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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.

A low-grade pro-inflammatory state is at the pathogenic core of obesity and type 2 diabetes. We tested the hypothesis that the plant terpenoid compound ginsenoside Rb1 (Rb1), known to exert anti-inflammatory effects, would ameliorate obesity, obesity-associated inflammation and glucose intolerance in the high-fat diet-induced obese mouse model. Furthermore, we examined the effect of Rb1 treatment on central leptin sensitivity and the leptin signaling pathway in the hypothalamus. We found that intraperitoneal injections of Rb1 (14 mg/kg, daily) for 21 days significantly reduced body weight gain, fat mass accumulation, and improved glucose tolerance in obese mice on a HF diet compared to vehicle treatment. Importantly, Rb1 treatment also reduced levels of pro-inflammatory cytokines (TNF-α, IL-6 and/or IL-1β) and NF-κB pathway molecules (p-IKK and p-IκBα) in adipose tissue and liver. In the hypothalamus, Rb1 treatment decreased the expression of inflammatory markers (IL-6, IL-1β and p-IKK) and negative regulators of leptin signaling (SOCS3 and PTP1B). Furthermore, Rb1 treatment also restored the anorexic effect of leptin in high-fat fed mice as well as leptin pSTAT3 signaling in the hypothalamus. Ginsenoside Rb1 has potential for use as an anti-obesity therapeutic agent that modulates obesity-induced inflammation and improves central leptin sensitivity in HF diet-induced obesity.

Chronic inflammation is involved in the pathogenesis of obesity and type 2 diabetes. Recently teasaponin, an extract from tea, has been shown to have antiinflammatory effects. We examined the effect of teasaponin on obesity, inflammation, glucose metabolism, and central leptin sensitivity in obese mice fed a high-fat (HF) diet for 16 weeks. Intraperitoneal injections of teasaponin (10 mg/kg, daily) for 21 days significantly decreased the food intake and body weight of HF diet-induced obese mice. Teasaponin treatment also reduced the protein levels of proinflammatory cytokines (TNF-α, IL-6, and/or IL-1β) and nuclear factor-κB signaling (phosphorylated inhibitory-κB kinase and phosphorylated inhibitory-κBα) in adipose tissue and the liver. The antiinflammatory effects of teasaponin were associated with improved glycemic status in the treated animals, evidenced by improved glucose tolerance, homeostasis model assessment, and fasting plasma insulin. In the hypothalamus, teasaponin decreased both proinflammatory cytokines and inflammatory signaling in the mediobasal hypothalamus. Teasaponin treatment also enhanced the anorexigenic effect of central leptin administration, restored leptin phosphorylated signal transducer and activator of transcription-3 (p-STAT3) signaling in the arcuate nucleus, and increased hypothalamic expression of the anorexigenic peptide proopiomelanocortin. These results identify a potential novel application for teasaponin as an antiobesity and antiinflammatory agent.

Treatment with second generation antipsychotics (SGAs), notably olanzapine and clozapine, causes severe obesity side effects. Antagonism of histamine H1 receptors has been identified as a main cause of SGA-induced obesity, but the molecular mechanisms associated with this antagonism in different stages of SGA-induced weight gain remain unclear. This review aims to explore the potential role of hypothalamic histamine H1 receptors in different stages of SGA-induced weight gain/obesity and the molecular pathways related to SGA-induced antagonism of these receptors. Initial data have demonstrated the importance of hypothalamic H1 receptors in both short- and long-term SGA-induced obesity. Blocking hypothalamic H1 receptors by SGAs activates AMP-activated protein kinase (AMPK), a well-known feeding regulator. During short-term treatment, hypothalamic H1 receptor antagonism by SGAs may activate the AMPK-carnitine palmitoyltransferase 1 signaling to rapidly increase caloric intake and result in weight gain. During long-term SGA treatment, hypothalamic H1 receptor antagonism can reduce thermogenesis, possibly by inhibiting the sympathetic outflows to the brainstem rostral raphe pallidus and rostral ventrolateral medulla, therefore decreasing brown adipose tissue thermogenesis. Additionally, blocking of hypothalamic H1 receptors by SGAs may also contribute to fat accumulation by decreasing lipolysis but increasing lipogenesis in white adipose tissue. In summary, antagonism of hypothalamic H1 receptors by SGAs may time-dependently affect the hypothalamus-brainstem circuits to cause weight gain by stimulating appetite and fat accumulation but reducing energy expenditure. The H1 receptor and its downstream signaling molecules could be valuable targets for the design of new compounds for treating SGA-induced weight gain/obesity.

