Abstract
It is widely recognized that obesity and associated metabolic changes are considered a risk factor to age-associated cognitive decline. Inflammation and increased oxidative stress in peripheral areas, following obesity, are patently the major contributory factors to the degree of the severity of brain insulin resistance as well as the progression of cognitive impairment in the obese condition. Numerous studies have demonstrated that the alterations in brain mitochondria, including both functional and morphological changes, occurred following obesity. Several studies also suggested that brain mitochondrial dysfunction may be one of underlying mechanism contributing to brain insulin resistance and cognitive impairment in the obese condition. Thus, this review aimed to comprehensively summarize and discuss the current evidence from various in vitro, in vivo, and clinical studies that are associated with obesity, brain insulin resistance, brain mitochondrial dysfunction, and cognition. Contradictory findings and the mechanistic insights about the roles of obesity, brain insulin resistance, and brain mitochondrial dysfunction on cognition are also presented and discussed. In addition, the potential therapies for obese-insulin resistance are reported as the therapeutic strategies which exert the neuroprotective effects in the obese-insulin resistant condition.
Highlights
Obesity has been of interest in several fields of medical research
Our previous reports demonstrated that peripheral insulin resistance develops before impaired cognition in obese-insulin resistant rat model [4, 6, 28]. All of these findings suggested that [1] The stimulation of insulin receptor plays the important roles in improving brain mitochondrial biogenesis and preserving cognitive function and [2] insulin resistance is associated with mitochondrial dysfunction and the cognitive impairment
In the third and fourth studies, the depletion of mitochondrial DNA resulted in an impaired glucose utilization and induced insulin resistance in the myotubes [55, 56]. All these findings suggest that brain mitochondrial dysfunction under obesity could be the cause of brain insulin resistance
Summary
It has been demonstrated that obesity can lead to the development of several complications, including cardiovascular diseases, diabetes, and neurodegeneration [1, 2] Several reports from both in vivo and clinical studies showed that obesity is associated with the development of cognitive impairment by several proposed mechanisms including the impairment of leptin signaling and the induction of Alzheimer’s-like pathologies which include β-amyloid accumulation and hyperphosphorylation of tau protein [1]. Another pathological condition that commonly occurs following obesity [3] is peripheral insulin resistance. Hyperinsulinemia can disturb the physiological function of several vital organs via the impairment of insulin signaling and the disturbance of intracellular signaling transduction
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