomatic adults with coronary artery calcification (CAC) remains unclear. Methods and results: We enrolled 1576 participants without cardiovascular disease (CVD), who underwent multidetector computed tomography. Logistic regression, restricted cubic spline models and receiver operating characteristic (ROC) curves were used to examine the association between METS-IR, the ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) and triglyceride glucose index (TyG index) and CAC. In multivariate logistic regression analysis, the increase in METS-IR was independently associated with a higher prevalence of CAC (all P < 0.05 in Models 1–3). Furthermore, restricted cubic splines indicated that the significance of METS-IR in predicting CAC was higher than that of other IR indexes. In ROC curve analysis, without considering the P value, the area under the curve of CAC predicted by METS-IR was higher than that of other IR indexes (METS-IR, 0.607; TyG index, 0.603; TG/HDL-C, 0.577). Conclusion: Compared with other IR indexes, METS-IR may have better discrimination ability in predicting the incidence of CAC in asymptomatic adults without CVD. [ABSTRACT FROM AUTHOR]

Introduction: Limited information exists about the relationship between body mass index (BMI) and the outcome of acute respiratory distress syndrome (ARDS). Objective: To evaluate the hospital mortality of patients with ARDS in relation to BMI. Materials and methods: We conducted a retrospective, multicenter study including patients with ARDS. ARDS was defined according to the Berlin criteria. Body weight and height were obtained to calculate BMI. The primary outcome was in‐hospital mortality. Secondary outcomes were intensive care unit (ICU) mortality, invasive positive pressure ventilation (IPPV) free days within 28 days and length of stays in the ICU and hospital. Results: Among 523 patients, 28 (5%) were underweight (BMI <18.5 kg/m2), 299 (57%) were normal weight (BMI 18.5‐24.9 kg/m2), 159 (30%) were overweight (BMI 25‐29.9 kg/m2) and 37 (7%) were obese (BMI ≥30 kg/m2). Increasing BMI was associated with younger age (P = 0.017), hypertension (P = 0.003) and diabetes (P = 0.02). Compared with normal weight, being overweight and obese resulted in lower mortality regardless of whether in the hospital (P = 0.019) or ICU (P = 0.044). However, after risk adjustment, only obesity was associated with lower hospital mortality (OR 0.393, 95% CI 0.169‐0.914, P = 0.030). With the increase of BMI, the in‐hospital mortality and ICU mortality of ARDS dropped gradually (from 57.1% to 24.3%, P = 0.021, and from 53.6% to 24.3%, P = 0.035). Conclusions: Obesity is associated with lower mortality in patients with ARDS. With the increase of BMI, the mortality of ARDS drops gradually. [ABSTRACT FROM AUTHOR]

A high-fat (HF) diet is a major predisposing factor of neuroinflammation and cognitive deficits. Recently, changes in the gut microbiota have been associated with neuroinflammation and cognitive impairment, through the gut-brain axis. Curdlan, a bacterial polysaccharide widely used as food additive, has the potential to alter the composition of the microbiota and improve the gut-brain axis. However, the effects of curdlan against HF diet-induced neuroinflammation and cognitive decline have not been investigated. We aimed to evaluate the neuroprotective effect and mechanism of dietary curdlan supplementation against the obesity-associated cognitive decline observed in mice fed a HF diet. C57Bl/6J male mice were fed with either a control, HF, or HF with curdlan supplementation diets for 7 days (acute) or 15 weeks (chronic). We found that acute curdlan supplementation prevented the gut microbial composition shift induced by HF diet. Chronic curdlan supplementation prevented cognitive declines induced by HF diet. In addition, curdlan protected against the HF diet-induced abnormities in colonic permeability, hyperendotoxemia, and colonic inflammation. Furthermore, in the prefrontal cortex (PFC) and hippocampus, curdlan mitigated microgliosis, neuroinflammation, and synaptic impairments induced by a HF diet. Thus, curdlan—as a food additive and prebiotic—can prevent cognitive deficits induced by HF diet via the colon-brain axis. [ABSTRACT FROM AUTHOR]