This study tested the effects of (1→3),(1→4) β-D-glucan from oats, on activation of the gut-hypothalamic (PYY₃₋₃₆-NPY) axis, satiety, and weight loss in diet-induced obesity (DIO) mice. DIO mice were fed standard lab chow diets or varied doses of β-glucan for 6 weeks. Energy intake, satiety, body weight changes and peptide Y-Y₃₋₃₆ (PYY₃₋₃₆) were measured together with a satiety test and measurement of neuropeptide Y (NPY) mRNA expression in the hypothalamic arcuate nucleus (Arc). The average energy intake (-13%, p<0.05) and body weight gain was lower with increasing β-glucan over 6 wk with acute suppression of energy intake over 4 h. The highest β-glucan diet significantly increased plasma PYY₃₋₃₆, with suppression of Arc NPY mRNA., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Weight regain after weight loss is a major hurdle for combating obesity. The aim of this study is to examine orexigenic and anorectic neuropeptides of the hypothalamic arcuate nucleus (Arc) in response to weight loss after chronic energy intake restriction. Thirty mice were fed with a high-fat diet for 8 weeks and then classified as diet-induced obese (DIO; n=10) or diet-resistant (DR; n=10) mice according to the highest and lowest body weight gainers. Five mice from DIO and DR groups were placed on an energy restricted diet or continued on their high-fat diet ad libitum for 6 weeks. An additional five mice were on a LF diet throughout the course of this study as controls. Results showed that a six-week energy restricted diet completely reversed the increased body weight, fat mass and leptin in the DIO mice to the levels of the LF and DR mice. Arc neuropeptide Y (NPY) and agouti-related protein (AgRP) mRNA expression in DIO mice after obesity reversal were significantly higher than DIO mice without obesity reversal (17%, 47%, both p<0.05), while the Arc pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA showed no difference. Both NPY and AgRP expression in DIO mice were negatively correlated with plasma leptin (R=-0.78, p<0.05; R=-0.72, p<0.05). In conclusion, while chronic energy restriction will lead to weight loss, it can up-regulate hypothalamic orexigenic peptides, which may be an important contributing factor to weight regain after a weight loss program from an energy restricted diet.

Peptide Y-Y (PYY) is an anorexigenic hormone implicated in appetite control, and beta-glucan is a fiber known to affect appetite. We hypothesized that plasma PYY levels would increase in overweight human adults consuming increasing doses of beta-glucan. The objective was to test whether the effect could be seen with beta-glucan delivered through extruded cereals containing a high beta-glucan oat bran with demonstrated high molecular weight and solubility. Fourteen subjects consumed a control meal and 3 cereals of varying beta-glucan concentration (between 2.2 and 5.5 g), and blood samples were collected over 4 hours. Analysis of raw PYY data showed a trend toward significant increases over 4 hours. An increasing dose of beta-glucan resulted in higher levels of plasma PYY, with significant differences between groups from 2 to 4 hours post test-meal. Data for the area under the curve analysis also approached significance, with post hoc analysis showing a difference (P = .039) between the control and the highest dose of beta-glucan (5.5 g). The PYY levels at 4 hours were significantly different between the control and high-dose meal test (P = .036). There was a significant dose response, with a positive correlation between the grams of beta-glucan and PYY area under the curve (r(2) = 0.994, P = .003). The optimal dose of beta-glucan appears to lie between 4 and 6 g, with the effects on PYY mediated by viscosity and concentration. Meal-test studies examining a range of hormones should measure hormones over a minimum of 4 hours and record meal intake for even longer time frames.

