Effects of Exercise Rehabilitation on Cardiorespiratory Fitness in Long-COVID-19 Survivors: A Meta-Analysis.

Background: Poor cardiorespiratory fitness poses the highest risk of mortality. Long-COVID-19 survivors exhibit a reduced cardiorespiratory fitness (CRF). While exercise rehabilitation, such as cardiopulmonary exercise, is used for long-COVID-19 survivors, the effects of exercise on CRF in this population remain inconclusive. In this study, we aim to systematically summarise and synthesise whether exercise rehabilitation improves CRF among long-COVID-19 survivors. Methods: A comprehensive search was performed through PubMed, CINAHL, Embase, Scopus, and the Cochrane Library (since their inception to November 2023) and study reference lists. Studies presenting the effects of exercise rehabilitation on CRF (peak oxygen consumption (VO2peak) and six-minute walk distance (6MWD)) in long-COVID-19 survivors were identified. The standardised mean difference (SMD), mean difference (MD), and 95% confidence interval (CI) were used for analyses. The certainty of evidence was measured using a Grading of Recommendation Assessment, Development and Evaluation approach. Results: Twelve eligible studies (five RCTs and seven non-RCTs) with 682 participants were analysed. The meta-analysis showed significantly improved 6MWDs (MD 76.47, 95% CI 59.19-93.71, low certainty) and significantly greater 6MWDs (SMD 0.85, 95% CI 0.11-1.59, very low certainty) in the exercise rehabilitation group compared to the control group. A significantly improved 6MWD was found in subgroups of young to middle-aged adults and subgroups of patients who undertook aerobic exercise combined with resistance and respiratory exercise and centre-based training programs. Conclusions: Exercise rehabilitation is effective for improving CRF, as measured by the 6MWD in long-COVID-19 survivors. Improvements are likely to be more pronounced in specific subgroups of young to middle-aged adults and patients undertaking aerobic exercise combined with resistance and respiratory exercise and centre-based training programs. However, recommendations for clinical practice are limited due to the very low evidence certainty.

Effects of combined dietary intervention and physical-cognitive exercise on cognitive function and cardiometabolic health of postmenopausal women with obesity: a randomized controlled trial.

BACKGROUND: Postmenopausal women with obesity are markedly at risk of cognitive impairment and several health issues. Emerging evidence demonstrated that both diet and exercise, particularly physical-cognitive exercise are involved in cognitive and health benefits. However, the comparative effect of diet, exercise, and combined interventions in postmenopausal women with obesity on cognition and cardiometabolic health is still lacking. Identifying the effective health promotion program and understanding changes in cardiometabolic health linking these interventions to cognition would have important medical implications. This RCT aimed to examine the effect of single and combined interventions of diet and exercise on cognitive function and cardiometabolic health in postmenopausal women with obesity. METHODS: Ninety-two postmenopausal women with obesity were randomly assigned to diet group (intermittent fasting 2 days/week, 3 months), exercise group (physical-cognitive exercise 3 days/week, 3 months), combined group, or control group (n = 23/group). All cognitive outcomes and cardiometabolic outcomes were measured at baseline and post-3 months. Primary outcomes were executive functions, memory, and plasma BDNF levels. Secondary outcomes were global cognition, attention, language domain, plasma adiponectin levels, IL-6 levels, metabolic parameters, and physical function. RESULTS: At the end of the 3-month intervention, the exercise and combined group demonstrated significant memory improvement which was accompanied by significant improvements in plasma BDNF level, insulin levels, HOMA-IR, %body fat, and muscle strength when compared to controls (p < 0.05). Only the combined intervention group demonstrated a significant improvement in executive function and increased plasma adiponectin levels when compared to control (p < 0.05). Surprisingly, no cognitive improvement was observed in the diet group (p > 0.05). Significant reduction in cholesterol levels was shown in the diet and combined groups when compared to controls (p < 0.05). Among the three intervention groups, there were no significant differences in all cognitive outcomes and cardiometabolic outcomes (p > 0.05). However, all three intervention groups showed significant improvements in plasma BDNF levels, weight, BMI, WHR, fat mass, and predicted VO2 max, when compared to control (p < 0.05). CONCLUSION: These findings suggest that combined physical-cognitive exercise and dietary intervention are promising interventions to improve cognition and obesity-related complications of postmenopausal women with obesity. TRIAL REGISTRATION: NCT04768725 ( https://clinicaltrials.gov ) 24th February 2021.