Aims: Many patients taking risperidone for the treatment of psychiatric disorders experience substantial body weight gain. Researchers have speculated that risperidone induces obesity by modulating central signals; however, the precise central mechanisms involved remain to be fully elucidated. Methods: Twenty‐four C57BL/6J mice were divided into four groups: a control group; a risperidone‐treated group; a lorcaserin‐treated group; and a combined risperidone + lorcaserin‐treated group. The mice were received the corresponding treatments for 4 weeks, and their brains were collected for in situ hybridization analysis. A subset of C57BL/6J mice was administrated with risperidone or placebo, and brains were collected 60 minutes post‐treatment for determination of c‐fos activity. In addition, brains of NPY‐GFP mice treated with or without risperidone were collected to perform colocalization of NPY and c‐fos, as well as NPY and 5‐HT2c receptor using immunohistochemistry. Results: There was significantly elevated c‐fos expression in the hypothalamic arcuate nucleus (Arc) of risperidone‐treated mice. More than 68% c‐fos‐positive neurons were NPY‐expressing neurons. Furthermore, in situ hybridization revealed that Arc NPY mRNA expression was significantly increased in the risperidone‐treated group compared with control group. Moreover, we identified that 95% 5‐HT2c receptors were colocalized with NPY positive neurons, and increased Arc NPY mRNA expression induced by risperidone was markedly reduced by cotreatment with lorcaserin, a specific 5‐HT2c receptor agonist. Conclusion: Our findings provide critical insight into the mechanisms underlying antipsychotic‐induced obesity, which may assist the development of therapeutic strategies to address metabolic side effects of risperidone. [ABSTRACT FROM AUTHOR]

Background: Antipsychotic drugs (APDs), olanzapine and clozapine, do not effectively address the cognitive symptoms of schizophrenia and can cause serious metabolic side-effects. Liraglutide is a synthetic glucagon-like peptide-1 (GLP-1) receptor agonist with anti-obesity and neuroprotective properties. The aim of this study was to examine whether liraglutide prevents weight gain/hyperglycaemia side-effects and cognitive deficits when co-administered from the commencement of olanzapine and clozapine treatment.Methods: Rats were administered olanzapine (2 mg/kg, three times daily (t.i.d.)), clozapine (12 mg/kg, t.i.d.), liraglutide (0.2 mg/kg, twice daily (b.i.d.)), olanzapine + liraglutide co-treatment, clozapine + liraglutide co-treatment or vehicle (Control) ( n = 12/group, 6 weeks). Recognition and working memory were examined using Novel Object Recognition (NOR) and T-Maze tests. Body weight, food intake, adiposity, locomotor activity and glucose tolerance were examined.Results: Liraglutide co-treatment prevented olanzapine- and clozapine-induced reductions in the NOR test discrimination ratio ( p < 0.001). Olanzapine, but not clozapine, reduced correct entries in the T-Maze test ( p < 0.05 versus Control) while liraglutide prevented this deficit. Liraglutide reduced olanzapine-induced weight gain and adiposity. Olanzapine significantly decreased voluntary locomotor activity and liraglutide co-treatment partially reversed this effect. Liraglutide improved clozapine-induced glucose intolerance.Conclusion: Liraglutide co-treatment improved aspects of cognition, prevented obesity side-effects of olanzapine, and the hyperglycaemia caused by clozapine, when administered from the start of APD treatment. The results demonstrate a potential treatment for individuals at a high risk of experiencing adverse effects of APDs. [ABSTRACT FROM AUTHOR]

