Protective Effect And Mechanism Of IGF-1 On Obesity-related Cognitive Impairment

Objective:In the last forty years,obesity has gradually become a major public health problem that endangers public health in China.Obesity is known to be a risk factor for a variety of chronic geriatric diseases,including dementia and cognitive impairment.Further studies reveal that obesity promotes neuroinflammation,oxidative stress,mitochondrial dysfunction,apoptosis and other processes in human and experimental animal brain tissues.Then,these abnormalities interfere with neuronal function and induce to neuronal death,and eventually cause cognitive impairment.In response to these mechanisms,the researchers tried to treat obesity-related cognitive impairments using natural plants,chemical reagents,or physical exercise,and achieved some results.However,in general,there is still a lack of understanding of the pathogenesis and treatment of the disease,and more studies have to be done.Insulin-like growth factor 1(IGF-1)is a polypeptide substance widely distributed in human tissues and organs.Its structure is similar to insulin,and exerts a variety of biological functions,such as promote growth and blood sugar regulation.Previous epidemiological and animal studies have found a significant association between the plasma IGF-1 concentration and the incidence of a variety of cognitive diseases.Further studies also found that exogenous IGF-1 intervention and endogenous IGF-1 expression had significant neuroprotective effects on cognitive impairment.However,the role of this factor in obesity-related cognitive impairment is still unknown.At present,we tried to explore the relationship between plasma IGF-1concentration and obesity-related cognitive impairment in a case-control study,and then to reveal the neuroprotective effect and its mechanism of exogenous IGF-1 on high-fat diet(obesity)rats.Method:The first section is a case-control study for elderly hospitalized patients.Wecollected 120 patients with mild cognitive impairment(MCI)and 120 cognitively normal patients,and separately served as MCI group and control group.Multivariate logistic regression analysis was used to evaluate whether baseline obesity(or overweight)was associated with the onset of MCI.Then,we collected the fasting blood of the subjects in the two groups,measured the IGF-1 concentration by ELISA method,adopted multivariate logistic regression analysis to evaluate the relationship between plasma IGF-1 concentration and MCI occurrence and used Pearson linear regression analysis to evaluate the relationship between plasma IGF-1 concentration and MCI severity.The second section is an animal experiment.The experimental rats were received a long-term and regular high-fat diet to induce obesity and metabolic disorders,and some rats were subjected to exogenous IGF-1 intervention.The protective effect of exogenous IGF-1 on cognitive impairment and anxiety behavior caused by high-fat diet in the rats was evaluated by Morris water maze and open field test.Activities of superoxide dismutase,reactive oxygen and propylene dialdehyde in the hippocampus tissues were measured to evaluate the protective effect of IGF-1 on oxidative stress caused by high-fat diet.Levels of tumor necrosis factor-?,interleukin-1?,interleukin-4 and interleukin-10 in hippocampus tissues were measured to evaluate the protective effect of IGF-1 on inflammation caused by high-fat diet.Levels of mitochondrial respiratory control rate,triphosphate adenosine and mitochondrial membrane potential were measured to evaluate the protective effect of IGF-1 on mitochondrial dysfunction caused by high-fat diet.Expression of mitochondrial dynamics proteins Drp1,Mfn1 and Mfn2 in hippocampus tissues were measured to evaluate the protective effect of IGF-1 on mitochondrial dynamics abnormalities caused by high-fat diet.The third section is also an animal experiment.The rats were received a long-term and regular high-fat diet to induce obesity and metabolic disorders,and some rats were subjected to exogenous IGF-1,PI3 K inhibitor LY294002 or CREB inhibitor 666-15.Morris water maze and open field test were adopted to reveal whether the protective effect of exogenous IGF-1 on cognitive impairment and anxiety behavior was related to the activation of PI3 K and CREB.The expressions ofPI3 K,Akt and CREB proteins in hippocampus tissue were measured with Western blotting to determine the existence of PI3K/Akt/CREB signaling pathway.The indicators about oxidative stress,inflammation,mitochondrial function and dynamics mentioned above were further determined to evaluate whether exogenous IGF-1improved these abnormalities by activating the PI3K/Akt/CREB signaling pathway.Results:The results in the first section showed that:(1)obesity(or overweight)at baseline was related to the occurrence of MCI;(2)the concentration of plasma IGF-1was significantly lower in the obese(or overweight)patients;(3)the low plasma IGF-1 concentration was associated with the occurrence of MCI and the relationship was not affected by obesity;and(4)the low concentration of plasma IGF-1 was related to the severity of MCI.The results in the second section showed that:(1)long-term and regular high-fat diet caused significant cognitive impairment and increased anxiety behavior in the experimental rats,(2)it also causes mitochondrial dysfunction,mitochondrial dynamics abnormalities,oxidative stress and inflammation in hippocampus tissue;(3)the protective effect of exogenous IGF-1 showed a dose-effect relationship.The results in the third section showed that:(1)the results of the third part show that:(1)PI3K/Akt/CERB signaling pathway did exist in hippocampus tissue;(2)long-term and regular high-fat diet inhibited the PI3K/Akt/CERB pathway,and exogenous IGF-1 can re-activate the signal pathway;(3)exogenous IGF-1 improved cognitive dysfunction,anxiety behavior,mitochondrial function and dynamics abnormalities,oxidative stress and inflammation response through the activation of the PI3K/Akt/CERB signaling pathway.Conclusion:In the epidemiological study,low plasma IGF-1 concentration was related to the occurrence and severity of obesity-related cognitive impairment.In the animal experiment,exogenous IGF-1 relieved mitochondrial function and dynamics,inhibited inflammation and oxidative stress response,and ultimately improvedcognitive function and anxiety behavior through activation of the PI3K/Akt/CREB signaling pathway.