Hippocampal Insulin Resistance Research Articles

Hindlimb immobilization induces insulin resistance and elevates mitochondrial ROS production in the hippocampus of female rats.

Alzheimer's Disease (AD) is the 5th leading cause of death in older adults and treatment options are severely lacking. Recent findings demonstrate a strong relationship between skeletal muscle and cognitive function, with evidence supporting that muscle quality and cognitive function are positively correlated in older adults. Conversely, decreased muscle function is associated with a 3-fold increased risk of cognitive decline. Based on these observations, the purpose of this study was to investigate the negative effects of muscle disuse (via a model of hindlimb immobilization (HLI)) on hippocampal insulin sensitivity and mitochondrial function and identify the potential mechanisms involved. HLI for 10 days in 4-month-old female Wistar rats resulted in the following novel findings: 1) hippocampal insulin resistance and deficits in whole body glucose homeostasis, 2) dramatically increased mitochondrial reactive oxygen species (ROS) production in the hippocampus, 3) elevated markers for amyloidogenic cleavage of APP and tau protein in the hippocampus, 4) and reduced BDNF expression. These findings were associated with global changes in iron homeostasis, with muscle disuse producing muscle iron accumulation in association with decreased serum and whole brain iron levels. We report the novel finding that muscle disuse alters brain iron homeostasis and reveal a strong negative correlation between muscle and brain iron content. Overall, HLI-induced muscle disuse has robust negative effects on hippocampal insulin sensitivity and ROS production in association with altered brain iron homeostasis. This work provides potential novel mechanisms that may help explain how loss of muscle function contributes to cognitive decline and AD risk.

The Role of Piromelatine on Peripheral and Hippocampal Insulin Resistance in Rat Offspring Exposed to Chronic Maternal Stress.

Prenatal stress (PNS), which alters the hypothalamic-pituitary-adrenal axis function in the offspring, predisposes to insulin resistance (IR) in later life and is associated with numerous disorders, including cognitive and memory impairments. At present, our main goal is to assess the effects of chronic piromelatine (Pir) administration, a melatonin analogue, on PNS-provoked IR in the periphery and the hippocampus in male and female offspring. Pregnant Sprague-Dawley rats were exposed to chronic stress (one short-term stressor on a daily basis and one long-term stressor on a nightly basis) from the first gestation week until birth. Vehicle or Pir 20 mg/kg were administered intraperitoneally for 21 days. Plasma glucose, serum insulin levels, and the homeostasis model assessment of insulin resistance (HOMA-IR) were determined as markers of peripheral IR. For the hippocampal IR assessment, insulin receptors (IRs) and glucose transporter 4 (GLUT4) were examined. Prenatally stressed offspring of both sexes indicated enhanced plasma glucose and serum insulin concentrations, increased HOMA-IR, and decreased hippocampal GLUT4 only in male rats. The PNS-induced changes were corrected by chronic treatment with Pir. The present results suggest that the melatoninergic compound Pir exerts beneficial effects on altered glucose/insulin homeostasis in PNS-exposed offspring.

Probucol mitigates high-fat diet-induced cognitive and social impairments by regulating brain redox and insulin resistance.

Probucol has been utilized as a cholesterol-lowering drug with antioxidative properties. However, the impact and fundamental mechanisms of probucol in obesity-related cognitive decline are unclear. In this study, male C57BL/6J mice were allocated to a normal chow diet (NCD) group or a high-fat diet (HFD) group, followed by administration of probucol to half of the mice on the HFD regimen. Subsequently, the mice were subjected to a series of behavioral assessments, alongside the measurement of metabolic and redox parameters. Notably, probucol treatment effectively alleviates cognitive and social impairments induced by HFD in mice, while exhibiting no discernible influence on mood-related behaviors. Notably, the beneficial effects of probucol arise independently of rectifying obesity or restoring systemic glucose and lipid homeostasis, as evidenced by the lack of changes in body weight, serum cholesterol levels, blood glucose, hyperinsulinemia, systemic insulin resistance, and oxidative stress. Instead, probucol could regulate the levels of nitric oxide and superoxide-generating proteins, and it could specifically alleviate HFD-induced hippocampal insulin resistance. These findings shed light on the potential role of probucol in modulating obesity-related cognitive decline and urge reevaluation of the underlying mechanisms by which probucol exerts its beneficial effects.

