Titikorn Chunchai

Vagus Nerve Stimulation Exerts the Neuroprotective Effects in Obese-Insulin Resistant Rats, Leading to the Improvement of Cognitive Function

Vagus nerve stimulation (VNS) therapy was shown to improve peripheral insulin sensitivity. However, the effects of chronic VNS therapy on brain insulin sensitivity, dendritic spine density, brain mitochondrial function, apoptosis and cognition in obese-insulin resistant subjects have never been investigated. Male Wistar rats (n = 24) were fed with either a normal diet (n = 8) or a HFD (n = 16) for 12 weeks. At week 13, HFD-fed rats were divided into 2 groups (n = 8/group). Each group was received either sham therapy or VNS therapy for an additional 12 weeks. At the end of treatment, cognitive function, metabolic parameters, brain insulin sensitivity, brain mitochondrial function, brain apoptosis, and dendritic spines were determined in each rat. The HFD-fed with Sham therapy developed brain insulin resistance, brain oxidative stress, brain inflammation, and brain apoptosis, resulting in the cognitive decline. The VNS group showed an improvement in peripheral and brain insulin sensitivity. VNS treatment attenuated brain mitochondrial dysfunction and cell apoptosis. In addition, VNS therapy increased dendritic spine density and improved cognitive function. These findings suggest that VNS attenuates cognitive decline in obese-insulin resistant rats by attenuating brain mitochondrial dysfunction, improving brain insulin sensitivity, decreasing cell apoptosis, and increasing dendritic spine density.

Vagus Nerve Stimulation Improves Cardiac Function by Preventing Mitochondrial Dysfunction in Obese-Insulin Resistant Rats.

Long-term high-fat diet (HFD) consumption leads to not only obese-insulin resistance, but also impaired left ventricular (LV) function. Vagus nerve stimulation (VNS) has been shown to exert cardioprotection. However, its effects on the heart and metabolic parameters under obese-insulin resistant condition is not known. We determined the effects of VNS on metabolic parameters, heart rate variability (HRV) and LV function in obese-insulin resistant rats. Male Wistar rats were fed with HFD for 12 weeks, and were randomly divided into sham and VNS groups. VNS was applied for the next 12 weeks. Echocardiography, blood pressure and HRV were examined. Blood samples were collected for metabolic parameters. At the end, the heart was removed for determination of apoptosis, inflammation, oxidative stress, and cardiac mitochondrial function. VNS for 12 weeks significantly decreased plasma insulin, HOMA index, total cholesterol, triglyceride, LDL and visceral fat. Serum adiponectin was significantly increased in the VNS group. VNS also significantly decreased blood pressure, improved HRV and LV function, decreased cardiac MDA, TNF-α and Bax levels, and improved cardiac mitochondrial function. VNS improves metabolic and hemodynamic parameters, and the LV function via its ability against apoptosis, inflammation and oxidative stress, and preserved cardiac mitochondrial function in obese-insulin resistant rats.

Lactobacillus paracasei HII01, xylooligosaccharides, and synbiotics reduce gut disturbance in obese rats

OBJECTIVES The beneficial effects of pro-, pre-, and synbiotics on obesity with insulin resistance have been reported previously. However, the strain-specific effect of probiotics and the combination with various types of prebiotic fiber yield controversial outcomes and limit clinical applications. Our previous study demonstrated that the probiotic Lactobacillus paracasei (L. paracasei) HII01, prebiotic xylooligosaccharide (XOS), and synbiotics share similar efficacy in attenuating cardiac mitochondrial dysfunction in obese-insulin resistant rats. Nonetheless, the roles of HII01 and XOS on gut dysbiosis and gut inflammation under obese-insulin resistant conditions have not yet, to our knowledge, been investigated. Our hypothesis was that pro-, pre-, and synbiotics improve the metabolic parameters in obese-insulin resistant rats by reducing gut dysbiosis and gut inflammation. METHODS Male Wistar rats were fed with either a normal or high-fat diet that contained 19.77% and 59.28% energy from fat, respectively, for 12 wk. Then, the high-fat diet rats were fed daily with a 108 colony forming unit of the probiotic HII01, 10% prebiotic XOS, and synbiotics for 12 wk. The metabolic parameters, serum lipopolysaccharide levels, fecal Firmicutes/Bacteroidetes ratios, levels of Enterobacteriaceae, Bifidobacteria, and gut proinflammatory cytokine gene expression were quantified. RESULTS The consumption of probiotic L. paracasei HII01, prebiotic XOS, and synbiotics for 12 wk led to a decrease in metabolic endotoxemia, gut dysbiosis (a reduction in the Firmicutes/Bacteroidetes ratio and Enterobacteriaceae), and gut inflammation in obese-insulin resistant rats. CONCLUSIONS Pro-, pre-, and synbiotics reduced gut dysbiosis and gut inflammation, which lead to improvements in metabolic dysfunction in obese-insulin resistant rats.

