Mitochondria-related transcriptional signature is downregulated in adipocytes in obesity: a study of young healthy MZ twins

Heinonen, Sini; Muniandy, Maheswary; Buzková, Jana; Mardinoğlu, Adil; Rodrı́guez, Amaia; Frühbeck, Gema; Hakkarainen, Antti; Lundbom, Jesper; Lundbom, Nina; Kaprio, Jaakko; Rissanen, Aila; Pietiläinen, Kirsi H.

doi:10.1007/s00125-016-4121-2

Cited by 65 publications

(61 citation statements)

References 51 publications

(69 reference statements)

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“…Table 1 summarizes the subjects’ anthropometric and clinical characteristics (26–28). In brief, the heavier co-twins of the discordant pairs weighed on average 18 kg more, had 28% more total fat, 67% more subcutaneous fat, 200% more intra-abdominal fat, and 300% more liver fat than their leaner counterparts.…”

Section: Resultsmentioning

confidence: 99%

“…The study population has been described in our previous studies (26–28). Briefly, the monozygotic (MZ) twin pairs (aged 22–36, 54% women) were identified through the national population registry of Finland from 10 population-based birth cohorts (FinnTwin12 and FinnTwin16); 26 pairs being discordant for BMI, within-pair difference (Δ) in BMI >3 kg/m 2 (mean Δweight 18 kg), and 14 pairs concordant for BMI (ΔBMI <3 kg/m 2 ) acting as their controls.…”

Section: Methodsmentioning

confidence: 99%

“…RNA was prepared from frozen fat tissue (26). Adipocytes were isolated from the fat biopsy specimens treated with collagenase (28). The diameter of fat cells was measured under a light microscope.…”

Section: Methodsmentioning

confidence: 99%

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Upregulation of Early and Downregulation of Terminal Pathway Complement Genes in Subcutaneous Adipose Tissue and Adipocytes in Acquired Obesity

et al. 2017

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Inflammation is an important mediator of obesity-related complications such as the metabolic syndrome but its causes and mechanisms are unknown. As the complement system is a key mediator of inflammation, we studied whether it is activated in acquired obesity in subcutaneous adipose tissue (AT) and isolated adipocytes. We used a special study design of genetically matched controls of lean and heavy groups, rare monozygotic twin pairs discordant for body mass index (BMI) [n = 26, within-pair difference (Δ) in body mass index, BMI >3 kg/m2] with as much as 18 kg mean Δweight. Additionally, 14 BMI-concordant (BMI <3 kg/m2) served as a reference group. The detailed measurements included body composition (DEXA), fat distribution (MRI), glucose, insulin, adipokines, C3a and SC5b-9 levels, and the expression of complement and insulin signaling pathway-related genes in AT and adipocytes. In both AT and isolated adipocytes, the classical and alternative pathway genes were upregulated, and the terminal pathway genes downregulated in the heavier co-twins of the BMI-discordant pairs. The upregulated genes included C1q, C1s, C2, ficolin-1, factor H, receptors for C3a and C5a (C5aR1), and the iC3b receptor (CR3). While the terminal pathway components C5 and C6 were downregulated, its inhibitor clusterin was upregulated. Complement gene upregulation in AT and adipocytes correlated positively with adiposity and hyperinsulinemia and negatively with the expression of insulin signaling-related genes. Plasma C3a, but not SC5b-9, levels were elevated in the heavier co-twins. There were no differences between the co-twins in BMI-concordant pairs. Obesity is associated with increased expression of the early, but not late, complement pathway components and of key receptors. The twins with acquired obesity have therefore an inflated inflammatory activity in the AT. The results suggest that complement is likely involved in orchestrating clearance of apoptotic debris and inflammation in the AT.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Upregulation of Early and Downregulation of Terminal Pathway Complement Genes in Subcutaneous Adipose Tissue and Adipocytes in Acquired Obesity

et al. 2017

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“…In this regard, subcutaneous fat cells taken from heavier versus leaner discordant twin donors show lower mitochondrial-encoded gene expression including the 12S rRNA gene 12. Whether this finding has any implications for muscle MOTS-c expression and release is unknown.…”

Section: Discussionmentioning

confidence: 99%

Plasma Mots-C Levels are Associated with Insulin Sensitivity in Lean but Not in Obese Individuals

Cataldo

Fernández‐Verdejo

Santos

et al. 2018

Journal of Investigative Medicine

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Mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) is a mitochondrial-derived peptide that attenuates weight gain and hyperinsulinemia when administered to high fat-fed mice. MOTS-c is therefore a potential regulator of metabolic homeostasis under conditions of high-energy supply. However, the effect of insulin resistance and obesity on plasma MOTS-c concentration in humans is unknown. To gain insight into MOTS-c regulation, we measured plasma MOTS-c concentration and analyzed its relationship with insulin sensitivity surrogates, in lean and obese humans (n=10 per group). Obese individuals had impaired insulin sensitivity as indicated by low Matsuda and high Homeostatic Model Assessment (HOMA) indexes. Although plasma MOTS-c concentration was similar in lean and obese individuals (0.48±0.16 and 0.52±0.15 ng/mL; p=0.60), it was correlated with HOMA (r=0.53; p<0.05) and Matsuda index (r=-0.46; p<0.05). Notably, when the groups were analyzed separately, the associations remained only in lean individuals. We conclude that plasma MOTS-c concentration is unaltered in human obesity. However, MOTS-c associates positively with insulin resistance mostly in lean individuals, indicating that plasma MOTS-c concentration depends on the metabolic status in this population. Such dependence seems altered when obesity settles. The implications of plasma MOTS-c for human metabolic homeostasis deserve future examination.

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“…When ROS production increases, the balance between oxidant and antioxidant factors is disturbed and oxidative stress occurs. 9 Proinflammatory adipokines and elevated levels of FFAs, in particular those released by visceral adipose tissue, cause IR and are pathogenic factors that can induce endothelial dysfunction in the earlier stages of obesity, which further deteriorates insulin signalling pathways in endothelial cells, thus leading to initiation of the atherosclerotic process. 2 Several studies have shown that an increase in ROS production in adipose tissue of experimental animal models of diabetes and obesity or in cultured adipocytes can cause altered synthesis and secretion of adipokines and promote cell senescence, IR and an inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

Obesity impairs leukocyte‐endothelium cell interactions and oxidative stress in humans

López‐Domènech

Bañuls

Díaz-Morales

et al. 2018

Eur J Clin Investigation

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Mitochondria-related transcriptional signature is downregulated in adipocytes in obesity: a study of young healthy MZ twins

Abstract: The datasets analysed and generated during the current study are available in the figshare repository, https://dx.doi.org/10.6084/m9.figshare.3806286.v1.

Cited by 65 publications

References 51 publications

Upregulation of Early and Downregulation of Terminal Pathway Complement Genes in Subcutaneous Adipose Tissue and Adipocytes in Acquired Obesity

Upregulation of Early and Downregulation of Terminal Pathway Complement Genes in Subcutaneous Adipose Tissue and Adipocytes in Acquired Obesity

Plasma Mots-C Levels are Associated with Insulin Sensitivity in Lean but Not in Obese Individuals

Obesity impairs leukocyte‐endothelium cell interactions and oxidative stress in humans

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