Hippocampal insulin resistance links maternal obesity with impaired neuronal plasticity in adult offspring

Schmitz, Lisa; Kuglin, Rebecca; Bae‐Gartz, Inga; Janoschek, Ruth; Appel, Sarah; Mesaros, Andrea; Jakovčevski, Igor; Vohlen, Christina; Handwerk, Marion; Ensenauer, Regina; Dötsch, Jörg; Hucklenbruch‐Rother, Eva

doi:10.1016/j.psyneuen.2017.12.023

Cited by 31 publications

(33 citation statements)

References 21 publications

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“…In addition, a recent study demonstrated that hippocampal insulin resistance, without a change in blood glucose, can result in reduced hippocampal mTOR signalling and altered expression of markers of neurogenesis and synaptic function. Induction of insulin resistance in cultured hippocampal neurons showed similar results [39]. After regulating insulin signaling in the hippocampus, the learning ability and memory of AD mice improved [40].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 61%

Gp91phox (NOX2) in Activated Microglia Exacerbates Neuronal Damage Induced by Oxygen Glucose Deprivation and Hyperglycemia in an in Vitro Model

Zeng¹,

Ren²,

Zhu³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Peri-operative cerebral ischemia reperfusion injury is one of the most serious peri-operative complications that can be aggravated in patients with diabetes. A previous study showed that microglia NOX₂ (a NADPH oxidase enzyme) may play an important role in this process. Here, we investigated whether increased microglial derived gp91^phox, also known as NOX2, reduced oxygen glucose deprivation (OGD) after induction of hyperglycemia (HG). Methods: A rat neuronal-microglial in vitro co-culture model was used to determine the effects of gp91^phox knockdown on OGD after HG using six treatment groups: A rat microglia and neuron co-culture model was established and divided into the following six groups: high glucose + scrambled siRNA transfection (HG, n = 5); HG + gp91^phoxsiRNA transfection (HG-gp91siRNA, n = 5); oxygen glucose deprivation + scrambled siRNA transfection (OGD, n = 5); OGD + gp91^phoxsiRNA transfection (OGD-gp91siRNA, n = 5); HG + OGD + scrambled siRNA transfection (HG-OGD, n = 5); and HG + OGD + gp91^phoxsiRNA transfection (HG-OGD-gp91siRNA, n = 5). The neuronal survival rate was measured by the MTT assay, while western blotting was used to determine gp91^phox expression. Microglial derived ROS and neuronal apoptosis rates were analyzed by flow cytometry. Finally, the secretion of cytokines, including IL-6, IL-8, TNF-α, and 8-iso-PGF2α was determined using an ELISA kit. Results: Neuronal survival rates were significantly decreased by HG and OGD, while knockdown of gp91^phox reversed these rates. ROS production and cytokine secretion were also significantly increased by HG and OGD but were significantly inhibited by knockdown of gp91^phoxsiRNA. Conclusion: Knockdown of gp91^phoxsiRNA significantly reduced oxidative stress and the inflammatory response, and alleviated neuronal damage after HG and OGD treatment in a rat neuronal-microglial co-culture model.

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Section: Cellular Physiology and Biochemistrymentioning

confidence: 61%

Gp91phox (NOX2) in Activated Microglia Exacerbates Neuronal Damage Induced by Oxygen Glucose Deprivation and Hyperglycemia in an in Vitro Model

Zeng¹,

Ren²,

Zhu³

et al. 2018

Cell Physiol Biochem

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“…As mentioned in the previous topics that insulin plays an important role in brain function, several studies demonstrated that neuronal insulin resistance can be found under obese condition ( 4 , 6 , 7 , 9 – 14 , 16 – 19 , 28 , 30 , 31 , 91 – 94 ). Moreover, the excessive free fatty acid (FFA) has been found under an obese condition.…”

Section: Excessive Free Fatty Acid and Neuronal Insulin Resistance ( mentioning

confidence: 88%

“…Supporting evidence shows that obese condition as a result of chronic consumption of a high-fat diet (HFD) or genetic-induced obesity and in obese-T2DM animals indicated the development of peripheral insulin resistance subsequently caused brain insulin resistance and could be associated with cognitive impairment ( 4 , 6 , 7 , 9 – 14 , 16 – 19 , 28 – 31 , 91 – 94 , 113 ). Interestingly, a recent study also showed that maternal obesity can lead to the development of metabolic disturbance, hippocampal insulin resistance, and further altered the distribution of markers of neurogenesis, neuronal synaptic plasticity and function of the offspring ( 94 ). This suggest that maternal obesity might affect the offspring's neurocognitive outcome.…”

