Piangkwan Sa-nguanmoo

Obesity accelerates cognitive decline by aggravating mitochondrial dysfunction, insulin resistance and synaptic dysfunction under estrogen-deprived conditions.

Chronic consumption of a high-fat diet (HF) causes peripheral insulin resistance, brain insulin resistance, brain mitochondrial dysfunction and cognitive impairment. Estrogen deprivation has also been found to impair cognition. However, the combined effect of both conditions on the brain is unclear. We hypothesized that estrogen deprivation causes brain insulin resistance, brain mitochondrial dysfunction, hippocampal synaptic dysfunction and cognitive impairment, and that consumption of a HF accelerates these impairments in an estrogen-deprived condition. Seventy-two female rats were divided into sham (S) and ovariectomized (O) groups. Rats in each group were further divided into two subgroups to be fed with either a normal diet (ND) or HF for 4, 8 and 12 weeks. At the end of each period, the Morris water maze test was carried out, after which the blood and brain were collected for metabolic and brain function analysis. Obesity, peripheral insulin resistance, increased brain oxidative stress and hippocampal synaptic dysfunction were observed at the eighth week in the NDO, HFS and HFO rats. However, these impairments were worse in the HFO rats. Interestingly, brain insulin resistance, brain mitochondrial dysfunction and cognitive impairment developed earlier (week eight) in the HFO rats, whereas these conditions were observed later at week 12 in the NDO and HFS rats. Either estrogen deprivation or HF appears to cause peripheral insulin resistance, increased brain oxidative stress, hippocampal synaptic dysfunction, brain mitochondrial dysfunction and brain insulin resistance, which together can lead to cognitive impairment. A HF accelerates and aggravates these deleterious effects under estrogen-deprived conditions.

Fibroblast growth factor 21 (FGF21) therapy attenuates left ventricular dysfunction and metabolic disturbance by improving FGF21 sensitivity, cardiac mitochondrial redox homoeostasis and structural changes in pre‐diabetic rats

Fibroblast growth factor 21 (FGF21) acts as a metabolic regulator and exerts cardioprotective effects. However, the effects of long‐term FGF21 administration on the heart under the FGF21‐resistant condition in obese, insulin‐resistant rats have not been investigated. We hypothesized that long‐term FGF21 administration reduces FGF21 resistance and insulin resistance and attenuates cardiac dysfunction in obese, insulin‐resistant rats.

FGF21 improves cognition by restored synaptic plasticity, dendritic spine density, brain mitochondrial function and cell apoptosis in obese-insulin resistant male rats.

Fibroblast growth factor 21 (FGF21) is an endocrine hormone which exerts beneficial effects on metabolic regulation in obese and diabetic models. However, the effect of FGF21 on cognition in obese-insulin resistant rats has not been investigated. We hypothesized that FGF21 prevented cognitive decline in obese-insulin resistant rats by improving hippocampal synaptic plasticity, dendritic spine density, brain mitochondrial function and brain FGF21 signaling as well as decreasing brain cell apoptosis. Eighteen male Wistar rats were divided into two groups, and received either a normal diet (ND) (n=6) or a high fat diet (HFD) (n=12) for 12weeks. At week 13, the HFD-fed rats were subdivided into two subgroups (n=6/subgroup) to receive either vehicle or recombinant human FGF21 (0.1mg/kg/day) for four weeks. ND-fed rats were given vehicle for four weeks. At the end of the treatment, cognitive function, metabolic parameters, pro-inflammatory markers, brain mitochondrial function, cell apoptosis, hippocampal synaptic plasticity, dendritic spine density and brain FGF21 signaling were determined. The results showed that vehicle-treated HFD-fed rats developed obese-insulin resistance and cognitive decline with impaired hippocampal synaptic plasticity, decreased dendritic spine density, brain mitochondrial dysfunction and increased brain cell apoptosis. Impaired brain FGF 21 signaling was found in these obese-insulin resistant rats. FGF21-treated obese-insulin resistant rats had improved peripheral insulin sensitivity, increased hippocampal synaptic plasticity, increased dendritic spine density, restored brain mitochondrial function, attenuated brain cells apoptosis and increased brain FGF21 signaling, leading to a prevention of cognitive decline. These findings suggest that FGF21 treatment exerts neuroprotection in obese-insulin resistant rats.