Abelmoschus esculentus Improves Hippocampal Function Associated with Dipeptidyl Peptidase‐4 in High Fat Diet‐Fed db/db Mice

Hippocampal function can be impaired by diabetes mellitus (DM) and obesity. Abelmoschus esculentus (AE) fractions reportedly mitigate the symptoms of Alzheimer’s disease (AD) by downregulating dipeptidyl peptidase‐4 (DPP‐4)‐mediated insulin resistance. AE extracted by alcohol (fraction 1, F1) and water (fraction 2, F2) contained quercetin glycosides and polysaccharides, respectively. In this study, we investigated whether AE affects hippocampal function in in vitro and in vivo systems. Our results indicate that F1 or F2 enhanced neurogenesis and synapse formation in palmitate‐treated hippocampal neural cells, presumably by downregulating DPP‐4. In db/db mice fed with high fat diet, the hippocampal insulin resistance correlated spatial recognition, with fraction F2 improving hippocampal function. Of note, the alteration of neurogenesis seems interconnecting with changes in gut microbiota. In summary, AE can improve hippocampal function, attenuate insulin resistance, and promote neurogenesis by regulating DPP‐4. AE, particularly F2, has the potential to serve as an adjuvant in preventing DM‐associated AD.

Simulated weightlessness induces hippocampal insulin resistance and cognitive impairment

Growing evidence highlights the potential consequences of long-term spaceflight, including gray matter volume reduction and cognitive dysfunction with subclinical manifestations of diabetes mellitus among astronauts, but the underlying mechanisms remain unknown. In this study, we found that long-term simulated weightlessness induced hippocampal insulin resistance and subsequent neuronal damage and cognitive impairment in rats. Rats subjected to 4-week tail suspension exhibited peripheral insulin resistance, evidenced by increased fasting blood glucose and abnormal glucose tolerance and insulin tolerance, alongside reduced spontaneous activity and impaired recognition memory. In addition, 4 weeks of simulated weightlessness induced neuronal apoptosis and degeneration in the hippocampus, as evidenced by increased TUNEL and Fluoro-Jade B staining-positive neurons. Mechanistically, insulin-stimulated hippocampal Akt phosphorylation was decreased, while PTEN, the negative regulator of insulin signaling, was increased in the hippocampus in tail-suspended rats. Interestingly, treatment with berberine, an insulin sensitizer, partly reversed the above-mentioned effects induced by simulated weightlessness. These data suggest that long-term simulated weightlessness induces cognitive impairment as well as neuronal apoptosis and neural degeneration, partially through hippocampal insulin resistance via PTEN up-regulation. Berberine treatment attenuates hippocampal insulin resistance and improves cognitive function.

Abelmoschus esculentus (Okra) Prevents Insulin Resistance and Restores Neuron Autophagy by Regulating Dipeptidyl Peptidase-4 and Thus Improving Hippocampal Function.

Diabetes is highly linked to the occurrence of Alzheimer disease (AD), which is characterized by beta amyloid peptide (Aβ) and hyperphosphorylation of tau (p-tau), and neuron damage particularly in hippocampus. Type 2 diabetes (T2D) is featured by insulin resistance, and phosphorylation of Ser307-IRS-1 is regarded as a resistance marker. Inhibitors of dipeptidyl peptidase-4 (DPP-4) are effective tools for treating T2D. Previously, we reported subfractions of Abelmoschus esculentus (AE, okra) (F1 rich in quercetin glycosides; F2 composed of polysaccharide) attenuated DPP-4 and its downstream signals of insulin resistance, thus preventing Aβ-induced neuron damage. Since autophagy could be protective, we now explore if AE works to modulate neuron autophagy by regulating DPP-4 and insulin resistance and, thus, improves the hippocampal function and behavior. We demonstrated that AE subfractions attenuate Aβ-induced insulin resistance and the expression of p-tau and normalize the autophagy and survival of hippocampal neurons. The action of AE may be attributed to the downregulation of DPP-4, which plays a critical role in mediating insulin resistance and hinders neuron autophagy. The in vivo findings reveal that the hippocampal insulin resistance appears to link with loss of memory, reduction of curiosity, and depression, whereas treatment with AE significantly improves the insulin sensitivity and hippocampal function. Noteworthy, even at only 5 μg/mL, F2 seems to exhibit a meaningful effect. In conclusion, we suggest that AE attenuates insulin resistance and recovers neuron autophagy which are regulated by DPP-4, thus preventing the damage to the hippocampus, improving recognition and emotion. AE may be an effective adjuvant or supplement to prevent insulin resistance-associated pathogenesis of AD if these results can be confirmed in human clinical trials.

