Olanzapine attenuates 5-HT2cR and GHSR1a interaction to increase orexigenic hypothalamic NPY: Implications for neuronal molecular mechanism of metabolic side effects of antipsychotics.

The main cause of second-generation antipsychotic (SGA)-induced obesity is considered due to the antagonism of serotonin 2c receptors (5-HT2cR) and activation of ghrelin receptor type 1a (GHSR1a) signalling. It is reported that 5-HT2cR interacted with GHSR1a, however it is unknown whether one of the SGA olanzapine alters the 5-HT2cR/GHSR1a interaction, affecting orexigenic neuropeptide signalling in the hypothalamus. We found that olanzapine treatment increased average energy intake and body weight gain in mice; olanzapine treatment also increased orexigenic neuropeptide (NPY) and GHSR1a signaling molecules, pAMPK, UCP2, FOXO1 and pCREB levels in the hypothalamus. By using confocal fluorescence resonance energy transfer (FRET) technology, we found that 5-HT2cR interacted/dimerised with the GHSR1a in the hypothalamic neurons. As 5-HT2cR antagonist, both olanzapine and S242084 decreased the interaction between 5-HT2cR and GHSR1a and activated GHSR1a signaling. The 5-HT2cR agonist lorcaserin counteracted olanzapine-induced attenuation of interaction between 5-HT2cR and GHSR1a and inhibited activation of GHSR1a signalling and NPY production. These findings suggest that 5-HT2cR antagonistic effect of olanzapine in inhibition of the interaction of 5-HT2cR and GHSR1a, activation GHSR1a downstream signaling and increasing hypothalamic NPY, which may be the important neuronal molecular mechanism underlying olanzapine-induced obesity and target for prevention metabolic side effects of antipsychotic management in psychiatric disorders.

Investigating the Therapeutic Potential of Plants and Plant-Based Medicines: Relevance to Antioxidant and Neuroprotective Effects.

Oxidative stress is a common characteristic of psychiatric, neurological, and neurodegenerative disorders. Therefore, compounds that are neuroprotective and reduce oxidative stress may be of interest as novel therapeutics. Phenolic, flavonoid and anthocyanin content, ORAC and DPPH free radical scavenging, and Cu2+ and Fe2+ chelating capacities were examined in variations (fresh/capsule) of Queen Garnet plum (QGP, Prunus salicina), black pepper (Piper nigrum) clove (Syzygium aromaticum), elderberry (Sambucus nigra), lemon balm (Melissa officinalis) and sage (Salvia officinalis), plus two blends (Astralagus membranaceus-lemon balm-rich, WC and R8). The ability of samples to prevent and treat H2O2-induced oxidative stress in SH-SY5Y cells was investigated. Pre-treatment with WC, elderberry, QGP, and clove prevented the oxidative stress-induced reduction in cell viability, demonstrating a neuroprotective effect. Elderberry increased cell viability following oxidative stress induction, demonstrating treatment effects. Clove had the highest phenolic and flavonoid content, DPPH, and Cu2+ chelating capacities, whereas QGP and elderberry were highest in anthocyanins. Black pepper had the highest ORAC and Fe2+ chelating capacity. These findings demonstrate that plant extracts can prevent and treat oxidative stress-induced apoptosis of neuron-like cells in vitro. Further research into phytochemicals as novel therapeutics for oxidative stress in the brain is needed.

Butyrate Attenuates Hepatic Steatosis Induced by a High-Fat and Fiber-Deficient Diet via the Hepatic GPR41/43-CaMKII/HDAC1-CREB Pathway.