Diabetes-induced atherosclerotic cardiovascular disease is the leading cause of death of diabetic patients. Neuronal regulation plays a critical role in glucose metabolism and cardiovascular function under physiological and pathological conditions, among which, neurotransmitter neuropeptide Y has been shown to be closely involved in these two processes. Elevated central neuropeptide Y level promotes food intake and reduces energy expenditure, thereby increasing adiposity. Neuropeptide Y is co-localized with noradrenaline in central and sympathetic nervous systems. As a major peripheral vascular contractive neurotransmitter, through interactions with its receptors, neuropeptide Y has been implicated in the pathology and progression of diabetes, by promoting the proliferation of endothelial cells and vascular fibrosis, which may contribute to diabetes-induced cardiovascular disease. Neuropeptide Y also participates in the pathogenesis of atherosclerosis, the major form of cardiovascular disease, via aggravating endothelial dysfunction, growth of vascular smooth muscle cells, formation of foam cells and platelets aggregation. This review highlights the causal role of neuropeptide Y and its receptor system in the development of diabetes mellitus and one of its complications: atherosclerotic cardiovascular disease. The information from this review provides both critical insights onto the mechanisms underlying the pathogenesis of atherosclerosis and evidence for the development of therapeutic strategies. [ABSTRACT FROM AUTHOR]

Olanzapine is the one of first line antipsychotic drug for schizophrenia and other serious mental illness. However, it is associated with troublesome metabolic side-effects, particularly body weight gain and obesity. The antagonistic affinity to histamine H1 receptors (H1R) of antipsychotic drugs has been identified as one of the main contributors to weight gain/obesity side-effects. Our previous study showed that a short term (2 weeks) combination treatment of betahistine (an H1R agonist and H3R antagonist) and olanzapine (O+B) reduced (−45%) body weight gain induced by olanzapine in drug-naïve rats. A key issue is that clinical patients suffering with schizophrenia, bipolar disease and other mental disorders often face chronic, even life-time, antipsychotic treatment, in which they have often had previous antipsychotic exposure. Therefore, we investigated the effects of chronic O+B co-treatment in controlling body weight in female rats with chronic and repeated exposure of olanzapine. The results showed that co-administration of olanzapine (3 mg/kg, t.i.d.) and betahistine (9.6 mg/kg, t.i.d.) significantly reduced (−51.4%) weight gain induced by olanzapine. Co-treatment of O+B also led to a decrease in feeding efficiency, liver and fat mass. Consistently, the olanzapine-only treatment increased hypothalamic H1R protein levels, as well as hypothalamic pAMPKα, AMPKα and NPY protein levels, while reducing the hypothalamic POMC, and UCP1 and PGC-1α protein levels in brown adipose tissue (BAT). The olanzapine induced changes in hypothalamic H1R, pAMPKα, BAT UCP1 and PGC-1α could be reversed by co-treatment of O+B. These results supported further clinical trials to test the effectiveness of co-treatment of O+B for controlling weight gain/obesity side-effects in schizophrenia with chronic antipsychotic treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] • PTP1B is increased in the serum of obese subjects and the forebrain of obese mice, correlated with cognitive decline. • Knockout of PTP1B in leptin receptor-expressing cells and forebrain regions prevents cognitive impairments in obese mice. • PTP1B allosteric inhibitors improved leptin synaptic signaling in obese mice and PTP1B-overexpressed-neuronal cells. Obesity has reached pandemic proportions and is a risk factor for neurodegenerative diseases, including Alzheimer's disease. Chronic inflammation is common in obese patients, but the mechanism between inflammation and cognitive impairment in obesity remains unclear. Accumulative evidence shows that protein-tyrosine phosphatase 1B (PTP1B), a neuroinflammatory and negative synaptic regulator, is involved in the pathogenesis of neurodegenerative processes. We investigated the causal role of PTP1B in obesity-induced cognitive impairment and the beneficial effect of PTP1B inhibitors in counteracting impairments of cognition, neural morphology, and signaling. We showed that obese individuals had negative relationship between serum PTP1B levels and cognitive function. Furthermore, the PTP1B level in the forebrain increased in patients with neurodegenerative diseases and obese cognitive impairment mice with the expansion of white matter, neuroinflammation and brain atrophy. PTP1B globally or forebrain-specific knockout mice on an obesogenic high-fat diet showed enhanced cognition and improved synaptic ultrastructure and proteins in the forebrain. Specifically, deleting PTP1B in leptin receptor-expressing cells improved leptin synaptic signaling and increased BDNF expression in the forebrain of obese mice. Importantly, we found that various PTP1B allosteric inhibitors (e.g., MSI-1436, well-tolerated in Phase 1 and 1b clinical trials for obesity and type II diabetes) prevented these alterations, including improving cognition, neurite outgrowth, leptin synaptic signaling and BDNF in both obese cognitive impairment mice and a neural cell model of PTP1B overexpression. These findings suggest that increased forebrain PTP1B is associated with cognitive decline in obesity, whereas inhibition of PTP1B could be a promising strategy for preventing neurodegeneration induced by obesity. [ABSTRACT FROM AUTHOR]