Rosa canina L. improves learning and memory-associated cognitive impairment by regulating glucose levels and reducing hippocampal insulin resistance in high-fat diet/streptozotocin-induced diabetic rats

Ethnopharmacological relevanceRecent studies claim that Type-2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) overlap in several common pathological pathways which from neuronal damage to impaired memory performance. It is known that the use of Rosa canina L. (R. canina) as medicine in folk medicine dates back to ancient times and is used in the treatment of nervous diseases in Persian medicine. However, the effect of R. canina on diabetes-related cognitive decline and memory impairment has not yet been studied. Aim of the studyWe evaluated the impact of T2DM on AD-like alterations and examined the molecular mechanism of a possible effect of R. canina on cognitive alterations in diabetic rats. Materials&methodsR. canina ethanol extract was obtained by maceration method. This study was performed with male Sprague-Dawley rats fed with a high-fat diet (HFD) for 8 weeks, low-dose streptozotocin (STZ; 35 mg/kg IP) injection for 4 weeks, and R. canina (250 mg/kg; per oral) and metformin (400 mg/kg; per oral) administration for 4 weeks. The weight and blood glucose of rats were measured weekly. To evaluate glucose tolerance area under the curve (AUC) was calculated by performing an oral glucose tolerance test. Then the rats were subjected to behavioural tests, and their hippocampus and cortex tissues were obtained for biochemical and morphological analyses. ResultsR. canina could manage glucose responsiveness by reducing post-prandial blood glucose levels, preventing weight loss, and raising serum insulin levels in T2DM-induced rats. Behavioural tests showed that R. canina significantly improves diabetes-related cognitive decline in recall and long-term memory. Treatment with R. canina significantly reversed HFD/STZ-induced increases in insulin, amyloid-β, amyloid precursor protein levels, and acetylcholinesterase activity in the prefrontal cortex and hippocampus. Furthermore, histological analyzes revealed the protection of R. canina against neuronal disruption in the cortical and hippocampal CA3 region caused by chronic hyperglycemia. ConclusionAnalyzed collectively, these results suggest that R. canina can correct T2DM-related cognitive decline may be attributed to insulin pathway modulation, prevention of amyloid deposition, and increased cholinergic transmission.

Neuroprotective Role of DPP-4 Inhibitor Linagliptin Against Neurodegeneration, Neuronal Insulin Resistance and Neuroinflammation Induced by Intracerebroventricular Streptozotocin in Rat Model of Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related, multifactorial progressive neurodegenerative disorder manifested by cognitive impairment and neuronal death in the brain areas like hippocampus, yet the precise neuropathology of AD is still unclear. Continuous failure of various clinical trial studies demands the utmost need to explore more therapeutic targets against AD. Type 2 Diabetes Mellitus and neuronal insulin resistance due to serine phosphorylation of Insulin Receptor Substrate-1 at 307 exhibits correlation with AD. Dipeptidyl Peptidase-4 inhibitors (DPP-4i) have also indicated therapeutic effects in AD by increasing the level of Glucagon-like peptide-1 in the brain after crossing Blood Brain Barrier. The present study is hypothesized to examine Linagliptin, a DPP-4i in intracerebroventricular streptozotocin induced neurodegeneration, and neuroinflammation and hippocampal insulin resistance in rat model of AD. Following infusion on 1st and 3rd day, animals were treated orally with Linagliptin (0.513mg/kg, 3mg/kg, and 5mg/kg) and donepezil (5mg/kg) as a standard for 8weeks. Neurobehavioral, biochemical and histopathological analysis was done at the end of treatment. Dose-dependently Linagliptin significantly reversed behavioral alterations done through locomotor activity (LA) and morris water maze (MWM) test. Moreover, Linagliptin augmented hippocampal GLP-1 and Akt-ser473 level and mitigated soluble Aβ (1-42), IRS-1 (s307), GSK-3β, TNF-α, IL-1β, IL-6, AchE and oxidative/nitrosative stress level. Histopathological analysis also exhibited neuroprotective and anti-amylodogenic effect in Hematoxylin and eosin and Congo red staining respectively. The findings of our study concludes remarkable dose-dependent therapeutic potential of Linagliptin against neuronal insulin resistance via IRS-1 and AD-related complication. Thus, demonstrates unique molecular mechanism that underlie AD.

