Dysregulation of mitochondrial function and biogenesis modulators in adipose tissue of obese children

Zamora-Mendoza, R; Rosas-Vargas, Haydeé; Ramos-Cervantes, María Teresa; García-Zuñiga, P.; Pérez-Lorenzana, Héctor; Mendoza‐Lorenzo, Patricia; Perez-Ortiz, Andric; Estrada-Mena, Francisco Javier; Miliar-García, Ángel; Lara‐Padilla, Eleazar; Ceballos, Guillermo; Rodríguez, Alberto Masaguer; Villarreal, Francisco; Ramírez-Sánchez, Israel

doi:10.1038/ijo.2017.274

Cited by 46 publications

(44 citation statements)

References 55 publications

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“…In youths and adults with T2DM, insulin resistance is associated with muscle mitochondrial dysfunction . In addition, a recent study demonstrated that in adipose tissue from obese children, there was dysregulation of mitochondrial function and biogenesis modulators relative to lean subjects . As MOTS‐c is a key novel endocrine signaling molecule that originates from mitochondria, mitochondrial DNA dysfunction could result in a direct decline in mitochondrial function and progressive loss of MDP expression, which will diminish their functionality as regulatory peptides .…”

Section: Discussionmentioning

confidence: 99%

“…7,[29][30][31][32] In addition, a recent study demonstrated that in adipose tissue from obese children, there was dysregulation of mitochondrial function and biogenesis modulators relative to lean subjects. 8 As MOTS-c is a key novel endocrine signaling molecule that originates from mitochondria, mitochondrial DNA dysfunction could result in a direct decline in mitochondrial function and progressive loss of MDP expression, which will diminish their functionality as regulatory peptides. 9 Thus, it is tempting to speculate that the significantly decreased levels of endogenous MOTS-c in insulin-resistant obese children and adolescents may be a consequence of mitochondrial dysfunction, and that the expression of MOTS-c decreases dramatically when the mitochondrial dysfunction reaches a certain threshold, but the presence of such a mechanism remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…In obese animal models and patients, metabolic disturbances associated with mitochondrial dysfunction, including reduced mitochondrial mass and mitochondrial biogenesis, altered mitochondrial morphology, and structural damage, have been identified . Also, a novel bioactive mitochondrial‐derived peptide (MDP)—mitochondrial open reading frame of the 12S rRNA‐c (MOTS‐c)—encoded in the mitochondrial DNA, was recently identified .…”

Section: Introductionmentioning

confidence: 99%

“…Abbreviations: BMI, body mass index; BMI-SDS, BMI SD score; HbA1c, glycated hemoglobin; HC, hip circumference; HDL cholesterol, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; LDL cholesterol, low-density lipoprotein cholesterol; MDP, mitochondrial-derived peptide; MOTS-c, mitochondrial open reading frame of the 12S rRNA-c; TC, total cholesterol; TG, triglyceride; WC, waist circumference; WHR, waist-to-hip ratio In obese animal models and patients, metabolic disturbances associated with mitochondrial dysfunction, including reduced mitochondrial mass and mitochondrial biogenesis, altered mitochondrial morphology, and structural damage, have been identified. 7,8 Also, a novel bioactive mitochondrial-derived peptide (MDP)-mitochondrial open reading frame of the 12S rRNA-c (MOTS-c)-encoded in the mitochondrial DNA, was recently identified. 9 Previous studies have demonstrated that MOTS-c treatment in mice prevented agedependent and high-fat diet-induced insulin resistance, as well as diet-induced obesity via AMP-activated protein kinase (AMPK), which is a well-characterized regulator of energy metabolism, and is capable of ameliorating obesity and T2DM.…”

Section: Introductionmentioning

confidence: 99%

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Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance

Zhang

et al. 2018

Pediatr Diabetes

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Background and Aims A novel bioactive peptide, mitochondrial‐derived peptide (MOTS‐c), has recently attracted attention as a potential prevention or therapeutic option for obesity and type 2 diabetes mellitus (T2DM). MOTS‐c profiles have not yet been reported in human obesity and T2DM. We aimed to determine circulating MOTS‐c levels in obesity and explore the association between MOTS‐c levels and various metabolic parameters. Methods In this case‐control study, 40 obese children and adolescents (27 males) and 57 controls (40 males) were recruited in the Hubei Province of China in 2017. Circulating MOTS‐c levels were measured, clinical data (eg, glucose, insulin, and lipid profile) were recorded, and anthropometric measurements were performed. Finally, we investigated correlations between MOTS‐c levels and related variables. Results MOTS‐c levels were significantly decreased in the obese group compared with the control group (472.61 ±22.83 vs 561.64 ±19.19 ng/mL, P <.01). After classification by sex, MOTS‐c levels were significantly decreased in obese male children and adolescents compared to their counterparts (465.26 ±24.53 vs 584.07 ±21.18 ng/mL, P <.001), while they were comparable between the obese and healthy female subjects (487.89 ±49.77 vs 508.85 ±38.76 ng/mL, P >.05). Further, MOTS‐c levels were negatively correlated with body mass index (BMI), BMI SD score, waist circumference, waist‐to‐hip ratio, fasting insulin level, homeostasis model assessment of insulin resistance (HOMA‐IR), and glycated hemoglobin (HbA1c) in the male cohort. Conclusions Circulating MOTS‐c levels were decreased in obese male children and adolescents and correlated with markers of insulin resistance and obesity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance

Zhang

et al. 2018

Pediatr Diabetes

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“…Mitochondrial dysfunction and damage have been implicated in obesity [12,13] and CVD [14]. In particular, platelet mitochondria are important in maintaining thrombosis and hemostasis [15].…”

Section: Introductionmentioning

confidence: 99%

Platelet mitochondrial DNA methylation predicts future cardiovascular outcome in adults with overweight and obesity

et al. 2020

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Background: The association between obesity and cardiovascular disease (CVD) is proven, but why some adults with obesity develop CVD while others remain disease-free is poorly understood. Here, we investigated whether mitochondrial DNA (mtDNA) methylation in platelets is altered prior to CVD development in a population of adults with overweight and obesity. Methods: We devised a nested case-control study of 200 adults with overweight or obesity who were CVD-free at baseline, of whom 84 developed CVD within 5 years, while 116 remained CVD-free. Platelet mtDNA was isolated from plasma samples at baseline, and mtDNA methylation was quantified in mitochondrially encoded cytochrome-C-oxidase I (MT-CO1; nt6797 and nt6807), II (MT-CO2; nt8113 and nt8117), and III (MT-CO3; nt9444 and nt9449); tRNA leucine 1 (MT-TL1; nt3247 and nt3254); D-loop (nt16383); tRNA phenylalanine (MT-TF; nt624); and light-strand-originof-replication (MT-OLR; nt5737, nt5740, and nt5743) by bisulfite-pyrosequencing. Logistic regression was used to estimate the contribution of mtDNA methylation to future CVD risk. ROC curve analysis was used to identify the optimal mtDNA methylation threshold for future CVD risk prediction. A model was generated incorporating methylation at three loci (score 0, 1, or 2 according to 0, 1, or 2-3 hypermethylated loci, respectively), adjusted for potential confounders, such as diastolic and systolic blood pressure, fasting blood glucose, and cholesterol ratio. mtDNA methylation at MT-CO1 nt6807 (OR = 1.08, 95% CI 1.02-1.16; P = 0.014), MT-CO3 nt9444 (OR = 1.22, 95% CI 1.02-1.46, P = 0.042), and MT-TL1 nt3254 (OR = 1.30, 95% CI 1.05-1.61, P = 0.008) was higher at baseline in those who developed CVD by follow-up, compared with those who remained CVD-free. Combined use of the three loci significantly enhanced risk prediction, with hazard ratios of 1.38 (95% CI 0.68-2.78) and 2.68 (95% CI 1.41-5.08) for individuals with score 1 or 2, respectively (P = 0.003). Methylation at these sites was independent of conventional CVD risk factors, including inflammation markers, fasting blood glucose concentration, and blood pressure. Conclusions: Methylations of MT-CO1, MT-CO3, and MT-TL1 are, together, strong predictors of future CVD incidence. Since methylation of these mtDNA domains was independent of conventional CVD risk factors, these markers may represent a novel intrinsic predictor of CVD risk in adults with overweight and obesity.

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Adipose Mitochondrial Respiratory Capacity in Obesity is Impaired Independently of Glycemic Status of Tissue Donors

Wessels

Honecker

Schöttl

et al. 2019

Obesity

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Objective The study aimed to investigate how obesity and glycemic state affect mitochondrial respiration and ATP–generating pathways in mature human adipocytes. Methods Subcutaneous (sc) and visceral (vc) adipocytes were isolated from patients undergoing abdominal surgery. Respiratory chain function was analyzed by high‐resolution respirometry. Adipocyte ATP levels and lactate release were measured separately in the presence of either glycolysis (2‐deoxy‐D‐glucose) or ATP synthase (oligomycin) inhibitors. Results A significant negative correlation between oxidative phosphorylation capacity and the BMI of tissue donors found in sc adipocytes (P < 0.05). Furthermore, respirometry revealed an inverse relationship between BMI and the electron transfer system capacity of sc (P < 0.05) but not vc adipocytes. In both depots, the respiratory capacity was not affected by the glycemic state. A positive correlation between BMI and adipocyte lactate release was measured independently of the tissue origin (sc: P = 0.01; vc: P < 0.05). Direct ATP measurements indicated that energy demands of adipocytes were predominantly fulfilled by glycolytic activity. Conclusions The study’s data suggest that obesity is the primary driver of impaired adipocyte mitochondrial respiration because the glycemic state did not further deteriorate this situation. The adipocytes’ energy needs are covered primarily by the glycolytic pathway.

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Dysregulation of mitochondrial function and biogenesis modulators in adipose tissue of obese children

Abstract: Adipose tissue from children with obesity demonstrates a dysregulation of key modulators of MB and organelle structure, and displays hyperacetylation of key proteins and altered expression of upstream regulators of cell metabolism.

Cited by 46 publications

References 55 publications

Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance

Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance

Platelet mitochondrial DNA methylation predicts future cardiovascular outcome in adults with overweight and obesity

Adipose Mitochondrial Respiratory Capacity in Obesity is Impaired Independently of Glycemic Status of Tissue Donors

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