Effects of mTOR inhibition on cardiac and adipose tissue pathology and glucose metabolism in rats with metabolic syndrome

Uchinaka, Ayako; Yoneda, Mamoru; Yamada, Yoshio; Murohara, Toyoaki; Nagata, Kazuya

doi:10.1002/prp2.331

Cited by 14 publications

(6 citation statements)

References 37 publications

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“…Similarly to muscle and adipose tissue, mTORC1 activity was observed to be increased in the livers of obese rodents, resulting in the degradation of insulin receptor substrate 1 and the onset of hepatic insulin resistance [36]. A recent study by Uchinaka et al reported that the activation of mTOR signaling contributes to MetS pathophysiology and associated complications [38].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Transcriptomic Regulations behind Metabolic Syndrome in Obese and Lean Subjects

Paczkowska-Abdulsalam

Niemira

Bielska

et al. 2020

IJMS

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Multiple mechanisms have been suggested to confer to the pathophysiology of metabolic syndrome (MetS), however despite great interest from the scientific community, the exact contribution of each of MetS risk factors still remains unclear. The present study aimed to investigate molecular signatures in peripheral blood of individuals affected by MetS and different degrees of obesity. Metabolic health of 1204 individuals from 1000PLUS cohort was assessed, and 32 subjects were recruited to four study groups: MetS lean, MetS obese, “healthy obese”, and healthy lean. Whole-blood transcriptome next generation sequencing with functional data analysis were carried out. MetS obese and MetS lean study participants showed the upregulation of genes involved in inflammation and coagulation processes: granulocyte adhesion and diapedesis (p < 0.0001, p = 0.0063), prothrombin activation pathway (p = 0.0032, p = 0.0091), coagulation system (p = 0.0010, p = 0.0155). The results for “healthy obese” indicate enrichment in molecules associated with protein synthesis (p < 0.0001), mitochondrial dysfunction (p < 0.0001), and oxidative phosphorylation (p < 0.0001). Our results suggest that MetS is related to the state of inflammation and vascular system changes independent of excess body weight. Furthermore, “healthy obese”, despite not fulfilling the criteria for MetS diagnosis, seems to display an intermediate state with a lower degree of metabolic abnormalities, before they proceed to a full blown MetS.

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Section: Discussionmentioning

confidence: 99%

Evaluation of Transcriptomic Regulations behind Metabolic Syndrome in Obese and Lean Subjects

Paczkowska-Abdulsalam

Niemira

Bielska

et al. 2020

IJMS

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“…LV, kidney, VAT, or SAT tissue was analyzed by hematoxylin-eosin (H&E), Azan-Mallory, or periodic acid–Schiff (PAS) staining as well as by immunohistochemical staining for the monocyte–macrophage marker CD68 (antibody clone ED-1, diluted 1:100; Chemicon, Temecula, CA, USA), as previously described 19 , 20 . The glomerulosclerosis index (GSI) was measured for 50 glomeruli in PAS-stained sections of each rat, also as described previously 21 .…”

Section: Methodsmentioning

confidence: 99%

Alleviation of salt-induced exacerbation of cardiac, renal, and visceral fat pathology in rats with metabolic syndrome by surgical removal of subcutaneous fat

et al. 2020

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Objectives Evidence suggests that visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) should be considered as distinct types of white fat. Although VAT plays a key role in metabolic syndrome (MetS), the role of subcutaneous adipose tissue (SAT) has been unclear. DahlS.Z- Lepr fa / Lepr fa (DS/obese) rats, an animal model of MetS, develop adipocyte hypertrophy and inflammation to similar extents in SAT and VAT. We have now investigated the effects of salt loading and SAT removal on cardiac, renal, and VAT pathology in DS/obese rats. Methods DS/obese rats were subjected to surgical removal of inguinal SAT or sham surgery at 8 weeks of age. They were provided with a 0.3% NaCl solution as drinking water or water alone for 4 weeks from 9 weeks of age. Results Salt loading exacerbated hypertension, insulin resistance, as well as left ventricular (LV) hypertrophy, inflammation, fibrosis, and diastolic dysfunction in DS/obese rats. It also reduced both SAT and VAT mass but aggravated inflammation only in VAT. Although SAT removal did not affect LV hypertrophy in salt-loaded DS/obese rats, it attenuated hypertension, insulin resistance, and LV injury as well as restored fat mass and alleviated inflammation and the downregulation of adiponectin gene expression in VAT. In addition, whereas salt loading worsened renal injury as well as upregulated the expression of renin–angiotensin-aldosterone system-related genes in the kidney, these effects were suppressed by removal of SAT. Conclusions SAT removal attenuated salt-induced exacerbation of MetS and LV and renal pathology in DS/obese rats. These beneficial effects of SAT removal are likely attributable, at least in part, to inhibition of both VAT and systemic inflammation.

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“…An animal model showing metabolic syndrome characteristics, where mTOR pathway inhibitors were administered, was analyzed. As a result, a reduction in oxidative stress (decrease in superoxide production and NADPH oxidase activity) and inflammatory response (reduction of macrophage influx), weight loss, reduction of adipose tissue hypertrophy, and hypertension were observed, which was beneficial to the cardiovascular system and reduced the risk of cardiometabolic complications [71]. Thus, cerebral insulin resistance in schizophrenia may induce reduced signal transduction for gamma-aminobutyric acid (GABA), N-methyl-d-aspartic acid (NMDA), dopamine-D2 receptors, and reduced levels of brain-derived neurotrophic factor (BDNF).…”

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confidence: 99%

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

et al. 2020

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Schizophrenia is a neurodevelopmental disorder featuring chronic, complex neuropsychiatric features. The etiology and pathogenesis of schizophrenia are not fully understood. Oxidative-antioxidant imbalance is a potential determinant of schizophrenia. Oxidative, nitrosative, or sulfuric damage to enzymes of glycolysis and tricarboxylic acid cycle, as well as calcium transport and ATP biosynthesis might cause impaired bioenergetics function in the brain. This could explain the initial symptoms, such as the first psychotic episode and mild cognitive impairment. Another concept of the etiopathogenesis of schizophrenia is associated with impaired glucose metabolism and insulin resistance with the activation of the mTOR mitochondrial pathway, which may contribute to impaired neuronal development. Consequently, cognitive processes requiring ATP are compromised and dysfunctions in synaptic transmission lead to neuronal death, preceding changes in key brain areas. This review summarizes the role and mutual interactions of oxidative damage and impaired glucose metabolism as key factors affecting metabolic complications in schizophrenia. These observations may be a premise for novel potential therapeutic targets that will delay not only the onset of first symptoms but also the progression of schizophrenia and its complications.

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Effects of mTOR inhibition on cardiac and adipose tissue pathology and glucose metabolism in rats with metabolic syndrome

Cited by 14 publications

References 37 publications

Evaluation of Transcriptomic Regulations behind Metabolic Syndrome in Obese and Lean Subjects

Evaluation of Transcriptomic Regulations behind Metabolic Syndrome in Obese and Lean Subjects

Alleviation of salt-induced exacerbation of cardiac, renal, and visceral fat pathology in rats with metabolic syndrome by surgical removal of subcutaneous fat

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

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