The Role of Insulin Signaling in Hippocampal-Related Diseases: A Focus on Alzheimer's Disease.

Alzheimer's disease (AD) is a global concern and has become a major public health event affecting human health. Insulin is a metabolic hormone secreted mainly by the peripheral tissue pancreas. In recent years, more and more evidence has proved that insulin regulates various functions of the brain. The hippocampus, one of the earliest brain regions affected by AD, is widely distributed with insulin receptors. Studies have shown that type 2 diabetes mellitus, characterized by insulin resistance, is closely related to AD, which has drawn extensive attention to the relationship between hippocampal insulin signaling and AD. Therefore, we provide an overview of intranasal insulin administration on memory and its underlying mechanism. We also highlight the molecular link between hippocampal insulin resistance and AD and provide a theoretical basis for finding new therapeutic targets for AD in clinical practice.

Prenatal Stress-induced Spatial Memory Deficit in a Sex-specific Manner in Mice: A Possible Involvement of Hippocampal Insulin Resistance.

In the present study, the effects of prenatal stress on spatial learning and memory deficit and its relationship with hippocampal insulin resistance were examined in male and female offspring. Female NMRI mice were mated with males overnight, and the 0-day of pregnancy was detected (Gestational day 0-GD0). The pregnant mice were then randomly divided into stress and control groups. The stress group received stress from the GD0 to GD10. On post natal day 30 (PND30), the offspring were divided into 4 subgroups, namely: male-control, female-control, male-stress, and female-stress. Barnes maze method was used for spatial learning evaluation. Plasma cortisol and insulin levels were measured at the beginning of the experiments. At the end of the experiments, the animals' brains were removed, and their hippocampus was extracted. The hippocampus was homogenized, and its insulin and insulin-receptor contents were evaluated. The stressed animals needed more time for reaching to target hole. In addition, they spend more distance to find the target hole, which was more pronounced in the male offspring. Both plasma and hippocampal insulin content were reduced in the stressed groups. Moreover, the hippocampal insulin receptors protein was reduced in the stressed animals. There was a positive relationship between plasma and hippocampal content and memory deficit in the stressed groups. These results indicated that prenatal stress could induce spatial learning and memory deficit in offspring, which is associated with plasma and hippocampal insulin and receptor content reduction (hippocampal insulin resistance) in these animals. Maternal stress is very harmful for fetus.The effect of stress is significant during the early days of gestation.This effect is due to several hormonal and neuronal disturbances including Insulin resistance.The effects of stress on the fetus is gender dependent. The possible effectiveness of prenatal stress on learning and memory in neonates and also the changes in hippocampus as of essential part of the brain involved in learning and memory. We found that prenatal stress can reduce the insulin effects in hippocampus and it may be the main cause of stress on neonatal memory deficits.