SCOPE: Hepatic steatosis is a major health issue that can be attenuated by a healthy diet. This study investigates the effects and molecular mechanisms of butyrate, a dietary fiber metabolite of gut microbiota, on lipid metabolism in hepatocytes. METHODS AND RESULTS: This study examines the effects of butyrate (0-8 mM) on lipid metabolism in primary hepatocytes. The results show that butyrate (2 mM) consistently inhibits lipogenic genes and activates lipid oxidation-related gene expression in hepatocytes. Furthermore, butyrate modulates lipid metabolism genes, reduces fat droplet accumulation, and activates the calcium/calmodulin-dependent protein kinase II (CaMKII)/histone deacetylase 1 (HDAC1)-cyclic adenosine monophosphate response element binding protein (CREB) signaling pathway in the primary hepatocytes and liver of wild-type (WT) mice, but not in G-protein-coupled receptor 41 (GPR41) knockout and 43 (GPR43) knockout mice. This suggests that butyrate regulated hepatic lipid metabolism requires GPR41 and GPR43. Finally, the study finds that dietary butyrate supplementation (5%) ameliorates hepatic steatosis and abnormal lipid metabolism in the liver of mice fed a high-fat and fiber-deficient diet for 15 weeks. CONCLUSION: This work reveals that butyrate improves hepatic lipid metabolism through the GPR41/43-CaMKII/HDAC1-CREB pathway, providing support for consideration of butyrate as a dietary supplement to prevent the progression of NAFLD induced by the Western-style diet.

Activated PKB/GSK-3ß synergizes with PKC-δ signaling in attenuating myocardial ischemia/reperfusion injury via potentiation of NRF2 activity: Therapeutic efficacy of dihydrotanshinone-I.

Disrupted redox status primarily contributes to myocardial ischemia/reperfusion injury (MIRI). NRF2, the endogenous antioxidant regulator, might provide therapeutic benefits. Dihydrotanshinone-I (DT) is an active component in Salvia miltiorrhiza with NRF2 induction potency. This study seeks to validate functional links between NRF2 and cardioprotection of DT and to investigate the molecular mechanism particularly emphasizing on NRF2 cytoplasmic/nuclear translocation. DT potently induced NRF2 nuclear accumulation, ameliorating post-reperfusion injuries via redox alterations. Abrogated cardioprotection in NRF2-deficient mice and cardiomyocytes strongly supports NRF2-dependent cardioprotection of DT. Mechanistically, DT phosphorylated NRF2 at Ser40, rendering its nuclear-import by dissociating from KEAP1 and inhibiting degradation. Importantly, we identified PKC-δ-(Thr505) phosphorylation as primary upstream event triggering NRF2-(Ser40) phosphorylation. Knockdown of PKC-δ dramatically retained NRF2 in cytoplasm, convincing its pivotal role in mediating NRF2 nuclear-import. NRF2 activity was further enhanced by activated PKB/GSK-3ß signaling via nuclear-export signal blockage independent of PKC-δ activation. By demonstrating independent modulation of PKC-δ and PKB/GSK-3ß/Fyn signaling, we highlight the ability of DT to exploit both nuclear import and export regulation of NRF2 in treating reperfusion injury harboring redox homeostasis alterations. Coactivation of PKC and PKB phenocopied cardioprotection of DT in vitro and in vivo, further supporting the potential applicability of this rationale.

N-acetylcysteine prevents olanzapine-induced oxidative stress in mHypoA-59 hypothalamic neurons.

Olanzapine is a second-generation antipsychotic (AP) drug commonly prescribed for the treatment of schizophrenia. Recently, olanzapine has been found to cause brain tissue volume loss in rodent and primate studies; however, the underlying mechanism remains unknown. Abnormal autophagy and oxidative stress have been implicated to have a role in AP-induced neurodegeneration, while N-acetylcysteine (NAC) is a potent antioxidant, shown to be beneficial in the treatment of schizophrenia. Here, we investigate the role of olanzapine and NAC on cell viability, oxidative stress, mitochondrial mass and mitophagy in hypothalamic cells. Firstly, cell viability was assessed in mHypoA-59 and mHypoA NPY/GFP cells using an MTS assay and flow cytometric analyses. Olanzapine treated mHypoA-59 cells were then assessed for mitophagy markers and oxidative stress; including quantification of lysosomes, autophagosomes, LC3B-II, p62, superoxide anion (O2-) and mitochondrial mass. NAC (10 mM) was used to reverse the effects of olanzapine (100 µM) on O2-, mitochondrial mass and LC3B-II. We found that olanzapine significantly impacted cell viability in mHypoA-59 hypothalamic cells in a dose and time-dependent manner. Olanzapine inhibited mitophagy, instigated oxidative stress and prompted mitochondrial abnormalities. NAC was able to mitigate olanzapine-induced effects. These findings suggest that high doses of olanzapine may cause neurotoxicity of hypothalamic neurons via increased production of reactive oxygen species (ROS), mitochondrial damage and mitophagy inhibition. This could in part explain data suggesting that APs may reduce brain volume.