Long-term impact of SARS-CoV-2 infection on cardiorespiratory fitness: a meta-analysis.

Background: Despite surviving Coronavirus disease 2019 (COVID-19), its long-term impact is of concern. Low cardiorespiratory fitness is a strong predictor of all-cause mortality, and likely affected by multisystem impairments following COVID-19 infection. Accumulating evidence has identified the impact of COVID-19 on cardiorespiratory fitness level. However, the findings have been controversial. Conclusive evidence is still needed. Objectives: This review aimed to systematically summarize and synthesize whether the SARS-CoV-2 infection diminishes cardiorespiratory fitness in COVID-19 survivors. Design: The study design was a systematic review and meta-analysis. Methods: A search was carried out using PubMed, CINAHL, Scopus, Embase and the Cochrane Library, together with reference lists (searching from their inception to January 2023). Observational studies investigating the impact of COVID-19 on outcomes relevant to cardiorespiratory fitness (i.e., peak oxygen uptake) were included. Weighted mean difference (WMD) and 95% confidence interval (CI) were used to identify a pooled effect estimate. Use of a random effects model was considered as the main method. Grading of Recommendation Assessment, Development and Evaluation approach was employed to determine the certainty of evidence. This meta-analysis was registered with PROSPERO (registration number: CRD42023393108). Results: Seven eligible studies (4 cross-sectional, 2 cohort, and 1 case-control studies) involving 4,773 participants were included in this meta-analysis. A pooled effect estimates showed that patients in the surviving COVID-19 group had a significant reduction in peak oxygen uptake when compared to their counterparts in the non-COVID-19 group (WMD -6.70, 95%CI -9.34 to -4.06, low certainty). A subgroup analysis by age found that COVID-19 survivors in the young- to middle-aged and middle- to older-aged subgroups had significant reductions in peak oxygen uptake when compared to their counterparts in the non-COVID-19 group (WMD -5.31, 95%CI -7.69 to -2.94, low certainty; WMD -15.63, 95%CI -28.50 to -2.75, very low certainty, respectively). Subgroup analyses by symptom found that patients with moderate to severe symptoms in the surviving COVID-19 group had significantly lower peak oxygen uptake than their counterparts in the non-COVID-19 group (WMD -15.63, 95%CI -28.50 to -2.75, very low certainty). Conclusion: The current meta-analysis concluded that patients in the COVID-19 survivors had poorer cardiorespiratory fitness than their counterparts in the non-COVID-19 group, but there is considerable uncertainty of evidence. Poorer cardiorespiratory fitness is likely to be more pronounced in COVID-19 survivors who are getting older and had severe symptoms, but it is uncertain whether such finding has a valuable in clinical context. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, CRD42023393108.

Obstructive Sleep Apnea Effects on Pulmonary and Respiratory Muscle Function of Obese Children and Adolescents: A Preliminary Study.

OBJECTIVE: Obstructive sleep apnea causes a marked decrease in lung volume and increases lung elasticity in obese adults. However, pulmonary and respiratory muscle function of obese children with obstructive sleep apnea who are more prone to develop airway obstruction than adults is less understood. This study aimed to determine the effects of obstructive sleep apnea on pulmonary and respiratory muscle function in obese children and adolescents compared to those without obstructive sleep apnea. MATERIAL AND METHODS: This cross-sectional study enrolled 12 obese children and adolescents with a known polysomnographic diagnosis of obstructive sleep apnea and 12 controls that were matched for age, gender, and body mass index. Pulmonary function, maximal inspiratory pressure, maximum voluntary ventilation, and anthropometric variables were measured. RESULTS Obese children and adolescents with obstructive sleep apnea exhibited significantly lower maximal mid-expiratory flow and displayed a forced expiratory flow at 50% and 75% of vital capacity (all P < .05) compared to the control group. However, there were no changes in other pulmonary function variables (all P > .05). Their maximal inspiratory pressure and maximum voluntary ventilation were lower than those of the controls, but this was not statistically significant (all P > .05). CONCLUSION: Obstructive sleep apnea did not change pulmonary and respiratory muscle function in obese children and adolescents. The special assessment should be warranted to identify a reduction in maximal mid-expiratory flow and forced expiratory flow at 50% and 75% of vital capacity observed in this population.