Docosahexaenoic acid enhances hippocampal insulin sensitivity to promote cognitive function of aged rats on a high-fat diet

IntroductionDiminished brain insulin sensitivity is associated with reduced cognitive function. Docosahexaenoic acid (DHA) is known to maintain normal brain function. ObjectivesThis study aimed to determine whether DHA impacts hippocampal insulin sensitivity and cognitive function in aged rats fed a high-fat diet (HFD). MethodsEight-month-old female Sprague-Dawley rats were randomly divided into three groups (n = 50 each). Rats in the aged group, HFD group, and DHA treatment group received standard diet (10 kcal% fat), HFD (45 kcal% fat), and DHA-enriched HFD (45 kcal% fat, 1% DHA, W/W) for 10 months, respectively. Four-month-old female rats (n = 40) that received a standard diet served as young controls. Neuroinflammation, oxidative stress, amyloid formation, and tau phosphorylation in the hippocampus, as well as systemic glucose homeostasis and cognitive function, were tested. ResultsDHA treatment relieved a block in the insulin signaling pathway and consequently protected aged rats against HFD-induced hippocampal insulin resistance. The beneficial effects were explained by a DHA-induced decrease in systemic glucose homeostasis dysregulation, hippocampal neuroinflammation and oxidative stress. In addition, DHA treatment broke the reciprocal cycle of hippocampal insulin resistance, Aβ burden, and tau hyperphosphorylation. Importantly, treatment of model rats with DHA significantly increased their cognitive capacity, as evidenced by their increased hippocampal-dependent learning and memory, restored neuron morphology, enhanced cholinergic activity, and activated cyclic AMP-response element-binding protein. ConclusionDHA improves cognitive function by enhancing hippocampal insulin sensitivity.

The Effect of Dietary Fat and Sucrose on Cognitive Functioning in Mice Lacking Insulin Signaling in Neuropeptide Y Neurons.

Obesogenic diets can produce hippocampal insulin resistance and impairments to hippocampal-dependent cognition. This study investigated the effect of disrupted insulin signaling in Neuropeptide Y (NPY) neurons on diet-induced deficits in hippocampal-dependent memory. Wild-type mice and mice that had a targeted knockout of insulin receptors on NPY cells (IRlox/lox;NPYCre/+) were given ad libitum access to a high-fat diet (high fat; HF), 10% sucrose solution (high sugar; HS), both high-fat diet and sucrose solution (high fat, high sugar; HFHS), or a normal fat control chow for 12 weeks. Mice were tested in the Morris Water Maze (MWM), a hippocampal-dependent spatial memory task. Glucose homeostasis was assessed via a glucose tolerance test. Independent of genotype, consumption of HF, but not HS, diet increased energy intake, body weight, and plasma leptin, and impaired glucose tolerance. Disrupted insulin signaling in NPY cells and dietary interventions did not significantly affect the ability of mice to learn the location of the platform in the MWM. However, for IRlox/lox control mice, consumption of HF, but not HS, diet resulted in reduced time spent in the target quadrant during the probe trial, suggesting a hippocampal-dependent memory deficit. IRlox/lox;NPYCre/+ mice had poor performance in the probe trial regardless of diet, suggesting a floor effect. This study did not find adverse effects of chronic sucrose intake on metabolic outcomes or hippocampal-dependent memory. These data also suggest that the effects of HF diet on hippocampal-dependent memory may be dependent on insulin signaling in hippocampal NPY cells.

Amelioration of Hippocampal Insulin Resistance Reduces Tau Hyperphosphorylation and Cognitive Decline Induced by Isoflurane in Mice.

General anesthetics can induce cognitive impairments and increase the risk of Alzheimer’s disease (AD). However, the underlying mechanisms are still unknown. Our previous studies shown that long-term isoflurane exposure induced peripheral and central insulin resistance (IR) in adult mice and aggravated IR in type 2 diabetes mellitus (T2DM) mice. Clinical and preclinical studies revealed an association between impaired insulin signaling and tau pathology in AD and other tauopathies. We investigated if alleviation of hippocampal IR by the antidiabetic agent metformin could reduce tau hyperphosphorylation and cognitive decline induced by isoflurane in mice. The effects of prolonged (6 h) isoflurane anesthesia on hippocampal IR, hippocampal tau hyperphosphorylation, and hippocampus-dependent cognitive function were evaluated in wild type (WT) adult mice and the high-fat diet plus streptozotocin (HFD/STZ) mouse model of T2DM. Here we shown that isoflurane and HFD/STZ dramatically and synergistically induced hippocampal IR and fear memory impairment. Metformin pretreatment strongly ameliorated hippocampal IR and cognitive dysfunction caused by isoflurane in WT mice, but was less effective in T2DM mice. Isoflurane also induced hippocampal tau hyperphosphorylation and metformin reversed this effect. In addition, isoflurane significantly increased blood glucose levels in both adult and T2DM mice, and metformin reversed this effect as well. Administration of 25% glucose to metformin-pretreated mice induced hyperglycemia, but surprisingly did not reverse the benefits of metformin on hippocampal insulin signaling and fear memory following isoflurane anesthesia. Our findings show hippocampal IR and tau hyperphosphorylation contribute to acute isoflurane-induced cognitive dysfunction. Brief metformin treatment can mitigate these effects through a mechanism independent of glycemic control. Future studies are needed to investigate whether long-term metformin treatment can also prevent T2DM-induced hippocampal IR and cognitive decline.