The possible factors affecting microglial activation in cases of obesity with cognitive dysfunction

Obesity has reached epidemic proportions in many countries around the world. Several studies have reported that obesity can lead to the development of cognitive decline. There is increasing evidence to demonstrate that microglia play a crucial role in cognitive decline in cases of obesity, Alzheimer’s disease and also in the aging process. Although there have been several studies into microglia over the past decades, the mechanistic link between microglia and cognitive decline in obese models is still not fully understood. In this review, the current available evidence from both in vitro and in vivo investigations regarding the association between the alteration in microglial activity in different obese models with respect to cognition are included. The metabolite profiles from obesity, adiposity, dietary and hormone affected microglial activation and its function in the brain are comprehensively summarized. In addition, the possible roles of microglial activation in relation to cognitive dysfunction are also presented and discussed. To ensure a balanced perspective controversial reports regarding these issues are included and discussed.

Energy restriction combined with dipeptidyl peptidase-4 inhibitor exerts neuroprotection in obese male rats.

Dipeptidyl peptidase-4 (DDP-4) inhibitors and energy restriction (ER) are widely used to treat insulin resistance and type 2 diabetes mellitus. However, the effects of ER or the combination with vildagliptin on brain insulin sensitivity, brain mitochondrial function, hippocampal synaptic plasticity and cognitive function in obese insulin-resistant rats have never been investigated. We hypothesised that ER with DDP-4 inhibitor exerts better efficacy than ER alone in improving cognition in obese insulin-resistant male rats by restoring brain insulin sensitivity, brain mitochondrial function and hippocampal synaptic plasticity. A total of twenty-four male Wistar rats were divided into two groups and fed either a normal diet or a high-fat diet (HFD) for 12 weeks. At week 13, the HFD rats were divided into three subgroups (n 6/subgroup) to receive one of the following treatments: vehicle, ER (60 % of energy received during the previous 12 weeks) or ER plus vildagliptin (3 mg/kg per d, p.o.) for 4 weeks. At the end of the treatment, cognitive function, metabolic parameters, brain insulin sensitivity, hippocampal synaptic plasticity and brain mitochondrial function were determined. We found that HFD-fed rats demonstrated weight gain with peripheral insulin resistance, dyslipidaemia, oxidative stress, brain insulin resistance, impaired brain mitochondrial function and cognitive dysfunction. Although HFD-fed rats treated with ER and ER plus vildagliptin showed restored peripheral insulin sensitivity and improved lipid profiles, only ER plus vildagliptin rats had restored brain insulin sensitivity, brain mitochondrial function, hippocampal synaptic plasticity and cognitive function. These findings suggest that only a combination of ER with DPP-4 inhibitor provides neuroprotective effects in obese insulin-resistant male rats.

Testosterone Deprivation Aggravates Left-Ventricular Dysfunction in Male Obese Insulin-Resistant Rats via Impairing Cardiac Mitochondrial Function and Dynamics Proteins

Background: We have previously reported that testosterone deprivation at a very young age accelerated, but did not aggravate, left-ventricular (LV) dysfunction in obese insulin-resistant rats. However, the effects of testosterone deprivation during adulthood on LV function in obese insulin-resistant rats remains unclear. We hypothesized that testosterone deprivation aggravates LV dysfunction and cardiac autonomic imbalance via the impairment of cardiac mitochondrial function and dynamics proteins, a reduction in insulin receptor function, and an increase in apoptosis in obese insulin-resistant rats. Methods: Male rats were fed on either a normal diet (ND) or a high-fat diet (HFD) for 12 weeks. They were then subdivided into 2 groups: sham operation (NDS, HFS) and orchiectomy (NDO, HFO). Metabolic parameters, blood pressure, heart rate variability (HRV), and LV function were determined at baseline and before and after orchiectomy. Mitochondrial function and dynamics proteins, insulin signaling, and apoptosis were determined 12 weeks postoperatively. Results: HFS rats exhibited obese insulin resistance, depressed HRV, and LV dysfunction. In HFO rats, systolic blood pressure was increased with more excessive depression of HRV and increased LV dysfunction, compared with HFS rats. These adverse cardiac effects were consistent with markedly increased mitochondrial dysfunction, reduced mitochondrial complex I and III proteins, reduced mitochondrial fusion proteins, and increased apoptosis, compared with HFS rats. However, testosterone deprivation did not lead to any alteration in the insulin-resistant condition in HFO rats, compared with HFS rats. Conclusion: We concluded that testosterone deprivation during adulthood aggravated the impairment of mitochondrial function, mitochondrial respiratory complex, mitochondrial dynamics proteins, and apoptosis, leading to LV dysfunction in obese insulin-resistant rats.