Comparative effects of sex hormone deprivation on the brain of insulin-resistant rats.

Obese-insulin resistance following chronic high-fat diet consumption led to cognitive decline through several mechanisms. Moreover, sex hormone deprivation, including estrogen and testosterone, could be a causative factor in inducing cognitive decline. However, comparative studies on the effects of hormone-deprivation on the brain are still lacking. Adult Wistar rats from both genders were conducted sham operations or orchiectomies/ovariectomies and given a normal diet or high-fat diet for 4, 8, and 12 weeks. Blood was collected to determine the metabolic parameters. At the end of the experiments, rats were decapitated and their brains were collected to determine brain mitochondrial function, brain oxidative stress, hippocampal plasticity, insulin-induced long-term depression, dendritic spine density, and cognition. We found that male and female rats fed a high-fat diet developed obese-insulin resistance by week 8 and brain defects via elevated brain oxidative stress, brain mitochondrial dysfunction, impaired insulin-induced long-term depression, hippocampal dysplasticity, reduced dendritic spine density, and cognitive decline by week 12. In normal diet-fed rats, estrogen-deprivation, not testosterone-deprivation, induced obese-insulin resistance, oxidative stress, brain mitochondrial dysfunction, impaired insulin-induced long-term depression, hippocampal dysplasticity, and reduced dendritic spine density. In high-fat-diet-fed rats, estrogen deprivation, not testosterone-deprivation, accelerated and aggravated obese-insulin resistance and brain defects at week 8. In conclusion, estrogen deprivation aggravates brain dysfunction more than testosterone deprivation through increased oxidative stress, brain mitochondrial dysfunction, impaired insulin-induced long-term depression, and dendritic spine reduction. These findings may explain clinical reports which show more severe cognitive decline in aging females than males with obese-insulin resistance.

Author Correction: Partial involvement of Nrf2 in skeletal muscle mitohormesis as an adaptive response to mitochondrial uncoupling.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

FGF21 and DPP-4 inhibitor equally prevents cognitive decline in obese rats.

The beneficial effects of Fibroblast Growth Factor 21 (FGF21) on metabolic function and neuroprotection have been shown in earlier research. We have previously shown that the Dipeptidyl Peptidase 4 inhibitor, vildagliptin, also led to improved insulin sensitivity and brain function in the obese-insulin resistant condition. However, the comparative efficacy on the improvement of metabolic function and neuroprotection between FGF21 and vildagliptin in the obese-insulin resistant condition has never been investigated. Twenty-four male Wistar rats were divided into two groups, and received either a normal diet (ND, n=6) or a high fat diet (HFD, n=18) for 16 weeks. At week 13, the HFD-fed rats were divided into three subgroups (n=6/subgroup) to receive either a vehicle, recombinant human FGF21 (0.1mg/kg/day) or vildagliptin (3mg/kg/day), for four weeks. ND-fed rats were given a vehicle for four weeks. The metabolic parameters and brain function were subsequently investigated. The results demonstrated that the rats fed on HFD had obese-insulin resistance, increased systemic inflammation, brain mitochondrial dysfunction, increased brain apoptosis, impaired hippocampal plasticity, and demonstrated cognitive decline. FGF21 and vildagliptin effectively attenuated peripheral insulin resistance, brain mitochondrial dysfunction, brain apoptosis and cognitive decline. However, only FGF21 treatment led to significantly reduced body weight gain, visceral fat, systemic inflammation, improved hippocampal synaptic plasticity, enhanced FGF21 mediated signaling in the brain leading to prevention of early cognitive decline. These findings suggest that FGF21 exerts greater efficacy than vildagliptin in restoring metabolic function as well as brain function in cases of obese-insulin resistant rats.