[Display omitted] • The participants with obesity have decreased Clostridium butyricum correlated with cognitive decline. • Clostridium butyricum improves hippocampal synaptic ultrastructure of obese mice. • Many hippocampal gene changes in AD are reversed by Clostridium butyricum. • Clostridium butyricum prevents cognitive decline via the microbiota-gut-brain axis. Obesity is a risk factor for cognitive dysfunction and neurodegenerative disease, including Alzheimer's disease (AD). The gut microbiota-brain axis is altered in obesity and linked to cognitive impairment and neurodegenerative disorders. Here, we targeted obesity-induced cognitive impairment by testing the impact of the probiotic Clostridium butyricum , which has previously shown beneficial effects on gut homeostasis and brain function. Firstly, we characterized and analyzed the gut microbial profiles of participants with obesity and the correlation between gut microbiota and cognitive scores. Then, using an obese mouse model induced by a Western-style diet (high-fat and fiber-deficient diet), the effects of Clostridium butyricum on the microbiota-gut-brain axis and hippocampal cognitive function were evaluated. Finally, fecal microbiota transplantation was performed to assess the functional link between Clostridium butyricum remodeling gut microbiota and hippocampal synaptic protein and cognitive behaviors. Our results showed that participants with obesity had gut microbiota dysbiosis characterized by an increase in phylum Proteobacteria and a decrease in Clostridium butyricum , which were closely associated with cognitive decline. In diet-induced obese mice, oral Clostridium butyricum supplementation significantly alleviated cognitive impairment, attenuated the deficit of hippocampal neurite outgrowth and synaptic ultrastructure, improved hippocampal transcriptome related to synapses and dendrites; a comparison of the effects of Clostridium butyricum in mice against human AD datasets revealed that many of the genes changes in AD were reversed by Clostridium butyricum ; concurrently, Clostridium butyricum also prevented gut microbiota dysbiosis, colonic barrier impairment and inflammation, and attenuated endotoxemia. Importantly, fecal microbiota transplantation from donor-obese mice with Clostridium butyricum supplementation facilitated cognitive variables and colonic integrity compared with from donor obese mice, highlighting that Clostridium butyricum's impact on cognitive function is largely due to its ability to remodel gut microbiota. Our findings provide the first insights into the neuroprotective effects of Clostridium butyricum on obesity-associated cognitive impairments and neurodegeneration via the gut microbiota-gut-brain axis. [ABSTRACT FROM AUTHOR]

Obesity is underpinned by both genetic and environmental factors, including a high-saturated-fat diet. Some mice develop diet-induced obesity (DIO), but others remain diet resistant (DR) despite intake of the same high-saturated-fat diet, a phenomenon that mimics characteristics of the human obese phenotype. Microbiota-colon-brain axis regulation is important for energy metabolism and cognition. Using DIO and DR mouse models, this study aimed to examine gut microbiota, colonic inflammation and cognitive function to elucidate the role of microbiota-gut-brain regulation in DIO. C57Bl6/J mice fed a chronic saturated-palmitic-acid diet for 22 weeks showed significant body weight gain differences, with the top one third gaining 48% heavier body weight than the lower one third. There was significant reduction in gut microbiota richness and diversity in DIO mice but not in DR mice. At the phylum level, DIO mice had increased abundance of Firmicutes and Antinobacteria, and decreased abundance of Bacterioides and Proteobacteria in gut microbiota. DIO mice exhibited reduced tight junction proteins, increased plasma endotoxin lipopolysaccharide (LPS) and increased inflammation in the colon and liver. Recognition memory and spatial memory were impaired in DIO mice, associated with decreased Bacteroidetes. Further examination showed that hippocampal brain-derived neurotrophic factor was significantly decreased in DIO mice (vs. DR). Conversely, DR mice showed no changes in the above parameters measured. Therefore, gut microbiota, colon inflammation and circulating LPS may play a major role in the development of the obese phenotype and cognitive decline associated with a chronic high-saturated-palmitic-acid diet. [ABSTRACT FROM AUTHOR]