Hippocampal-specific insulin resistance elicits behavioral despair and hippocampal dendritic atrophy

Insulin resistance is a major contributor to the neuroplasticity deficits observed in patients with metabolic disorders. However, the relative contribution of peripheral versus central insulin resistance in the development of neuroplasticity deficits remains equivocal. To distinguish between peripheral and central insulin resistance, we developed a lentiviral vector containing an antisense sequence selective for the insulin receptor (LV-IRAS). We previously demonstrated that intra-hippocampal injection of this vector impairs synaptic transmission and hippocampal-dependent learning and memory in the absence of peripheral insulin resistance. In view of the increased risk for the development of neuropsychiatric disorders in patients with insulin resistance, the current study examined depressive and anxiety-like behaviors, as well as hippocampal structural plasticity in rats with hippocampal-specific insulin resistance. Following hippocampal administration of either the LV-control virus or the LV-IRAS, anhedonia was evaluated by the sucrose preference test, despair behavior was assessed in the forced swim test, and anxiety-like behaviors were determined in the elevated plus maze. Hippocampal neuron morphology was studied by Golgi-Cox staining. Rats with hippocampal insulin resistance exhibited anxiety-like behaviors and behavioral despair without differences in anhedonia, suggesting that some but not all components of depressive-like behaviors were affected. Morphologically, hippocampal-specific insulin resistance elicited atrophy of the basal dendrites of CA3 pyramidal neurons and dentate gyrus granule neurons, and also reduced the expression of immature dentate gyrus granule neurons. In conclusion, hippocampal-specific insulin resistance elicits structural deficits that are accompanied by behavioral despair and anxiety-like behaviors, identifying hippocampal insulin resistance as a key factor in depressive illness.

Supplementation of milk polar lipids to obese dams improves neurodevelopment and cognitive function in male offspring.

Milk contains about 4% fat globules with its surface covered by polar lipids. Despite the abundant consumption of dairy products, the biological effects of dietary milk polar lipids on metabolic health have only been sparsely examined. Maternal obesity results in neurodevelopmental disorders and cognitive impairment in offspring. Considering the importance of maternal nutrition, the effects of polar lipids-enriched milk fat globule membrane (MFGM-PL) supplementation to dams during pregnancy and lactation on neurodevelopment and its long-term programming effects on offspring cognition were examined. Female Sprague-Dawley rats consumed 8-week control diet (CON) or high-fat diet (HFD) to induce obesity before mating. Then, female rats were fed CON or HFD with or without the supplementation of 400mg/kg body weight MFGM-PL during pregnancy and lactation. The offspring were fed 11-week HFD after weaning. MFGM-PL supplementation to obese dams suppressed body weight gain and hyperinsulinemia in both dams and offspring. Offspring born to obese dams displayed delayed neurological reflexes development, impaired neurogenesis before weaning, and cognitive impairment in adulthood, which were recovered by maternal MFGM-PL supplementation. Insulin resistance and aberrant brain-derived neurotrophic factor signaling were induced in the hippocampus of neonatal and adult offspring due to maternal and progeny HFD, but recovered by maternal MFGM-PL administration. This study demonstrates that maternal MFGM-PL supplementation can promote neurodevelopment and exert long-term effects against HFD-induced cognitive impairment in offspring via alleviating hippocampal insulin resistance. Hence, MFGM-PL is a promising ingredient for exerting beneficial programming effects on the brain health of offspring.

Hippocampal insulin resistance and the Sirtuin 1 signaling pathway in diabetes-induced cognitive dysfunction.