Dipeptidyl Peptidase-4 Inhibitor, Vildagliptin, Improves Trabecular Bone Mineral Density and Microstructure in Obese, Insulin-Resistant, Pre-diabetic Rats.

OBJECTIVE: Obese insulin resistance and type 2 diabetes mellitus profoundly impair bone mechanical properties and bone quality. However, because several antidiabetes drugs, especially thiazolidinediones, further aggravate bone loss in individuals with diabetes, diabetic osteopathy should not be treated by using simply any glucose-lowering agents. Recently, incretins have been reported to affect osteoblast function positively. The present study aimed to investigate the effects of vildagliptin, an inhibitor of dipeptidyl peptidase-4, on bone of rats with high-fat-diet-induced prediabetes. METHODS: Male rats were fed a high-fat diet for 12 weeks to induce obese insulin resistance and then treated with vildagliptin for 4 weeks. The effects of the drug on bone were determined by microcomputed tomography and bone histomorphometry. RESULTS: Vildagliptin markedly improved insulin resistance in these obese insulin-resistant rats. It also significantly increased volumetric bone mineral density. Specifically, vildagliptin-treated obese insulin-resistant rats exhibited higher trabecular volumetric bone mineral density than vehicle-treated obese insulin-resistant rats, whereas cortical volumetric bone mineral density, cortical thickness and area were not changed. Bone histomorphometric analysis in a trabecular-rich area (i.e. tibial metaphysis) revealed greater trabecular bone volume and number and less trabecular separation without change in trabecular thickness, osteocyte lacunar area or cortical thickness in the vildagliptin-treated group. CONCLUSIONS: Vildagliptin had a beneficial effect on the bone of obese insulin-resistant rats with prediabetes, particularly at the trabecular site. Such benefit probably results from enhanced bone formation rather than from suppressed bone resorption.

Factors associated with cognitive impairment in elderly versus nonelderly patients with metabolic syndrome: the different roles of FGF21.

Increased fibroblast growth factor 21 (FGF21) levels have been found in patients with metabolic syndrome (MetS). MetS is also associated with cognitive decline. However, the correlation between FGF21 and cognitive decline in elderly and nonelderly MetS patients has not been investigated. 116 non-elderly patients (age <65 years old) and 96 elderly patients (≥65 years old) with MetS were enrolled. Blood samples for FGF21 were collected from all participants after 12-hour fasting. Cognitive function was assessed using the Montreal cognitive assessment (MoCA) test. The MoCA score was negatively associated with age and was different among different levels of education in these MetS patients. In the non-elderly group, body mass index (BMI) showed positively correlated with MoCA score while, FGF21 level and HbA1C were negatively associated with the MoCA score in non-elderly MetS patients. BMI was the only factor which showed a negative correlation with the MoCA score in elderly MetS patients. This study demonstrated that FGF21 level was independently associated with cognitive impairment in non-elderly patients but not in elderly patients. The possible role of FGF21 level in cognitive impairment in non-elderly should be confirmed in a prospective study.

Partial involvement of Nrf2 in skeletal muscle mitohormesis as an adaptive response to mitochondrial uncoupling.

Mitochondrial dysfunction is usually associated with various metabolic disorders and ageing. However, salutary effects in response to mild mitochondrial perturbations have been reported in multiple organisms, whereas molecular regulators of cell-autonomous stress responses remain elusive. We addressed this question by asking whether the nuclear factor erythroid-derived-like 2 (Nrf2), a transcription factor and master regulator of cellular redox status is involved in adaptive physiological responses including muscle mitohormesis. Using a transgenic mouse model with skeletal muscle-specific mitochondrial uncoupling and oxidative phosphorylation (OXPHOS) inefficiency (UCP1-transgenic, TG) we show that additional genetic ablation of Nrf2 abolishes an adaptive muscle NAD(P)H quinone dehydrogenase 1 (NQO1) and catalase induction. Deficiency of Nrf2 also leads to decreased mitochondrial respiratory performance although muscle functional integrity, fiber-type profile and mitochondrial biogenesis were not significantly altered. Importantly, Nrf2 ablation did not abolish the induction of key genes and proteins of muscle integrated stress response including the serine, one-carbon cycle, and glycine synthesis (SOG) pathway in TG mice while further increasing glutathione peroxidase (GPX) activity linked to increased GPX1 protein levels. Conclusively, our results tune down the functions controlled by Nrf2 in muscle mitohormesis and oxidative stress defense during mitochondrial OXPHOS inefficiency.