Obesity caused by the consumption of a high-fat (HF) diet is a major risk factor for the development of associated complications, such as heart and kidney failure. A semi-synthetic triterpenoid, bardoxolone methyl (BM) was administrated to mice fed a HF diet for 21 weeks to determine if it would prevent the development of obesity-associated cardiac and renal pathophysiologies. Twelve week old male C57BL/6J mice were fed a lab chow (LC), HF (40% fat), or a HF diet supplemented with 10 mg/kg/day BM in drinking water. After 21 weeks, the left ventricles of hearts and cortex of kidneys of mice were collected for analysis. Histological analysis revealed that BM prevented HF diet-induced development of structural changes in the heart and kidneys. BM prevented HF diet-induced decreases in myocyte number in cardiac tissue, although this treatment also elevated cardiac endothelin signalling molecules. In the kidneys, BM administration prevented HF diet-induced renal corpuscle hypertrophy and attenuated endothelin signalling. Furthermore, in both the hearts and kidneys of mice fed a HF diet, BM administration prevented HF diet-induced increases in fat accumulation, macrophage infiltration and tumour necrosis factor alpha (TNFα) gene expression. These findings suggest that BM prevents HF diet-induced developments of cardiac and renal pathophysiologies in mice fed a chronic HF diet by preventing inflammation. Moreover, these results suggest that BM has the potential as a therapeutic for preventing obesity-induced cardiac and renal pathophysiologies. [ABSTRACT FROM AUTHOR]

High-fat (HF) diet-induced obesity is a major risk factor for the development of insulin resistance and hepatic steatosis. We examined the hypothesis that bardoxolone methyl (BM) would prevent the development of insulin resistance and hepatic steatosis in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC), HF (40% fat), or HF diet supplemented with 10 mg/kg/day BM orally for 21 weeks. Glucose metabolism was assessed using a glucose tolerance test (GTT) and insulin sensitivity test (IST). Signalling molecules involved in insulin resistance, inflammation, and lipid metabolism were examined in liver tissue via western blotting and RT-PCR. BM prevented HF diet-induced insulin resistance and alterations in the protein levels of protein tyrosine phosphatase 1B (PTP1B), forkhead box protein O1 (FOXO1) and BDNF, and expression of the insulin receptor ( IR) , IRS-1 and glucose-6-phosphatase (G6Pase) genes. Furthermore, BM prevented fat accumulation in the liver and decreases in the β-oxidation gene, peroxisomal acyl-coenzyme A oxidase 1 (ACOX) in mice fed a HF diet. In the livers of HF fed mice, BM administration prevented HF diet-induced macrophage infiltration, inflammation as indicated by reduced IL-6 and signal transducer and activator of transcription 3 (STAT3) protein levels and TNFα mRNA expression, and increased nuclear factor-like 2 (Nrf2) mRNA expression and nuclear protein levels. These findings suggest that BM prevents HF diet induced insulin resistance and the development of hepatic steatosis in mice fed a chronic HF diet through modulation of molecules involved in insulin signalling, lipid metabolism and inflammation in the liver. [ABSTRACT FROM AUTHOR]