In the peripheral nervous system, the activation of Sirtuin 1 can improve insulin resistance; however, the role played by Sirtuin 1 in the central nervous system remains unknown. In this study, rat models of diabetes mellitus were generated by a single injection of streptozotocin. At 8 weeks after streptozotocin injection, the Morris water maze test and western blot assays confirmed that the diabetic model rats had learning and memory deficits, insulin resistance, and Sirtuin 1 expression could be detected in the hippocampus. Insulin and the insulin receptor inhibitor S961 were intranasally administered to investigate the regulatory effects of insulin signaling on Sirtuin 1. The results showed that insulin administration improved the impaired cognitive function of diabetic model rats and increased the expression levels of phosphorylated insulin receptor, phosphorylated insulin receptor substrate 1, and Sirtuin 1 in the hippocampus. Conversely, S961 administration resulted in more severe cognitive dysfunction and reduced the expression levels of phosphorylated insulin receptor, phosphorylated insulin receptor substrate 1, and Sirtuin 1. The Sirtuin 1 activator SRT2104 and the inhibitor Sirtinol were injected into the lateral ventricle, which revealed that the activation of Sirtuin 1 increased the expression levels of target of rapamycin complex 1, phosphorylated cAMP-response element-binding protein, and brain-derived neurotrophic factor. Hippocampal dendritic length and spine density also increased in response to Sirtuin 1 activation. In contrast, Sirtinol decreased the expression levels of target of rapamycin complex 1, phosphorylated cAMP-response element-binding protein, and brain-derived neurotrophic factor and damaged the dendritic structure. These findings suggest that the Sirtuin 1 signaling pathway plays an important role in the development of insulin resistance-related cognitive deficits in diabetic rats. This study was approved by the Animal Ethics Welfare Committee of the First Affiliated Hospital of Hunan University of Chinese Medicine (approval No. ZYFY201811207) in November 2018.

Alogliptin reversed hippocampal insulin resistance in an amyloid-beta fibrils induced animal model of Alzheimer's disease

The complications of Alzheimer's disease (AD) have made the development of its treatment a challenging task. Several studies have indicated the disruption of insulin receptor substrate-1 (IRS-1) signaling during the development and progression of AD. The role of a dipeptidyl peptidase-4 (DPP-4) inhibitor on hippocampal IRS-1 signaling has not been investigated before. In this study, we evaluated the efficacy of alogliptin (DPP-4 inhibitor) on hippocampal insulin resistance and associated AD complications. In the present study, amyloid-β (1–42) fibrils were produced and administered intrahippocampally for inducing AD in Wistar rats. After 7 days of surgery, rats were treated with 10 and 20 mg/kg of alogliptin for 28 days. Morris water maze (MWM) test was performed in the last week of our experimental study. Post 24 h of final treatment, rats were euthanized and hippocampi were separated for biochemical and histopathological investigations. In-silico analysis revealed that alogliptin has a good binding affinity with Aβ and beta-secretase-1 (BACE-1). Alogliptin significantly restored cognitive functions in Aβ (1–42) fibrils injected rats during the MWM test. Alogliptin also significantly attenuated insulin level, IRS-1pS307 expression, Aβ (1–42) level, GSK-3β activity, TNF-α level and oxidative stress in the hippocampus. The histopathological analysis supported alogliptin mediated neuroprotective and anti-amyloidogenic effect. Immunohistochemical analysis also revealed a reduction in IRS-1pS307 expression after alogliptin treatment. The in-silico, behavioral, biochemical and histopathological analysis supports the protective effect of alogliptin against hippocampal insulin resistance and AD.