Dipeptidyl peptidase-4 inhibitor enhances restoration of salivary glands impaired by obese-insulin resistance.

OBJECTIVE: Chronic high-fat diet consumption causes not only obese- insulin resistance, but also leads to pathological changes in salivary glands, including increased mitochondrial dysfunction, apoptosis, oxidative stress, and inflammation. Dipeptidyl peptidase-4 inhibitor (vildagliptin) is an oral anti-diabetic drug, using for treatment of type 2 diabetes. Vildagliptin has been shown to exert beneficial effects on several organs in cases of obese-insulin resistant condition. However, the effect of vildagliptin on salivary glands impaired by obese-insulin resistance has not been investigated. The hypothesis in this study is that vildagliptin confers beneficial effects on the salivary gland impaired by obese-insulin resistance via decreasing mitochondrial dysfunction, apoptosis, oxidative stress, and inflammation. DESIGN: Twenty-four male Wistar rats were divided into two groups. Each group was fed with either a normal (ND; n=8) or a high fat diet (HFD; n=16) for 16 weeks. At week 13, the HFD-fed rats were subdivided into 2 subgroups to receive either a vehicle or vildagliptin (3mg/kg/day) for 28days via gavage feeding. ND-fed rats were treated with the vehicle. At the end of treatment, metabolic parameters were examined, and rats were killed. Submandibular glands were removed to appraise inflammatory markers, apoptosis and mitochondrial function. RESULTS: Vehicle-treated HFD-fed rats developed obese-insulin resistance with an increase in oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction in the salivary glands. Vildagliptin therapy reduced oxidative stress, inflammation, apoptosis and mitochondrial dysfunction in salivary gland of HFD-fed rats. CONCLUSION: Vildagliptin prevented salivary gland injury occurring due to obese-insulin resistance.

Cardioprotection of dapagliflozin and vildagliptin in rats with cardiac ischemia-reperfusion injury.

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.

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

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 16weeks. At week 13, the HFD-fed rats were divided into four subgroups (n=8/subgroup) to receive either a vehicle, vildagliptin (3mg/kg/day) dapagliflozin (1mg/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.

Comparisons of cardioprotective efficacy between fibroblast growth factor 21 and dipeptidyl peptidase-4 inhibitor in prediabetic rats.

AIMS: Comparative efficacy between fibroblast growth factor 21 (FGF21) and vildagliptin on metabolic regulation, cardiac mitochondrial function, heart rate variability (HRV), and left ventricular (LV) function is not known. We hypothesized that FGF21 and vildagliptin share a similar efficacy in improving these parameters in high fat diet (HFD)-induced obese-insulin resistant rats. METHODS: Twenty-four male Wistar rats were fed with either a normal diet (ND) or a HFD for 12 weeks. Then, ND rats were received vehicle (NDV). Rats in the HFD group were divided into three subgroups to receive either vehicle (HFV), recombinant human FGF21 (rhFGF21, 0.1 mg/kg/d, ip; HFF), or vildagliptin (3 mg/kg/d, PO; HFVil) for 28 days. RESULTS: HFV rats developed obese-insulin resistance, increased serum tumor necrosis factors alpha (TNF-α) level, impaired heart rate variability (HRV) together with cardiac mitochondrial dysfunction, and LV dysfunction. Cardiac apoptosis was markedly increased in HFV rats indicated by decreased B-cell lymphoma 2 (Bcl-2) with increased Bcl2-associated X-protein (Bax) and cleaved caspase 3 expression. Cardiac FGF21 signaling pathways were markedly decreased in HFV rats indicated by decreased phosphor-fibroblast growth factor receptors 1 (p-FGFR1), phosphor-extracellular signal-regulated protein kinases 1 (p-ERK1/2), proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and carnitine palmitoyltransferase-1 (CPT-1) expression. Although both FGF21 and vildagliptin similarly attenuated these impairments, only HFF rats had decreased body weight, visceral fat, and serum TNF-α levels. CONCLUSIONS: FGF21 exerts better metabolic regulation and inflammation reduction than vildagliptin. However, FGF21 and vildagliptin shared a similar efficacy for cardioprotection by improving HRV and LV function.