DHA reduces hypothalamic inflammation and improves central leptin signaling in mice.

AIMS: 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. MAIN METHODS: 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. KEY FINDINGS: 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 ß-oxidation, and cholesterol synthesis in the liver. DHA increased leptin-induced activation of TH in the hypothalamus. SIGNIFICANCE: 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.

Supplement of microbiota-accessible carbohydrates prevents neuroinflammation and cognitive decline by improving the gut microbiota-brain axis in diet-induced obese mice.

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-pGSK3ß-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.

Olanzapine increases AMPK-NPY orexigenic signaling by disrupting H1R-GHSR1a interaction in the hypothalamic neurons of mice.

Second generation antipsychotics, particularly olanzapine, induce severe obesity, which is associated with their antagonistic effect on the histamine H1 receptor (H1R). We have previously demonstrated that oral administration of olanzapine increases the concentration of neuropeptide Y (NPY) in the hypothalamus of rats, accompanied by hyperphagia and weight gain. However, it is unclear if the increased NPY after olanzapine administration is due to its direct effect on hypothalamic neurons and its H1R antagonistic property. In the present study, we showed that with an inverted U-shape dose-response curve, olanzapine increased NPY expression in the NPY-GFP hypothalamic neurons; however, this was not the case in the hypothalamic neurons of H1R knockout mice. Olanzapine inhibited the interaction of H1R and GHSR1a (ghrelin receptor) in the primary mouse hypothalamic neurons and NPY-GFP neurons examined by confocal fluorescence resonance energy transfer (FRET) technology. Furthermore, an H1R agonist, FMPH inhibited olanzapine activation of GHSR1a downstream signaling pAMPK and transcription factors of NPY (pFOXO1 and pCREB) in the hypothalamic NPY-GFP cell. However, an olanzapine analogue (E-Olan) with lower affinity to H1R presented negligible enhancement of pCREB within the nucleus of NPY neurons. These findings suggest that the H1R antagonist property of olanzapine inhibits the interaction of H1R and GHSR1a, activates GHSR1a downstream signaling pAMPK-FOXO1/pCREB and increases hypothalamic NPY: this could be one of the important molecular mechanisms of H1R antagonism of olanzapine-induced obesity in antipsychotic management of psychiatric disorders.

Dietary Galacto-Oligosaccharides and Resistant Starch Protect Against Altered CB1 and 5-HT1A and 2A Receptor Densities in Rat Brain: Implications for Preventing Cognitive and Appetite Dysfunction During a High-Fat Diet.

SCOPE: A high-fat, but low-fiber, diet is associated with obesity and cognitive dysfunction, while dietary fiber supplementation can improve cognition. METHODS AND RESULTS: This study examines whether dietary fibers, galacto-oligosaccharides (GOS) and resistant starch (RS), could prevent high-fat (HF)-diet-induced alterations in neurotransmitter receptor densities in brain regions associated with cognition and appetite. Rats are fed a HF diet, HF diet with GOS, HF diet with RS, or a low-fat (LF, control) diet for 4 weeks. Cannabinoid CB1 (CB1R) and 5HT1A (5HT1A R) and 5-HT2A (5HT2A R) receptor binding densities are examined. In the hippocampus and hypothalamus, a HF diet significantly increases CB1R binding, while HF + GOS and HF + RS diets prevented this increase. HF diet also increases hippocampal and hypothalamic 5-HT1A R binding, while HF + GOS and HF + RS prevented the alterations. Increased 5-HT2A binding is prevented by HF + GOS and HF + RS in the medial mammillary nucleus. CONCLUSIONS: These results demonstrate that increased CB1R, 5-HT1A R and 5-HT2A R induced by a HF diet can be prevented by GOS and RS supplementation in brain regions involved in cognition and appetite. Therefore, increased fiber intake may have beneficial effects on improving learning and memory, as well as reducing excessive appetite, during the chronic consumption of a HF (standard Western) diet.