Section: Peripheral Insulin Resistance Induced Brain Insulin Resistanmentioning

confidence: 99%

“…Several previous studies demonstrated that chronic HFD consumption induced obese-insulin resistance prior to causing brain insulin resistance, as indicated by decreasing phosphorylation of insulin receptors (IR), insulin receptor substrate (IRS) and downstream signaling, including PI3K-Akt, GSK3β, and AMPK pathways ( 4 , 6 , 7 , 9 – 14 , 16 – 19 , 28 – 31 , 91 – 94 ). Impaired brain insulin signaling in the obese-insulin resistant condition also resulted in a loss of inhibitory function to FoxO transcription factors, which normally modulate cellular metabolism and autophagy ( 115 ).…”

Section: Peripheral Insulin Resistance Induced Brain Insulin Resistanmentioning

confidence: 99%

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

2018

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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.

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“…Second, maternal obesity exposes the fetus to an excessive nutrient supply, which may in turn stimulate fetal hyperinsulinemia (Lecoutre et al, ; Murabayashi et al, ). Fetal hyperinsulinemia has been shown to alter hippocampal development via impaired insulin signaling and reduced neurogenesis in the hippocampus (Schmitz et al, ). Notably, insulin signaling in the hippocampus is important for both neurogenesis and learning and memory (Benedict, ; Hui, Pei, Zhang, Guan, & Zhang, ; Kern et al, ; Park, Seeley, Craft, & Woods, ).…”

Section: Discussionmentioning

confidence: 99%

Sex differences in the association between prenatal exposure to maternal obesity and hippocampal volume in children

Luo

Chow²,

Herting

et al. 2020

Brain and Behavior

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Introduction Animal studies have shown that male but not female offspring exposed to maternal obesity have abnormal hippocampal development. Similar sex differences were observed in animal models of developmental programming by prenatal stress or maternal diabetes. We aimed to translate this work into humans by examining sex‐specific effects of exposure to maternal obesity on hippocampal volume in children. Methods Eighty‐eight children (37 boys and 51 girls) aged 7–11 years completed the study. Maternal prepregnancy body mass index (BMI) was obtained from electronic medical records. A high‐resolution anatomical scan was performed using a 3‐Tesla magnetic resonance imaging (MRI) scanner. Total hippocampal volume and hippocampal subfield volumes were analyzed using FreeSurfer 6.0. Linear regression was used to investigate sex differences in relationships between maternal prepregnancy BMI and child hippocampal volume. Results Maternal prepregnancy BMI ranged from 19.0 to 50.4 kg/m2. We observed a significant interaction between maternal prepregnancy BMI and sex on total hippocampal volume (p < .001) such that boys (r = −.39, p = .018) but not girls (r = .11, p = .45) had a significant negative relationship between maternal prepregnancy BMI and total hippocampal volume. This relationship in boys remained significant after adjusting for child and maternal covariates (β = −126.98, p = .012). The sex interactions with prepregnancy BMI were consistently observed in hippocampal subfields CA1 (p = .008), CA2/3 (p = .016), CA4 (p = .002), dentate gyrus (p < .001), and subiculum (p < .001). Conclusions Our results support findings in animal models and suggest that boys may be more vulnerable to the adverse effects of exposure to maternal obesity on hippocampal development than girls.

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Hippocampal insulin resistance links maternal obesity with impaired neuronal plasticity in adult offspring

Cited by 31 publications

References 21 publications

Gp91phox (NOX2) in Activated Microglia Exacerbates Neuronal Damage Induced by Oxygen Glucose Deprivation and Hyperglycemia in an in Vitro Model

Gp91phox (NOX2) in Activated Microglia Exacerbates Neuronal Damage Induced by Oxygen Glucose Deprivation and Hyperglycemia in an in Vitro Model

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

Sex differences in the association between prenatal exposure to maternal obesity and hippocampal volume in children

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