Tyrosine hydroxylase is the rate-limiting enzyme in the synthesis of dopamine, a key neurotransmitter in the regulation of food intake. This study examined tyrosine hydroxylase mRNA expression in obese mice fed a high-fat diet. After 8 week feeding of high-fat diet mice were classified as diet-induced obese and obese-resistant according to body weight gain. They were then placed on different dietary interventions including a high-fat diet, a low-fat diet and an energy-restricted high-fat diet for six weeks. The control group was fed a low-fat diet. The results revealed that tyrosine hydroxylase mRNA expression was significantly decreased in the ventral tegmental area (VTA), ventromedial hypothalamic nucleus (VMH), and substantia nigra (SN) of the high-fat diet-induced obese (-29%, -26% and -26%) and obese-resistant mice (-21%, -24% and -18%) compared to controls. After switching the diet from high to low-fat diet tyrosine hydroxylase mRNA was increased in the VTA, VMH, and SN of the diet-induced obese mice and in the VMH, and SN of the obese-resistant mice. Energy restriction, even with high-fat feeding, reduced tyrosine hydroxylase mRNA expression in the VTA, VMH, and SN compared to controls. In addition, tyrosine hydroxylase mRNA expression in the VTA, VMH, and SN showed a significant negative correlation with plasma leptin levels. This study suggests that the up- or down-regulation of tyrosine hydroxylase mRNA expression in the VTA, VMH, and SN is mainly due to the intake of macronutrient type rather than body weight.

This study examined changes in neuropeptide Y (NPY) Y2 receptor binding in the brains of C57BL/6 mice in response to different levels of high-fat diets via three dietary intervention methods: high-fat diet, switching from high- to low-fat diet and finally, energy restricted high-fat diet. Forty-five C57Bl/6 male mice were fed a high-fat diet for 8 weeks and then classified as diet-induced obese (DIO) or diet-resistant (DR) mice according to the highest and lowest body weight gainers, respectively. The DIO and DR mice were then randomly divided into three groups each and either continued on their high-fat diet ad libitum (DIO-H and DR-H), changed to a low-fat diet (DIO-L and DR-L) or pair-fed via energy restricted high-fat diet (DIO-P and DR-P) for a further 6 weeks. During the course of this study, body weight, energy intake and plasma peptide YY (PYY) were measured. The study revealed that the replacement of a high-fat diet with a low-fat diet was associated with a significant lowering of ventromedial hypothalamic (VMH) Y2 receptor binding in both the DIO-L and DR-L mice (-37%, -36%), and also a lowered plasma PYY level in the DIO-L mice (-25%). Despite a continued consumption of the high-fat diet, energy restricted pair feeding caused a lower VMH Y2 receptor binding in the obese mice (DIO-P) following weight loss compared to the DR-P mice (-14%). In conclusion, this study showed that changing diets from high- to low-fat can significantly lower the VMH Y2 receptor binding irrespective to the obesity phenotype. Energy restriction, even while on high-fat feeding, can cause a lower VMH Y2 receptor binding compared to DR mice even after body weight loss to similar levels. This suggests either a possible intrinsic nature of the DIO mice or a body weight set-point re-establishment to drive body weight regain.

