High fat diet produces brain insulin resistance, synaptodendritic abnormalities and altered behavior in mice

Abstract

Insulin resistance and other features of the metabolic syndrome are increasingly recognized for their effects on cognitive health. To ascertain mechanisms by which this occurs, we fed mice a very high fat diet (60% kcal by fat) for 17 days or a moderate high fat diet (HFD, 45% kcal by fat) for 8 weeks and examined changes in brain insulin signaling responses, hippocampal synaptodendritic protein expression, and spatial working memory. Compared to normal control diet mice, cerebral cortex tissues of HFD mice were insulin-resistant as evidenced by failed activation of Akt, S6 and GSK3β with ex-vivo insulin stimulation. Importantly, we found that expression of brain IPMK, which is necessary for mTOR/Akt signaling, remained decreased in HFD mice upon activation of AMPK. HFD mouse hippocampus exhibited increased expression of serine-phosphorylated insulin receptor substrate 1 (IRS1-pS616), a marker of insulin resistance, as well as decreased expression of PSD-95, a scaffolding protein enriched in post-synaptic densities, and synaptopodin, an actin-associated protein enriched in spine apparatuses. Spatial working memory was impaired as assessed by decreased spontaneous alternation in a T-maze. These findings indicate that HFD is associated with telencephalic insulin resistance and deleterious effects on synaptic integrity and cognitive behaviors.

Insulin Resistance Prevents AMPK-induced Tau Dephosphorylation through Akt-mediated Increase in AMPKSer-485 Phosphorylation

“…There are reports for both increased (28,29) and decreased (25)(26)(27)50) Tau phosphorylation by AMPK activation; however, none of the studies examined the role of AMPK Ser-485 phosphorylation, and very few examined the connection between IR and AMPK in the brain (49,50). Of note, insulin antagonizes AMPK activation by increased phosphorylation of AMPK Ser-485 (31, 52); therefore, we believe that IR overactivates Akt, resulting in increased AMPK Ser-485 phosphorylation and subsequent inhibition of Tau dephosphorylation.…”

Metabolic Stress Induces Cognitive Disturbances and Inflammation in Aged Mice: Protective Role of Resveratrol

“…5 Feeding mice with a high-fat (HF) diet induced glucose metabolism disturbances with increases in weight and insulin resistance. 6 In APP/PS1 mice, in an extended model of Alzheimer's disease (AD), HF produced cognitive disturbances, jointly with changes in the insulin pathway, an increase in tau kinase activity and tau hyperphosphorylation, and changes in amyloid beta production, demonstrating the role of insulin resistance in AD. 7 Metabolic stress increases cognitive impairment in SAMP8, a murine model of senescence.…”

Insulin resistance: associations of personal characteristics and factors of lifestyle

“…[4][5][6]. Значительное количество работ посвящено взаимосвязи МС и ИР с различными переменными образа жизни, например характером питания [7][8][9], вредными привычками, такими как курение и злоупотребление алкоголем [10,11]. Ин-тересно, что обнаруженные тенденции не являются однородными.…”