TESTOSTERONE DEFICIENCY AGGRAVATES COGNITIVE DECLINE IN OBESE CONDITION VIA INCREASED OXIDATIVE STRESS, GLIAL ACTIVITY AND CELL APOPTOSIS IN HIPPOCAMPUS

activation of astrocytes, one of the primary immune cells of the brain. Methods: Primary mouse astrocytes were harvested from postnatal day 0-1 CD1 mice and conditioned with combinations of 50 nM heme, Hb, and Ab1-42. Cytokine expression into culture medium was analyzed using a multiplexed immunoassay (EMD Millipore). Western blot, immunocytochemistry, and phagocytosis assays were performed to quantify astrocyte scavenger activity. Size exclusion chromatography was used to identify and isolate heme and Hb bound Ab1-42 species. Results:Our work revealed that heme and Hb suppressed immune activity of primary mouse astrocytes. Both heme and Hb significantly reduced expression of a panel of inflammatory cytokines which was upregulated by Ab1-42 (p<0.01). Furthermore, both heme and Hb suppressed scavenger activity of astrocytes, as seen by decreased expression of the scavenger receptor CD36 (p<0.01), and internalization of Ab1-42. Finally, we identified that a soluble, high molecular weight (>75kDa), Ab1-42 oligomeric species is primarily responsible for astrocyte activation and that heme or Hb association with these oligomers reverses inflammation. Conclusions:Our data indicated that heme and Hb are potent modulators of astrocyte immune activity and suppress a number of critical immune functions, including the ability to clear pathogens such as Ab.

LACK OF TESTOSTERONE IN OBESE-INSULIN RESISTANT CONDITION AGGRAVATES CARDIOMETABOLIC DYSFUNCTION THROUGH THE IMPAIRMENT OF CARDIAC MITOCHONDRIAL FUNCTION

Background: Obese-insulin resistance occurring in testosterone-deprived young-age rats has been shown to accelerate, but not aggravate, left ventricular (LV) dysfunction. However, in a clinical setting, whether testosterone deprivation occurring later at older age following obese-insulin resistance

PREBIOTICS, PROBIOTICS OR SYNBIOTICS THERAPY RESTORES COGNITIVE DECLINE IN OBESE RATS

(Ph&M) maintain cognitive functions and protect against dementia but their role versus risk factors needs more attention. Epigallocatechin-3-gallate (EGCG) act as an antioxidant and anti-inflammatory against b-amyloid aggregation in hippocampus thus may exhibit neuroprotective effects. Vitamin E (VE), Vitamin C (VC) and Selenium (Se) are antioxidant and have ability to counteract free radicals that contribute to pathological process in AD. Methods: Four major groups of rats were daily received (for 5 weeks): Saline (for normal groups), 10% casein diet with SI (for SI&PM-model groups) or 70mg/kg of AlCl3 (IP) either alone (for AD-model groups) or with SI&PM (for AD-associated SI&PM model groups). Each of them was subdivided to 3 subgroups: One as control for each of them and 2 were exposed/week to Ph&M (Swimming and Y-maze tests) either alone or with combination of EGCG (10 mg/kg, IP), VC (400mg/kg, PO), VE (100mg/kg, PO) and Se (1 mg/kg, PO). Biochemical parameters (AChE, Ab, Tau, b-secretase, monoamins, oxidative stress and inflammatory markers) were measured in the brain as well as brain derived neurotrophic factor (BDNF), DNA fragmentation and histopathological changes in different brain regions. Results: Combination of EGCG, VE, VC and Se together with Ph&M showed higher protection than Ph&M alone against hazards of AlCl3 and/or SI&PM especially in AD-associated SI&PM group. Their protection was indicated by the increase in brain monoamins, SOD, TAC and BDNF together with the decrease in AChE, Ab, Tau, b-secretase, MDA, TNF-a, IL-1b, DNA fragmentation and confirmed by the histopathological examinations. Conclusions: Combination of EGCG with VE, VC and Se together with Ph&M have more pronounced protective effect against risk of SI and PM inducing progression of AD than Ph&M alone. Consequently, their use is advisable to enhance the power of Ph&M especially in elderly and with risk conditions.