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.

Feasibility of Internet-Based Physical-Cognitive Exercise for Health Benefits of Middle-Aged Obese Women.

INTRODUCTION: Obesity in middle-aged women markedly increases the risk for non-communicable diseases, neurodegenerative diseases, and physical and cognitive problems. Exercise, particularly combined physical-cognitive exercise, has been demonstrated to have beneficial effects on both physical and cognitive health. However, middle-aged women often face barriers to engaging in exercise, which include time constraints, lack of motivation, and enjoyment. Incorporating an exercise program into a technology-based intervention in the home environment may help overcome these barriers and promote health benefits. Therefore, this study aimed to assess the feasibility of home-based, physical-cognitive internet-based exercise for middle-aged obese women. METHODS: A total of 33 middle-aged obese women were enrolled in the study. Participants performed an intervention for 60 min/day, 3 days/week for 3 months. Feasibility outcomes (adherence, adverse events, physical performances, obesity parameters, and enjoyment of the program) were measured. RESULTS: Average exercise adherence was 91.67%, and no adverse events were reported in this feasibility study. At the end of the training period, body weight and BMI were significantly decreased compared to baseline. As for physical performances, both cardiorespiratory fitness and lower limb muscle power were significantly improved at post-training when compared to baseline. Furthermore, the participants experienced a high level of exercise enjoyment, and it was maintained over the 3-month training period. CONCLUSION: These findings suggest that home-based, internet-based physical-cognitive exercise was safe and feasible for reducing obesity parameters, improving physical function, maintaining enjoyment over the course of training, and facilitating adherence to exercise in middle-aged obese women.

Cognitive Benefits of Physical Exercise, Physical-Cognitive Training, and Technology-Based Intervention in Obese Individuals with and without Postmenopausal Condition: A Narrative Review.

Obesity and estrogen deprivation have been identified as significant risk factors for cognitive impairment. Thus, postmenopausal conditions when paired with obesity may amplify the risks of developing dementia. Physical exercise has been recommended as a primary treatment for preventing obesity-related comorbidities and alleviating menopausal symptoms. This narrative review aimed to summarize the effects of exercise on cognition in obese individuals with and without menopausal condition, along with potential physiological mechanisms linking these interventions to cognitive improvement. Research evidence has demonstrated that exercise benefits not only physical but also cognitive and brain health. Among various types of exercise, recent studies have suggested that combined physical-cognitive exercise may exert larger gains in cognitive benefits than physical or cognitive exercise alone. Despite the scarcity of studies investigating the effects of physical and combined physical-cognitive exercise in obese individuals, especially those with menopausal condition, existing evidence has shown promising findings. Applying these exercises through technology-based interventions may be a viable approach to increase accessibility and adherence to the intervention. More evidence from randomized clinical trials with large samples and rigorous methodology is required. Further, investigations of biochemical and physiological outcomes along with behavioral changes will provide insight into underlying mechanisms linking these interventions to cognitive improvement.

A combination of an antioxidant with a prebiotic exerts greater efficacy than either as a monotherapy on cognitive improvement in castrated-obese male rats.

Previous studies by ourselves and others have demonstrated that both obesity and testosterone deprivation have been related to cognitive decline. We have also shown that a prebiotic and n-acetyl cysteine (NAC) improved cognitive dysfunction in obese rats and castrated-male rats. However, the effects of NAC, a prebiotic (inulin), and a combination of the two on cognition in castrated-obese rats has never been investigated. The hypothesis was that NAC and inulin attenuated cognitive decline in castrated-obese rats by improving gut dysbiosis, and decreasing oxidative stress, glial activation and apoptosis. Male Wistar rats (n = 36) were fed with either a normal diet (ND: n = 6) or a high-fat diet (HFD: n = 30) for twenty-eight weeks. The resultant obese rats had a bilateral orchiectomy (ORX) and were randomly divided into five subgroups (n = 6/ subgroup). Each subgroup was treated with one of five therapies: a vehicle; testosterone replacement (2 mg/kg/day); NAC (100 mg/kg); inulin (10%, w/w), or a combination of the NAC and inulin for four weeks. The results demonstrated that castrated-obese rats developed gut dysbiosis, metabolic disturbance, brain pathologies, and cognitive decline. All of the pathological conditions in the brain were ameliorated to an equal extent by testosterone replacement, NAC, and inulin supplementation. Interestingly, a combination of NAC and inulin had the greatest beneficial effect on cognitive function by synergistically reducing hippocampal inflammation and ameliorating glial dysmorphology. These findings suggest that a combination of NAC and inulin may confer the greatest benefits in improving cognitive function in castrated-obese male rats.

N-acetyl cysteine, inulin and the two as a combined therapy ameliorate cognitive decline in testosterone-deprived rats.