High fat (HF) diets are known to induce changes in synaptic plasticity in the forebrain leading to learning and memory impairments. Previous studies of oleanolic acid derivatives have found that these compounds can cross the blood–brain barrier to prevent neuronal cell death. We examined the hypothesis that the oleanolic acid derivative, bardoxolone methyl (BM) would prevent diet-induced cognitive deficits in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC) (5% of energy as fat), a HF (40% of energy as fat), or a HF diet supplemented with 10 mg/kg/day BM orally for 21 weeks. Recognition memory was assessed by performing a novel object recognition test on the treated mice. Downstream brain-derived neurotrophic factor (BDNF) signalling molecules were examined in the prefrontal cortex (PFC) and hippocampus of mice via Western blotting and N -methyl- d -aspartate (NMDA) receptor binding. BM treatment prevented HF diet-induced impairment in recognition memory ( p < 0.001). In HF diet fed mice, BM administration attenuated alterations in the NMDA receptor binding density in the PFC ( p < 0.05), however, no changes were seen in the hippocampus ( p > 0.05). In the PFC and hippocampus of the HF diet fed mice, BM administration improved downstream BDNF signalling as indicated by increased protein levels of BDNF, phosphorylated tropomyosin related kinase B (pTrkB) and phosphorylated protein kinase B (pAkt), and increased phosphorylated AMP-activated protein kinase (pAMPK) ( p < 0.05). BM administration also prevented the HF diet-induced increase in the protein levels of inflammatory molecules, phosphorylated c-Jun N-terminal kinase (pJNK) in the PFC, and protein tyrosine phosphatase 1B (PTP1B) in both the PFC and hippocampus. In summary, these findings suggest that BM prevents HF diet-induced impairments in recognition memory by improving downstream BDNF signal transduction, increasing pAMPK, and reducing inflammation in the PFC and hippocampus. [ABSTRACT FROM AUTHOR]

Although many studies have confirmed the effects of the built environment on adiposity outcomes in the general population, evidence for young adults is scarce. Furthermore, most prior studies are prone to residential self-selection bias due to the nature of cross-sectional research design, which makes the built environment–adiposity relationship spurious. In this study, we explored the associations between the built environment and three objectively measured adiposity outcomes for a large representative sample of 20,227 undergraduate students from 89 university campuses in China. The adiposity outcomes were measured by body mass index (BMI), waist circumstance (WC), and waist-to-height ratio (WHtR). The residential self-selection bias was largely mitigated because these students are required to live in campus dormitories. As shown by multilevel models, street connectivity, population density, and Normalized Difference Vegetation Index (NDVI) within and around the campus environment were negatively associated with the odds of adiposity to different extents. Furthermore, the adiposity outcomes of male and low cost-of-living undergraduates were more likely to be affected by built environment characteristics compared to female and high cost-of-living undergraduates. Hence, to deliver effective environment interventions to curb the prevalence of adiposity among undergraduate students, policymakers and university managers are advised to create a more carefully conceived campus environment. • First nationwide study exploring the link between built environment and adiposity outcomes for undergraduate students. • Three adiposity outcomes were objectively measured by professionals for 20,227 undergraduate students throughout China. • The residential self-selection bias is largely mitigated because these students were required to live in campus dormitories. • Street connectivity, population density, and NDVI within and around campuses were negatively associated with adiposity. [ABSTRACT FROM AUTHOR]

Anti-obesity effects and improved leptin sensitivity from n-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported in diet-induced obese animals. This study sought to determine the beneficial central effects and mechanism of docosahexaenoic acid (DHA, 22:6 n-3) in high-fat (HF) diet fed mice. Male C57BL/6J mice were given HF diet with or without intracerebroventricular (icv) injection of docosahexaenoic acid (DHA, 22:6 n-3) for two days. Central leptin sensitivity, hypothalamic inflammation, leptin signaling molecules and tyrosine hydroxylase (TH) were examined by central leptin sensitivity test and Western blot. Furthermore, the expression of hepatic genes involved in lipid metabolism was examined by RT-PCR. We found that icv administration of DHA not only reduced energy intake and body weight gain but also corrected the HF diet-induced hypothalamic inflammation. DHA decreased leptin signaling inhibitor SOCS3 and improved the leptin JAK2-Akt signaling pathways in the hypothalamus. Furthermore, icv administration of DHA improved the effects of leptin in the regulation of mRNA expression of enzymes related to lipogenesis, fatty acid β-oxidation, and cholesterol synthesis in the liver. DHA increased leptin-induced activation of TH in the hypothalamus. Therefore, increasing central DHA concentration may prevent the deficit of hypothalamic regulation, which is associated with disorders of energy homeostasis in the liver as a result of a high-fat diet. [ABSTRACT FROM AUTHOR]