SGLT2-inhibitor and DPP-4 inhibitor improve brain function via attenuating mitochondrial dysfunction, insulin resistance, inflammation, and apoptosis in HFD-induced obese rats

ABSTRACT Dipeptidyl peptidase‐4 inhibitor (vildagliptin) has been shown to exert beneficial effects on insulin sensitivity and neuroprotection in obese‐insulin resistance. Recent studies demonstrated the neuroprotection of the sodium‐glucose co‐transporter 2 inhibitor (dapagliflozin) in diabetes. However, the comparative effects of both drugs and a combination of two drugs on metabolic dysfunction and brain dysfunction impaired by the obese‐insulin resistance have never been investigated. Forty male Wistar rats were divided into two groups, and received either a normal‐diet (ND, n = 8) or a high‐fat diet (HFD, n = 32) for 16 weeks. At week 13, the HFD‐fed rats were divided into four subgroups (n = 8/subgroup) to receive either a vehicle, vildagliptin (3 mg/kg/day) dapagliflozin (1 mg/kg/day) or combined drugs for four weeks. ND rats were given a vehicle for four weeks. Metabolic parameters and brain function were investigated. The results demonstrated that HFD rats developed obese‐insulin resistance and cognitive decline. Dapagliflozin had greater efficacy on improved peripheral insulin sensitivity and reduced weight gain than vildagliptin. Single therapy resulted in equally improved brain mitochondrial function, insulin signaling, apoptosis and prevented cognitive decline. However, only dapagliflozin improved hippocampal synaptic plasticity. A combination of the drugs had greater efficacy in improving brain insulin sensitivity and reducing brain oxidative stress than the single drug therapy. These findings suggested that dapagliflozin and vildagliptin equally prevented cognitive decline in the obese‐insulin resistance, possibly through some similar mechanisms. Dapagliflozin had greater efficacy than vildagliptin for preserving synaptic plasticity, thus combined drugs could be the best therapeutic approach for neuroprotection in the obese‐insulin resistance. HighlightsHFD‐induced obesity increased brain dysfunction and cognitive decline.Dapagliflozin had greater efficacy than vildagliptin for preserving brain function.The combined drugs had the greatest efficacy improving brain function.

Potential roles of fibroblast growth factor 21 in the brain

Fibroblast growth factor 21 (FGF21) is an endocrine hormone, playing an important role in the regulation of metabolism. FGF21 is primarily expressed by several tissues, including liver, pancreas, thymus, heart, muscle, adipose tissue, and brain. In addition to the effects of FGF21 in lowering glucose and lipid levels, increasing insulin sensitivity and regulating energy homeostasis in rodents and non-human primate models of diabetes and obesity, previous reports have demonstrated that FGF21 also plays an important role in the brain involving it in potential effects in metabolic regulation, neuroprotection and cognition. In this review, the current available evidence from both in vitro and in vivo investigations regarding the roles of FGF21 and its function in the brain are comprehensively summarized. In addition, the mechanistic insights regarding the roles of FGF21 in the brain and its potential neuroprotective benefits are also presented and discussed.

Testosterone deprivation has neither additive nor synergistic effects with obesity on the cognitive impairment in orchiectomized and/or obese male rats

OBJECTIVE Previous studies demonstrated a correlation between cognitive decline and either testosterone deprivation or obesity. However, the effect of obesity combined with testosterone deprivation on cognitive function has not been investigated. This study investigated the effects of obesity on brain insulin sensitivity, brain mitochondrial function, hippocampal synaptic plasticity and cognitive function in testosterone-deprived male rats. MATERIALS/METHODS Male Wistar rats were divided into sham-operated (control) and bilateral orchiectomized (ORX) groups. Rats in each group were further divided into two subgroups to receive either a normal diet (ND) or a high fat diet (HFD) for 4, 8 or 12weeks. Blood samples were collected to determine metabolic parameters. Cognitive function was tested using the Morris Water Maze Test. At the end of the study, brains were removed to investigate brain insulin sensitivity, brain mitochondrial function and hippocampal synaptic plasticity. RESULTS Both control-obese and ORX-obese rats developed peripheral insulin resistance at week eight, and brain insulin resistance as well as brain mitochondrial dysfunction at week 12. However, the ORX-obese rats developed cognitive impairment and decreased hippocampal synaptic plasticity beginning at week eight, whereas the control-obese rats developed these impairments later at week 12. Although both peripheral and brain insulin resistance were not observed in both the control-lean and ORX-lean rats, impaired cognition and decreased hippocampal synaptic plasticity were found in the ORX-lean rats beginning at week eight. CONCLUSION These findings suggest that testosterone deprivation has neither additive nor synergistic effects over obesity in the development of cognitive dysfunction in orchiectomized-obese male rats.

Estrogen and DPP4 inhibitor, but not metformin, exert cardioprotection via attenuating cardiac mitochondrial dysfunction in obese insulin-resistant and estrogen-deprived female rats.