Cocaine- and amphetamine-regulated transcript (CART) peptide is widely expressed in the hypothalamus and is involved in the central regulation of energy balance. Using in situ hybridization, this study examined the roles of CART peptide in the hypothalamus of diet-induced obese (DIO) or diet-resistant (DR) mice under different dietary interventions including high-fat (HF), low-fat (LF) and pair-feeding (PF) diet for 6 weeks. Pair feeding the energy intake of the DIO and DR mice was used to determine whether there is an inherent difference in baseline CART expression that may cause the DIO and DR phenotypes. The results demonstrated that CART mRNA expression in the hypothalamus of the DIO mice responded differently on the high-fat diet compared to DR mice. The arcuate nucleus and paraventricular nucleus showed a significant reduction in CART mRNA expression in DIO mice compared to DR mice on the HF diet (-19.6%, p=0.019; -26.1%, p=0.003); whilst a profound increase in CART mRNA expression was observed in the dorsomedial nucleus and lateral hypothalamic area (+44.5%, p=0.007; +37.4%, p=0.033). Our study suggests that the decrease of CART mRNA expression in Arc and PVN regions of DIO mice may contribute to the development of high-fat diet-induced obesity. In addition, CART in the dorsomedial nucleus (DM) of hypothalamus and lateral hypothalamus (LH) may be involved in the activation of an orexigenic effect. Since pair feeding of the high-fat diet eliminated both the body weight and CART mRNA differences between the DIO and DR mice, it is likely that their alterations in gene expression were a consequence of their dissimilar body weight levels.

It is well known that the peripheral peptide YY (PYY)-central neuropeptide Y (NPY) Y2 receptor axis plays an important role in promoting negative energy balance regulation. Both the hypothalamus and medulla oblongata express a high level of Y2 receptors; however, the functional role of this receptor in chronic high-fat diet-induced obesity has not been fully examined. Using quantitative autoradiography, this study measured binding densities of total [(125)I]PYY and Y2 receptors in the hypothalamus and medulla of chronic high-fat diet-induced obese (DIO), obese-resistant, and low-fat-fed mice. Plasma PYY was also measured using RIA after 22 wk of dietary intervention. The results revealed that body weight gain was significantly higher in the obese mice, compared with the lean mice. Furthermore, PYY and NPY Y2 receptor binding densities in the medulla of the obese mice were significantly higher, compared with the lean mice, whereas the level of plasma PYY was significantly lower in the DIO mice than the low-fat-fed mice. In conclusion, this study showed that the DIO mice had low plasma PYY, which may have caused a compensatory up-regulation of PYY and Y2 receptor densities in the medulla. A low-level response of PYY-medullary regulation to positive energy balance may have contributed to the development of high-fat diet-induced obesity in DIO mice; conversely, a normal response of this regulatory axis in the obese-resistant mice may have contributed to the maintenance of body weight while on a high-fat diet.

This study examined the density of dopamine transporter (DAT) and D2 receptors in the brains of chronic high-fat diet-induced obese (cDIO), obese-resistant (cDR) and low-fat-fed (LF) control mice. Significantly decreased DAT densities were observed in cDR mice compared to cDIO and LF mice, primarily in the nucleus accumbens, striatal and hypothalamic regions. D2 receptor density was significantly lower in the rostral part of caudate putamen in cDIO mice compared to cDR and LF mice.

Obesity has been proposed to be a result of an imbalance in the physiological system that controls and maintains the body energy homeostasis. Several G-protein coupled receptors (GPCRs) are involved in the regulation of energy homeostasis. To investigate the importance of GPCR12, mice deficient of this receptor (GPCR12 KO) were studied regarding metabolism. Expression of GPCR12 was found primarily in the limbic and sensory systems, indicating its possible involvement in motivation, emotion together with various autonomic functions, and sensory information processing. GPCR12 KO mice were found to have higher body weight, body fat mass, lower respiratory exchange ratio (RER), hepatic steatosis, and were dyslipidemic. Neither food intake nor energy in faeces was affected in the GPCR12 KO mice. However, lower energy expenditure was found in the GPCR12 KO mice, which may explain the obesity. In conclusion, GPCR12 is considered important for the energy balance since GPCR12 KO mice develop obesity and have lower energy expenditure. This may be important for future drugs that target this receptor.