Our previous studies reported that testosterone-deprived rats developed cognitive decline as a result of increased brain oxidative stress, microglia hyperactivity, and hippocampal dysplasticity. In addition, gut dysbiosis occurred in these rats. Previous studies demonstrated that n-acetyl cysteine (NAC) and a prebiotic (inulin) improved cognition in several pathological conditions. However, its effects on cognition in the testosterone-deprived condition have never been investigated. This study hypothesized that the administration of NAC, inulin, and a combined therapy improved cognition in castrated rats. Here we report that metabolic disturbance was not observed in the ORX rats, but gut dysbiosis was found in these rats. ORX rats developed blood-brain-barrier (BBB) breakdown, and increased brain oxidative stress as indicated by increased hippocampal production of reactive oxygen species (ROS) and an increase in brain malondialdehyde level. ORX rats also demonstrated glia hyperactivation, resulting in hippocampal apoptosis, hippocampal dysplasticity, and cognitive decline. All treatments equally ameliorated cognitive decline by improving gut dysbiosis, alleviating BBB dysfunction, decreasing hippocampal ROS production, decreasing hippocampal apoptosis, and reducing microglia and astrocyte activity. These findings suggest that NAC, inulin, and the combined therapy ameliorated the deleterious effects on the brain in castrated male rats similar to those treated with testosterone.

Combined dipeptidyl peptidase-4 inhibitor with low-dose testosterone exerts greater efficacy than monotherapy on improving brain function in orchiectomized obese rats.

Both obesity and orchiectomy lead to the development of brain pathologies and cognitive decline. Testosterone replacement therapy (2 mg/kg/day TRT) and dipeptidyl peptidase-4 inhibitor (vildagliptin) improved cognition in orchiectomized rats, and obese rats. However, both had no beneficial effects in brain of orchiectomized-obese rats. TRT (>2 mg/kg/day) is possible to attenuate brain defects in those rats, but high dose of TRT causes adverse effects. Then, combined effect of low-dose TRT (1 mg/kg/day) and vildagliptin on brain and cognitive functions in orchiectomized-obese rats should be investigated. Sixty male rats were fed with either a normal diet (ND) or a high-fat diet (HFD) for 28 weeks. At week 13, both ND and HFD-fed rats had either a sham-operation or an orchiectomy. At week 25, orchiectomized rats were treated with either: a vehicle, 2 mg/kg/day TRT, vildagliptin (3 mg/kg/day) or a combined vildagliptin with 1 mg/kg/day TRT for 4 weeks. Then, metabolic parameters, brain and cognitive functions were determined. Hippocampal oxidative stress, apoptosis, dendritic spine loss, microglial hyperactivity, and cognitive decline were found in orchiectomized ND-fed rats and sham-operated HFD-fed rats. Interestingly, orchiectomy aggravated these brain pathologies and cognitive decline in HFD-fed rats. In orchiectomized ND-fed rats, all treatments restored brain and cognitive functions. In orchiectomized HFD-fed rats, monotherapies ameliorated these brain pathologies, while the combined therapies had the greatest beneficial effect on the brains. These findings suggest the combined therapies may be the best therapeutic approach for restoring brain functions in the orchiectomized-obese condition.

Testosterone deprivation intensifies cognitive decline in obese male rats via glial hyperactivity, increased oxidative stress, and apoptosis in both hippocampus and cortex.

AIM: The study hypothesized that testosterone deprivation aggravates cognitive decline in obesity through increasing oxidative stress, glial activation, and apoptosis. METHODS: Male Wistar rats (n = 24) were fed with either normal-diet (ND) or high-fat diet (HFD) for 24 weeks. At week 13, ND-fed rats and HFD-fed rats were randomly assigned to two subgroups to receive either a sham-operation or bilateral-orchiectomy (ORX). Rats were evaluated for metabolic parameters and cognition at 4, 8, and 12 weeks after the operation. At the end of protocol, the reactive oxygen species (ROS), glial morphology, and cell apoptosis were determined in hippocampus and cortex. RESULTS: Both HFD-fed groups developed obese-insulin resistance, but ND-fed rats did not. HFD-fed rats with sham-operation showed cognitive decline, when compared to ND-fed rats with sham-operation at all time points. At 4- and 8-week after ORX, the cognitive impairment of ND-fed rats and both HFD-fed groups was not different. However, 12-week after ORX, cognitive decline and of glial hyperactivity of HFD-fed rats had the greatest increase among all groups. Hippocampal ROS levels and apoptotic cells in both HFD-fed groups were equally increased, but the cortical ROS levels and apoptotic cells of HFD-fed rats with ORX were the highest ones. CONCLUSIONS: These findings suggest that testosterone deprivation aggravates cognitive decline in obesity via increasing oxidative stress, glial activity and apoptosis.