Ginsenoside Rb1 improves leptin sensitivity in the prefrontal cortex in obese mice.

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.

Dietary teasaponin ameliorates alteration of gut microbiota and cognitive decline in diet-induced obese mice.

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.

Chronic rhein treatment improves recognition memory in high-fat diet-induced obese male mice.

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.

Bardoxolone methyl prevents obesity and hypothalamic dysfunction.

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.

Teasaponin improves leptin sensitivity in the prefrontal cortex of obese mice.

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.

Arachidonic acid impairs hypothalamic leptin signaling and hepatic energy homeostasis in mice.

Epidemiological evidence suggests that the consumption of a diet high in n-6 polyunsaturated fatty acids (PUFA) is associated with the development of leptin resistance and obesity. We aim to examine the central effect of n-6 PUFA, arachidonic acid (ARA) on leptin sensitivity and leptin-regulated hepatic glucose and lipid metabolism. We found that intracerebroventricular injection of ARA (25 nmol/day) for 2.5 days reversed the effect of central leptin on hypothalamic JAK2, pSTAT3, pAkt, and pFOXO1 protein levels, which was concomitant with a pro-inflammatory response in the hypothalamus. ARA also attenuated the effect of central leptin on hepatic glucose and lipid metabolism by reversing the mRNA expression of the genes involved in gluconeogenesis (G6Pase, PEPCK), glucose transportation (GLUT2), lipogenesis (FAS, SCD1), and cholesterol synthesis (HMG-CoA reductase). These results indicate that an increased exposure to central n-6 PUFA induces central cellular leptin resistance with concomitant defective JAK2-STAT3 and PI3K-Akt signaling.

Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice.

The consumption of diets rich in saturated fat largely contributes to the development of obesity in modern societies. A diet high in saturated fats can induce inflammation and impair leptin signaling in the hypothalamus. However, the role of saturated fatty acids on hypothalamic leptin signaling, and hepatic glucose and lipid metabolism remains largely undiscovered. In this study, we investigated the effects of intracerebroventricular (icv) administration of a saturated fatty acid, palmitic acid (PA, C16:0), on central leptin sensitivity, hypothalamic leptin signaling, inflammatory molecules and hepatic energy metabolism in C57BL/6J male mice. We found that the icv administration of PA led to central leptin resistance, evidenced by the inhibition of central leptin's suppression of food intake. Central leptin resistance was concomitant with impaired hypothalamic leptin signaling (JAK2-STAT3, PKB/Akt-FOXO1) and a pro-inflammatory response (TNF-α, IL1-ß, IL-6 and pIκBa) in the mediobasal hypothalamus and paraventricular hypothalamic nuclei. Furthermore, the pre-administration of icv PA blunted the effect of leptin-induced decreases in mRNA expression related to gluconeogenesis (G6Pase and PEPCK), glucose transportation (GLUT2) and lipogenesis (FAS and SCD1) in the liver of mice. Therefore, elevated central PA concentrations can induce pro-inflammatory responses and leptin resistance, which are associated with disorders of energy homeostasis in the liver as a result of diet-induced obesity.

Elevated audiovisual temporal interaction in patients with migraine without aura.