The present study examined brain dopamine D2 and D4 receptor and tyrosine hydroxylase (TH) mRNA expression in chronic high-fat diet-induced obese (cDIO) and obese-resistant (cDR) mice. Twenty-eight mice were fed a high-fat diet (HF: 40% of calories from fat) for 6 weeks and then classified as cDIO (n = 8) or cDR (n = 8) mice according to the highest and lowest body weight gainers, respectively. Seven mice were fed a low-fat diet (LF: 10% of calories from fat) and used as controls. After 20 weeks of feeding, visceral fat per gram of initial body weight was significantly higher in the cDIO group (ratio: 0.25, 0.09, and 0.04; P < 0.01 cDIO vs. cDR and LF, respectively). Using quantitative in situ hybridization techniques, the levels of D2 and D4 receptor and tyrosine hydroxylase (TH) mRNAs were measured in multiple brain sections. The cDIO mice had a significantly higher level of D2 receptor mRNA expression in the core of the nucleus accumbens (AcbC, +16%) and ventral parts of caudate putamen (CPu, 21% and 24%) compared to the cDR and LF mice. The levels of D2 receptor mRNA expression in the AcbC and ventromedial part of the CPu were positively related to the final body weight. This study is the first to systematically examine the D4 mRNA expression in the mouse brain using in situ hybridization method. D4 receptor mRNA expression in the ventromedial hypothalamic nucleus (VMH) and the ventral part of the lateral septal nucleus were also significantly higher in the cDIO mice compared to the cDR and LF mice (+31% and +60%; P < 0.05). TH mRNA expression was significantly higher in the ventral tegmental area (+17%, P

The present study examined the density of 5-HT2A/2C receptors and 5-HT transporters in the brains of chronic high-fat diet-induced obese (cDIO) and obese-resistant (cDR) mice. Thirty-five male mice were used in this study. Twenty-eight mice were fed with a high-fat diet (40% of calories from fat) for 6 weeks and then classified as the cDIO (n=8) or cDR (n=8) mice according to the highest and lowest body weight gainers. Seven mice were placed on a low-fat diet (LF: 10% of calories from fat) and were used as controls. After 20 weeks of feeding, the sum of epididymal, perirenal, omental and inguinal fat masses was 9.3+/-0.3 g in the cDIO group versus 3.1+/-0.5 g in the cDR (p<0.005) and 1.5+/-0.1 g in the LF (p<0.001) groups. Using quantitative autoradiography techniques, the binding site densities of 5-HT2A/2C receptors and 5-HT transporters were measured in multiple brain sections of mice from the three groups. Most regions did not differ between groups but, importantly, the cDIO mice had a significantly higher 5-HT2A/2C binding density in the anterior olfactory nucleus and ventromedial hypothalamic nucleus (VMH) compared to the cDR and LF mice (+39% and +47%, p=0.003 and 0.045, respectively), whereas the latter two groups did not differ. The density of 5-HT2A/2C receptors in the VMH was associated with total amount of fat mass (r=0.617, p=0.032). On the other hand, the cDR mice had significantly lower 5-HT transporter binding than the cDIO and LF mice, respectively, in the nucleus accumbens (-44%, -38%, both p<0.02), central nucleus of the amygdaloid nucleus (-40%, -44%, p=0.003 and 0.009), and olfactory tubercle nucleus (-42%, -42%, both p=0.03). In conclusion, this study has demonstrated differentially regulated levels of the 5-HT2A/2C receptor and 5-HT transporter in specific brain regions of the cDIO and cDR mice. It provides neural anatomical bases by which genetic variability in 5-HT2A/2C receptors and 5-HT transporter may influence satiety and sensory aspects of energy balance.