Aerobic Exercise Counteracts Mitochondrial Dysfunction In The Insulin Resistant Brain

Insulin resistance (IR) increases the risk for Alzheimer’s disease and other dementias; however, the underpinning mechanisms for this increased risk remain to be fully defined. Impaired mitochondrial function is one component contributing to cognitive impairment. PURPOSE: As insulin resistance impairs mitochondrial oxidative metabolism and increases reactive oxygen species (ROS) in skeletal muscle, we considered whether similar events occur in the brain, which like muscle is rich in insulin receptors and mitochondria. Further, we sought to determine whether aerobic exercise (AE) could prevent the hypothesized deficits in mitochondrial function accompanying diet-induced IR. METHODS: 12-week-old, male, C57BL6 mice were fed a standard (Chow) or high fat diet (HFD) (60% kcal from fat) for four-weeks and provided access to running wheels (EX) or sedentary (SED) conditions (n = 9-10 per group). Following treatment, mitochondria were freshly isolated from the cerebrum to assess mitochondrial respiration, ROS production, and ATP production. Insulin resistance was determined ex-vivo in the hippocampus by the ability of insulin to stimulate AKT-phosphorylation. mtDNA copy number, mRNA expression, and proteomic measurements were performed on isolated hippocampal tissue. RESULTS: HFD induced hippocampal insulin resistance (p < 0.001), which was corrected by AE. HFD decreased ATP production 12% (p = 0.01) and increased ROS emission 79% (p < 0.01) in isolated cerebral mitochondria, which were rescued with AE. Impairments in mitochondrial function with HFD were paralleled by reductions in mtDNA copy number (1.00 ± 0.06 vs 0.85 ± 0.06; p = 0.02) and mRNA expression of mitochondrial genes, such as PGC1a1 (1.00 ± 0.05 vs 0.78 ± 0.07; p = 0.03) and TFAM (1.00 ± 0.08 vs 0.62 ± 0.11; p = 0.03), which were corrected by AE. Proteomic analysis of the hippocampus showed that HFD led to oxidative post-translational modifications (PTMs) to 17 mitochondrial proteins (corrected p-value ≤ 0.05 and absolute log2 fold change ≥ 0.5); however, this increase in oxidative PTMs to mitochondrial proteins with HFD was almost completely reversed by AE. CONCLUSIONS: HFD induces IR in the cerebrum and hippocampus, which associates with mitochondrial dysfunction. Brain IR and mitochondrial dysfunction accompanying HFD are prevented with AE.

Neuroprotective role of pioglitazone in reversing hippocampal insulin resistance in Amyloid-β fibrils induced animal model of Alzheimer's disease

Neuroprotective role of pioglitazone in reversing hippocampal insulin resistance in Amyloid-β fibrils induced animal model of Alzheimer's disease

289-OR: Aerobic Exercise Counteracts Mitochondrial Dysfunction in the Insulin Resistant Brain

Insulin resistance increases the risk for Alzheimer’s disease and other dementias; however, the underpinning mechanisms for this increased risk remain to be fully defined. Insulin resistance impairs mitochondrial oxidative metabolism and increases reactive oxygen species (ROS) in skeletal muscle, both of which are counteracted by aerobic exercise (AE). Therefore, we considered whether similar events occur in the brain, specifically in regions such as cerebrum and hippocampus which are rich in insulin receptors and mitochondria. We determined whether AE would counteract mitochondrial deficits in hippocampal and cerebral mitochondrial function in high fat diet (HFD) induced insulin resistance. Four weeks of HFD in mice induced hippocampal insulin resistance which was corrected by AE. HFD decreased ATP production and increased ROS emission in isolated cerebral mitochondria, which were rescued with AE. Impairments in mitochondrial function with HFD were paralleled by reductions in mtDNA copy number, mRNA expression of mitochondrial genes, and oxidative enzyme activities (e.g., citrate synthase, COX) in the hippocampus, which were corrected by AE. We also observed excessive mitochondrial fission in the hippocampus following HFD, which was prevented by AE. Proteomic analysis of the hippocampus showed that HFD led to oxidative post-translational modifications (PTMs) of mitochondrial proteins; however, this increase in oxidative PTMs to mitochondrial proteins with HFD was almost completely reversed by AE. Further, intranasal administration of the insulin receptor antagonist S961 prevented AE-induced improvements in ATP production and ROS emission in isolated cerebral mitochondrial during HFD, demonstrating that AE enhances cerebral mitochondrial function during HFD by resensitizing brain insulin signaling. Disclosure G. Ruegsegger: None. P.M. Vanderboom: None. S. Dasari: Consultant; Self; The Binding Site. K. Klaus: None. K. Nair: None.