BACKGROUND: Photophobia and phonophobia are the most prominent symptoms in patients with migraine without aura. Hypersensitivity to visual stimuli can lead to greater hypersensitivity to auditory stimuli, which suggests that the interaction between visual and auditory stimuli may play an important role in the pathogenesis of migraine. However, audiovisual temporal interactions in migraine have not been well studied. Therefore, our aim was to examine auditory and visual interactions in migraine. METHODS: In this study, visual, auditory, and audiovisual stimuli with different temporal intervals between the visual and auditory stimuli were randomly presented to the left or right hemispace. During this time, the participants were asked to respond promptly to target stimuli. We used cumulative distribution functions to analyze the response times as a measure of audiovisual integration. RESULTS: Our results showed that audiovisual integration was significantly elevated in the migraineurs compared with the normal controls (p < 0.05); however, audiovisual suppression was weaker in the migraineurs compared with the normal controls (p < 0.05). CONCLUSIONS: Our findings further objectively support the notion that migraineurs without aura are hypersensitive to external visual and auditory stimuli. Our study offers a new quantitative and objective method to evaluate hypersensitivity to audio-visual stimuli in patients with migraine.

The molecular mechanisms underpinning the therapeutic properties of oleanolic acid, its isomer and derivatives for type 2 diabetes and associated complications.

Recent research has uncovered the molecular mechanisms responsible for the therapeutic properties of oleanolic acid (OA), its isomer ursolic acid (UA), and derivatives. In particular, recent reports have highlighted the benefits of these compounds in the prevention and treatment of type 2 diabetes and associated life-threatening complications, such as nonalcoholic fatty liver disease, nephropathy, retinopathy, and atherosclerosis. The prevalence of type 2 diabetes is of major concern since it is reaching global epidemic levels. Treatments targeting the signaling pathways altered in type 2 diabetes are being actively investigated, and OA and UA in natural and derivative forms are potential candidates to modulate these pathways. We will explore the findings from in vitro and in vivo studies showing that these compounds: (i) improve insulin signaling and reduce hyperglycemia; (ii) reduce oxidative stress by upregulating anti-oxidants and; (iii) reduce inflammation by inhibiting proinflammatory signaling. We will discuss the molecular mechanisms underpinning these therapeutic properties in this review in order to provide a rationale for the future use of OA, UA, and their derivatives for the prevention and treatment of type 2 diabetes and associated comorbidities.

Central inflammation and leptin resistance are attenuated by ginsenoside Rb1 treatment in obese mice fed a high-fat diet.

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-1ß) 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-1ß 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.

Reduction of histamine H1 receptor binding induced by high-fat diet can be prevented by DHA and dietary fiber in specific brain areas of male rats.

High-fat (HF) diet and obesity are risk factors for a number of mental health problems including depression, cognitive dysfunction, dementia, and neurodegenerative diseases. Histamine H1 receptors (H1Rs) are involved in many of these conditions. This study examined H1R receptor binding density in the brain of male rats fed a high-saturated fat (HF) diet, as well as the effect of docosahexaenoic acid (DHA), galacto-oligosaccharide (GOS) and resistant starch (RS) supplementation of HF diet. Alterations of H1R expression in the post-mortem rat brain were detected by [(3)H]-pyrilamine binding autoradiography. We found that HF diet significantly decreased H1R binding densities in the substantia nigra (SN), caudate putamen (CPu), hypothalamic arcuate nucleus (Arc), ventral tegmental area (VTA), piriform cortex (Pir) and primary motor cortex (M1), compared with low-fat fed rats, and the suppression of receptor binding density ranged from 31% to 48%. Interestingly, supplementing the HF diet with 0.5% n-3 polyunsaturated docosahexaenoic acid (DHA) prevented reduction of H1R binding densities in the SN and CPu. Addition of galacto-oligosaccharide (GOS) and resistant starch (RS) to the diet blunted HF induced reduction of H1R ligand binding in the SN and Pir, respectively. In conclusion this study showed that HF diet can alter H1R binding densities in various brain regions, and many of these changes can be prevented by adding DHA, GOS or RS to the diet.