The present study examined the levels of 5-HT(2A) and 5-HT(2C) (2A and 2C receptors of 5-hydroxytryptamine; serotonin) receptor messenger RNA (mRNA) expressions in the brain of chronic high-fat diet-induced obese (DIO) and obese-resistant (DR) mice. Thirty-one mice were used in this study. Twenty-four mice were fed with a high-fat diet (HF: 40% of calories from fat) for 4 weeks and then classified as the DIO (n = 8) or DR (n = 8) mice according to the highest and lowest body weight (BW) gainers. Seven mice were placed on a low-fat diet (LF: 10% of calories from fat) and were used as controls. After 20 weeks of feeding, the visceral fat accumulation was 620 +/- 42 mg in the DIO group versus 198 +/- 89 mg in the DR and 84 +/- 18 mg in the LF groups. Using quantitative in situ hybridization techniques, levels of 2A and 2C serotonin (5-HT) receptor mRNAs were measured in multiple brain sections of mice from the three groups. Most regions did not differ between groups but, importantly, the DIO mice had a significantly higher level of 5-HT(2A) receptor mRNA expression in the olfactory nucleus (Olf) compared to the DR and LF mice (+30% and +37%, respectively). The levels of Olf 5-HT(2A) receptor mRNA expression were related to body fat mass. The level of 5-HT(2C) mRNA receptor expression in the ventromedial hypothalamic (VMH) nucleus was 40% higher in the DIO mice than in the LF mice. Furthermore, the 5-HT(2C) receptor mRNA expression in the posterodorsal part of the medial amygdaloid (MePD) nucleus was 25% higher in the DIO mice than in the DR mice. The level of VMH 5-HT(2C) receptor mRNA expression was correlated with body fat mass. In conclusion, this study has demonstrated differentially regulated levels of the 5-HT(2A) and 5-HT(2C) receptor mRNA expressions in the specific brain regions of the DIO and DR mice. It provides neural anatomical bases that the 5-HT(2C) receptors positively influence satiety center (VMH) while the 5-HT(2A) receptor regulates olfactory sensory effects. The findings also assist us to understand the role of these receptors in mice susceptible or resistant to diet-induced obesity.

The melanocortinergic system plays an important role in promoting negative energy balance and preventing excessive fat deposition. This study has investigated the levels of mRNA expression of proopiomelanocortin (POMC), agouti-related protein (AgRP) and the melanocortin-4 receptor (MC4-R) in diet-induced obese (DIO) and diet-resistant (DR) mice. Thirty C57 mice were used in this study. Twenty-four mice were fed with a high-fat diet (HF: 40% of calories from fat, 20% from saturated fat) for 4 weeks and then classified as DIO and DR according to their body weight gain. Six mice were placed on a low-fat diet (LF: 10% of calories from fat, 1% from saturated fat) and were used as controls. After 22 weeks of feeding, visceral fat deposits were more than twice as heavy in the DIO mice as in the DR and LF mice, while the latter two groups had no significant difference. Using quantitative in situ hybridization techniques, this study found that the DIO mice had a significantly lower level of Arc POMC (-29%) and AgRP (-31%) mRNA expression than the DR and LF mice, respectively. The mice on high-fat diets had higher levels of AgRP mRNA expression in the bed nucleus of stria terminalis (BST), and ventral part of the lateral septal nucleus (LSV) than the LF mice. Furthermore, the DIO mice had a 40% higher level of MC4-R mRNA expression in the ventromedial hypothalamic nucleus (VMH) and posterodorsal part of the medial amygdaloid nucleus (MePD) than the LF mice. In conclusion, this study has demonstrated that differential expression of POMC, AgRP and MC4-R mRNA levels exists in DIO, DR and LF mice. These differences were shown to occur in the specific nuclei of the hypothalamus and other parts of the limbic system. These findings may assist in understanding the involvement of the melanocortinergic system in the regulation of body weight via the autonomic and limbic systems.

