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Brain Metabolism Alterations in Type 2 Diabetes: What Did We Learn From Diet-Induced Diabetes Models?

ABSTRACT: Type 2 diabetes (T2D) is a metabolic disease with impact on brain function through mechanisms that include glucose toxicity, vascular damage and blood-brain barrier (BBB) impairments, mitochondrial dysfunction, oxidative stress, brain insulin resistance, synaptic failure, neuroinflammation, and gliosis. Rodent models have been developed for investigating T2D, and have contributed to our understanding of mechanisms involved in T2D-induced brain dysfunction. Namely, mice or rats exposed to diabetogenic diets that are rich in fat and/or sugar have been widely used since they develop memory impairment, especially in tasks that depend on hippocampal processing. Here we summarize main findings on brain energy metabolism alterations underlying dysfunction of neuronal and glial cells promoted by diet-induced metabolic syndrome that progresses to a T2D phenotype.

SUBMITTER: Garcia-Serrano AM

PROVIDER: S-EPMC7101159 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Brain Metabolism Alterations in Type 2 Diabetes: What Did We Learn From Diet-Induced Diabetes Models?

Garcia-Serrano Alba M AM Duarte João M N JMN

Frontiers in neuroscience 20200320

Type 2 diabetes (T2D) is a metabolic disease with impact on brain function through mechanisms that include glucose toxicity, vascular damage and blood-brain barrier (BBB) impairments, mitochondrial dysfunction, oxidative stress, brain insulin resistance, synaptic failure, neuroinflammation, and gliosis. Rodent models have been developed for investigating T2D, and have contributed to our understanding of mechanisms involved in T2D-induced brain dysfunction. Namely, mice or rats exposed to diabeto ...[more]

PMID: 32265637

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Project description:BackgroundMaternal obesity may program the fetus and increase the susceptibility of the offspring to adult diseases. Metformin crosses the placenta and has been associated with decreased inflammation and reversal of fatty liver in obese leptin-deficient mice. We investigated the effects of metformin on maternal and fetal lipid metabolism and hepatic inflammation using a rat model of diet-induced obesity during pregnancy.MethodsFemale Wistar rats (6-7 weeks old) were fed normal or high calorie diets for 5 weeks. After mating with normal-diet fed males, half of the high calorie-fed dams received metformin (300 mg/kg, daily); dams (8 per group) continued diets through gestational day 19. Maternal and fetal livers and fetal brains were analyzed for fatty acids and for fatty acid metabolism-related gene expression. Data were analyzed by ANOVA followed by Dunnett's post hoc testing.ResultsWhen compared to control-lean maternal livers, obesogenic-diet-exposed maternal livers showed significantly higher saturated fatty acids (14:0 and 16:0) and monounsaturated fatty acids (16:1n7 and 18:1n9) and lower polyunsaturated (18:2n6 and 20:4n6 [arachidonic acid]) and anti-inflammatory n3 polyunsaturated fatty acids (18:3n3 and 22:6n3 [docosahexaenoic acid]) (p < 0.05). Metformin did not affect diet-induced changes in maternal livers. Fetal livers exposed to the high calorie diet showed significantly increased saturated fatty acids (18:0) and monounsaturated fatty acids (18:1n9 and 18:1n7) and decreased polyunsaturated fatty acids (18:2n6, 20:4n6 and 22:6n3) and anti-inflammatory n3 polyunsaturated fatty acids, along with increased gene expression of fatty acid metabolism markers (Fasn, D5d, D6d, Scd1, Lxrα). Metformin significantly attenuated diet-induced inflammation and 18:1n9 and 22:6n3 in fetal livers, as well as n3 fatty acids (p < 0.05). Prenatal obesogenic diet exposure significantly increased fetal liver IFNγ levels (p < 0.05), which was reversed by maternal metformin treatment (p < 0.05).ConclusionsConsumption of a high calorie diet significantly affected maternal and fetal fatty acid metabolism. It reduced anti-inflammatory polyunsaturated fatty acids in maternal and fetal livers, altered gene expression of fatty acid metabolism markers, and induced inflammation in the fetal livers. Prenatal metformin attenuated some diet-induced fatty acid changes and inflammation in the fetal livers without affecting maternal livers, suggesting that maternal metformin may impact fetal/neonatal fatty acid/lipid metabolism.

Project description:Type 2 Diabetes mellitus (T2DM) is an evident growing disease that affects different cultures throughout the world. T2DM occurs under the influence of three main factors: the genetic background, environmental and behavioral components. Obesity is strongly associated to the development of T2DM in the occident, while in the orient most of the diabetic patients are considered lean. Genetics may be a key factor in the development of T2DM in societies where obesity is not a recurrent public health problem. Herein, two different models of rats were used to understand their differences and reliability as experimental models to study the pathophysiology of T2DM, in two different approaches: the genetic (GK rats) and the environmental (HFD-induced obese rats) influences. GK rats were resistant to weight gain even though food/energy consumption (relative to body weight) was higher in this group. HFD, on the other hand, induced obesity in Wistar rats. White adipose tissue (WAT) expansion in this group was accompanied by immune cells infiltration, inflammation and insulin resistance. GK rats also presented WAT inflammation and insulin resistance; however, no immune cells infiltration was observed in the WAT of this group. Liver of HFD group presented fat accumulation without differences in inflammatory cytokines content, while liver of GK rats didn't present fat accumulation, but showed an increase of IL-6 and IL-10 content and glycogen. Also, GK rats showed increased plasma GOT and GPT. Soleus muscle of HFD presented normal insulin signaling, contrary to GK rats, which presented higher content of basal phosphorylation of GSK-3β. Our results demonstrated that HFD developed a mild insulin resistance in Wistar rats, but was not sufficient to develop T2DM. In contrast, GK rats presented all the typical hallmarks of T2DM, such as insulin resistance, defective insulin production, fasting hyperglycemia/hyperinsulinemia and lipid plasma alteration. Thus, on the given time point of this study, we may conclude that only GK rats shown to be a reliable model to study T2DM.

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Brain Metabolism Alterations in Type 2 Diabetes: What Did We Learn From Diet-Induced Diabetes Models?

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Brain Metabolism Alterations in Type 2 Diabetes: What Did We Learn From Diet-Induced Diabetes Models?

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