Objective:Cardiac function was markedly compromised in obese insulin-resistant and estrogen-deprived rats. Metformin and dipeptidyl peptidase-4 inhibitor (vildagliptin) were reported to improve cardiac function in insulin-resistant rats. Their effects on the heart under estrogen-deprived conditions are, however, unknown. Therefore, the effects of metformin, vildagliptin, and estrogen on the cardiac function in estrogen-deprived insulin-resistant female rats were investigated. Methods:Bilateral ovariectomized female rats (n = 48) were divided to be fed with either a normal diet (ND) or a high-fat diet (HFD) for 12 weeks. Then, both ND- and HFD-fed groups were subdivided to receive a vehicle, estrogen (50 &mgr;g/kg), metformin (30 mg/kg), or vildagliptin (3 mg/kg) for 4 weeks (n = 6/group). Heart rate variability, echocardiography, metabolic and biochemical parameters, cardiac function, and mitochondrial function were determined. Sham-operated female rats (n = 6) were used as a control. Results:Both ND- and HFD-fed ovariectomized rats developed insulin resistance, depressed heart rate variability, and decreased cardiac contractility. Although treatment with metformin, vildagliptin, and estrogen improved metabolic status and cardiac function, only estrogen and vildagliptin improved diastolic blood pressure and left ventricular ±dP/dt, and also reduced mitochondrial impairment, apoptosis, and oxidative stress in HD-fed ovariectomized rats. Conclusions:Treatment with estrogen and vildagliptin provided more beneficial effects in the inhibition of oxidative stress, apoptosis, and cardiac mitochondrial dysfunction, and preserved cardiac contractile performance in estrogen-deprived insulin-resistant female rats.

Cardioprotection of dapagliflozin and vildagliptin in cardiac reperfusion injury rats

Sodium-glucose cotransporter 2 inhibitor (SGLT2-i) effects on cardiac ischemia/reperfusion (I/R) injury are unclear. Unlike SGLT2-i, dipeptidyl peptidase 4 inhibitors (DPP4-i) have shown effective cardioprotection in cardiac I/R injury. We aimed to investigate whether SGLT2-i reduces myocardial dysfunction and myocardial injury to a greater extent than DPP4-i in obese insulin-resistant rats with/without cardiac I/R injury. The high-fat (HF) diet-induced obese insulin-resistant rats were divided into 4 groups and received the following treatments for 28 days: vehicle (HFV); vildagliptin at a dosage of 3 mg/kg/day (HFVil); dapagliflozin at a dosage of 1 mg/kg/day (HFDa) and combination drugs (HFDaVil). At the end, I/R injury was induced by a 30-min left anterior descending coronary occlusion and 120-min reperfusion. Dapagliflozin showed a greater efficacy than vildagliptin in improving the metabolic impairments, low frequency/high frequency (LF/HF) ratio, systolic blood pressure and left ventricular (LV) function in comparison to HFV rats. In cardiac I/R injury, dapagliflozin had a greater efficacy than vildagiptin in decreasing mitochondrial DRP1, cleaved caspase 3, LV dysfunction and infarct size in comparison to HFV rats. However, the combined therapy showed the greatest efficacy in attenuating LV dysfunction, mitochondrial DRP1 and infarct size in comparison to HFV rats. In conclusion, dapagliflozin has a more pronounced effect than vildagliptin in obese insulin-resistant rats for the improvement of LV function. In rats with cardiac I/R injury, although dapagliflozin had a greater efficacy on cardioprotection than vildagliptin, the combined therapy exerted the highest cardioprotective effects potentially by reducing mitochondrial fission.

Impaired mitochondria and intracellular calcium transients in the salivary glands of obese rats

Long-term consumption of a high-fat diet (HFD) causes not only obese-insulin resistance, but is also associated with mitochondrial dysfunction in several organs. However, the effect of obese-insulin resistance on salivary glands has not been investigated. We hypothesized that obese-insulin resistance induced by HFD impaired salivary gland function by reducing salivation, increasing inflammation, and fibrosis, as well as impairing mitochondrial function and calcium transient signaling. Male Wistar rats (200-220 g) were fed either a ND or an HFD (n = 8/group) for 16 weeks. At the end of week 16, salivary flow rates, metabolic parameters, and plasma oxidative stress were determined. Rats were then sacrificed and submandibular glands were removed to determine inflammation, fibrosis, apoptosis, mitochondrial function and dynamics, and intracellular calcium transient signaling. Long-term consumption of an HFD caused obese-insulin resistance and increased oxidative stress, fibrosis, inflammation, and apoptosis in the salivary glands. In addition, impaired mitochondrial function, as indicated by increased mitochondrial reactive oxygen species, mitochondrial membrane depolarization, and mitochondrial swelling in salivary glands and impaired intracellular calcium regulation, as indicated by a reduced intracellular calcium transient rising rate, decay rates, and amplitude of salivary acinar cells, were observed in HFD-fed rats. However, salivary flow rate and level of aquaporin 5 protein were not different between both groups. Although HFD consumption did not affect salivation, it caused obese-insulin resistance, leading to pathophysiological alteration of salivary glands, including impaired intracellular calcium transients, increased oxidative stress and inflammation, and salivary mitochondrial dysfunction.

Protocatechuic acid protects brain mitochondrial function in streptozotocin-induced diabetic rats

Brain mitochondrial dysfunction has been demonstrated in diabetic animals with neurodegeneration. Protocatechuic acid (PCA), a major metabolite of anthocyanin, has been shown to exert glycemic control and oxidative stress reduction in the heart. However, its effects on oxidative stress and mitochondrial function in the brain under diabetic condition have never been investigated. We found that PCA exerted glycemic control, attenuates brain mitochondrial dysfunction, and contributes to the prevention of brain oxidative stress in diabetic rats.