Some mice become obese whereas others remain lean when raised on a high-energy diet. This study examined the levels of neuropeptide Y (NPY), and of Y1, Y2, Y5 and leptin receptor mRNA expression in the hypothalamic arcuate nucleus (Arc) of chronic high-energy diet-induced obese (DIO) and resistant (DR) mice. Forty mice were divided into two groups and fed either a high-fat (HF: 40% of calories from fat, 20% of calories from saturated fat; n=34) or low-fat (LF: 10% of calories from fat, 1% from saturated fat; n=6) diet. After 22 weeks of feeding, visceral fat accumulation was 69% higher in DIO mice compared with DR mice, and the former showed a moderate level of glucose intolerance. In DIO mice, the levels of NPY and leptin receptor mRNA expressions were significantly higher than in LF mice (+32 and +14%, P<0.001 and 0.05 respectively), indicating central leptin resistance, whereas the DR and LF groups did not differ. The level of Y2 receptor mRNA expression was similar between the DIO and LF groups but, importantly, was reduced approximately 20% in DR mice (P<0.005). The level of Y5 receptor mRNA was 36% lower in DR mice than DIO mice (P<0.05). The differences between DIO and DR mice identified by this study may assist in a better understanding of genetic predisposition to an increased fat deposition induced by a chronic high-fat diet. A low level of Y2 and Y5 receptor mRNA expression may contribute to the prevention of chronic high-energy diet-induced obesity in DR mice.

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]

Abstract: The second generation antipsychotic drug (SGA) olanzapine has an efficacy to treat schizophrenia, but can cause obesity and type II diabetes mellitus. Cholinergic muscarinic M3 receptors (M3R) are expressed on pancreatic β-cells and in the brain where they influence insulin secretion and may regulate other metabolic hormones via vagal innervation of the gastrointestinal tract. Olanzapine''s M3R antagonism is an important risk factor for its diabetogenic liability. However, the effects of olanzapine on central M3Rs are unknown. Rats were treated with 0.25, 0.5, 1.0 or 2.0mg olanzapine/kg or vehicle (3×/day, 14-days). M3R binding densities in the hypothalamic arcuate (Arc) and ventromedial nuclei (VMH), and dorsal vagal complex (DVC) of the brainstem were investigated using [3H]4-DAMP plus pirenzepine and AF-DX116. M3R binding correlations to body weight, food intake, insulin, ghrelin and cholecystokinin (CCK) were analyzed. Olanzapine increased M3R binding density in the Arc, VMH and DVC, body weight, food intake, circulating plasma ghrelin and CCK levels, and decreased plasma insulin and glucose. M3R negatively correlated to insulin, and positively correlated to ghrelin, CCK, food intake and body weight. Increased M3R density is a compensatory up-regulation in response to olanzapine''s M3R antagonism. Olanzapine acts on M3R in regions of the brain that control food intake and insulin secretion. Olanzapine''s M3R blockade in the brain may inhibit the acetylcholine pathway for insulin secretion. These findings support a role for M3Rs in the modulation of insulin, ghrelin and CCK via the vagus nerve and provide a mechanism for olanzapine''s diabetogenic and weight gain liability. [Copyright &y& Elsevier]

This study examined the effects of different food sources of protein on energy intake, body weight maintenance, and on the responses of plasma leptin, insulin and adiponectin in chronic high-fat diet-induced obese mice. Obesity was induced in 47 mice with a high-fat diet for 20 weeks. They were divided into five diet groups to test the effects of a higher protein proportion (30% energy), achieved at the expense of carbohydrate. For the next eight weeks, four of the groups were fed diets of chow formulated with whey, soy, red meat or milk while the control group continued on their high-fat diet. The results showed that: (i) increasing the protein : carbohydrate ratio (both at 30% energy) in a high-fat diet did not reduce the level of obesity; (ii) the type of protein added, however, did have a significant effect on the level of obesity attained; (iii) whey protein stabilised weight gain the most, had the strongest satiety effects and also stimulated the highest production of adiponectin; and (iv) whey protein also was associated with the lowest insulin values among all proteins tested. Plasma leptin levels were not affected by any of the diets. Dietary fat remains a potent factor in weight management, but the type and amount of protein may also be important through its effects on food intake. In particular, the apparent decreased appetite associated with increased adiponectin in the whey-based high-protein diet may contribute to stabilised body mass in chronic high-fat diet-induced obesity. [ABSTRACT FROM AUTHOR]