Estrogen and DPP-4 inhibitor share similar efficacy in reducing brain pathology caused by cardiac ischemia-reperfusion injury in both lean and obese estrogen-deprived rats.

OBJECTIVE: Cardiac ischemia-reperfusion injury (I/R) caused an oxidative burst, increased beta-amyloid production, and decreased dendritic spine density in the brain. However, the effect of cardiac I/R in the brain of estrogen-deprived rats who were or were not obese have not been investigated. Moreover, the benefits of estrogen or dipeptidyl peptidase-4 (DDP-4) inhibitor therapies in those conditions have never been determined. We hypothesized that cardiac I/R aggravates brain pathology in estrogen-deprived obese rats, to a greater extent when compared with estrogen-deprived lean rats, and treatment with either estrogen or a DPP-4 inhibitor attenuates those adverse effects. METHODS: In protocol 1, rats were divided into sham operation (n = 12) or ovariectomy (n = 24). Sham-operated rats were fed with normal diet (ND) and ovariectomized rats were fed with either ND or high-fat diet (HF) for 12 weeks. Then, rats were subdivided to sham operation or cardiac I/R injury. In protocol 2, ovariectomized rats were given either ND (n = 18) or HF (n = 18). At week 13, ovariectomized rats were subdivided to receive vehicle, estradiol, or DPP-4 inhibitor for 4 weeks. Then, all rats were subjected to cardiac I/R. RESULTS: Cardiac I/R injury aggravated brain oxidative stress, beta-amyloid production, and decreased dendritic spine density in either sham-operated or ovariectomized ND-fed rats, but not in ovariectomized HF-fed rats. Either estrogen or DPP-4 inhibitor therapies reduced those conditions in all rats with cardiac I/R. CONCLUSIONS: Cardiac I/R aggravates brain toxicity in estrogen-deprived lean rats, but not in the estrogen-deprived obese rats. Estrogen and DPP-4 inhibitor treatments attenuate those effects in all groups.

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.

Fibroblast growth factor-21 restores insulin sensitivity but induces aberrant bone microstructure in obese insulin-resistant rats.

Fibroblast growth factor (FGF)-21 is a potent endocrine factor that improves insulin resistance and obesity-associated metabolic disorders. However, concomitant activation of peroxisome proliferator-activated receptor-γ by FGF-21 makes bone susceptible to osteopenia and fragility fracture. Since an increase in body weight often induced adaptive change in bone by making it resistant to fracture, it was unclear whether FGF-21 would still induce bone defects in overweight rats. Therefore, the present study aimed to investigate bone microstructure and its mechanical properties in high fat diet (HF)-fed rats treated with 0.1 mg/kg/day FGF-21. Eighteen male rats were divided into two groups to receive either a normal diet or HF for 12 weeks. HF rats were then divided into two subgroups to receive either vehicle or FGF-21 for 4 weeks. The results showed that HF led to obesity, dyslipidemia and insulin resistance, as indicated by hyperinsulinemia with euglycemia. In HF rats, there was an increase in tibial yield displacement (an indicator of ability to be deformed without losing toughness, as determined by 3-point bending) without changes in tibial trabecular volumetric bone mineral density (vBMD) or cortical bone parameters, e.g., cortical thickness and bone area. FGF-21 treatment strongly improved the metabolic parameters and increased insulin sensitivity in HF rats. However, FGF-21-treated HF rats showed lower yield displacement, trabecular vBMD, trabecular bone volume, trabecular thickness, and osteoblast surface compared with vehicle-treated HF rats. These findings suggest that, despite being a potent antagonist of insulin resistance and visceral fat accumulation, FGF-21 is associated with bone defects in HF rats.

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.

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.

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 µg/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.