Links Between Obesity-Induced Brain Insulin Resistance, Brain Mitochondrial Dysfunction, and Dementia

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

Combined therapy of iron chelator and antioxidant completely restores brain dysfunction induced by iron toxicity.

BACKGROUND: Excessive iron accumulation leads to iron toxicity in the brain; however the underlying mechanism is unclear. We investigated the effects of iron overload induced by high iron-diet consumption on brain mitochondrial function, brain synaptic plasticity and learning and memory. Iron chelator (deferiprone) and antioxidant (n-acetyl cysteine) effects on iron-overload brains were also studied. METHODOLOGY: Male Wistar rats were fed either normal diet or high iron-diet consumption for 12 weeks, after which rats in each diet group were treated with vehicle or deferiprone (50 mg/kg) or n-acetyl cysteine (100 mg/kg) or both for another 4 weeks. High iron-diet consumption caused brain iron accumulation, brain mitochondrial dysfunction, impaired brain synaptic plasticity and cognition, blood-brain-barrier breakdown, and brain apoptosis. Although both iron chelator and antioxidant attenuated these deleterious effects, combined therapy provided more robust results. CONCLUSION: In conclusion, this is the first study demonstrating that combined iron chelator and anti-oxidant therapy completely restored brain function impaired by iron overload

Effects of the pharmacological interventions by deferiprone and n-acetyl cysteine on brain synaptic plasticity.

<p>Each panel represented brain synaptic plasticity in NDV vs. HFeV (A), ND groups (B) and HFe groups (C). ND: normal diet fed group; HFe: high iron diet fed group; L1: deferiprone; NAC: n-acetyl cysteine.</p

Effects of the pharmacological interventions by deferiprone and n-acetyl cysteine on BBB breakdown and apoptosis.

<p>Each panel represented the expression of tight junction protein; occludin (A), apoptotic-protein; Bax (B) and anti-apoptotic protein; Bcl-2 (C) and Bax/Bcl-2 ratio (D). *<i>P</i><0.05 vs. Normal diet treated with vehicle (NDV); ^†<i>P</i><0.05 vs. HFe treated with vehicle (HFeV); ^‡<i>P</i><0.05 vs. HFe treated with either L1 or NAC (HFeL1 or HFeNAC). ND: normal diet fed groups; HFe: high-iron diet fed groups; L1: deferiprone; NAC: n-acetyl cysteine.</p

Diagram illustrated the proposed mechanisms.

<p>The diagram showed the proposed mechanisms of brain dysfunctions as well as the pharmacological therapy on brain dysfunctions following iron overload. Dotted arrows indicate the effects of either L1 or NAC treatment, dashed arrows indicate the combined L1 and NAC treatment. L1: deferiprone; NAC: n-acetyl cysteine.</p

Effects of the pharmacological interventions on body weight, plasma NTBI, plasma MDA, brain MDA and brain iron level in high iron diet-fed rats.

<p>p<0.05 vs. Normal diet-fed rats,</p><p>p<0.05 vs. High iron diet-fed rats treated with vehicle,</p><p>p<0.05 vs. High iron diet-fed rats treated with either L1 or NAC. ND; normal diet-fed rats, HFe; high iron diet-fed rats, V; vehicle, L1; deferiprone, NAC; n-acetyl cysteine, NTBI; non-transferrin bound iron, MDA; malondialdehyde.</p

Effects of iron overload on brain mitochondrial function.

<p>Each panel represented brain mitochondrial ROS production (A), brain mitochondrial membrane potential changes (B) and brain mitochondrial swelling (C). *<i>P</i><0.05 vs. Normal diet groups; ^†<i>P</i><0.05 vs. HFe4w. ND: normal diet fed groups; HFe: high-iron diet fed groups.</p

Effects of the pharmacological interventions by deferiprone and n-acetyl cysteine on learning and memory behavior.

<p>Each panel represented locomotors activity (A) and learning and memory behavior indicated by time to reach platform (B, D and F) and time spent in target quadrant (C and E). *<i>P</i><0.05 vs. Normal diet treated with vehicle (NDV); ^†<i>P</i><0.05 vs. HFe treated with vehicle (HFeV); ^‡<i>P</i><0.05 vs. HFe treated with either L1 or NAC (HFeL1 or HFeNAC). ND: normal diet fed groups; HFe: high-iron diet fed groups; L1: deferiprone; NAC: n-acetyl cysteine.</p