| 11. |
- Pietiläinen, Kirsi H, et al.
(författare)
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Association of lipidome remodeling in the adipocyte membrane with acquired obesity in humans
- 2011
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Ingår i: PLoS biology. - : Public Library of Science. - 1544-9173 .- 1545-7885. ; 9:6
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Tidskriftsartikel (refereegranskat)abstract
- Identification of early mechanisms that may lead from obesity towards complications such as metabolic syndrome is of great interest. Here we performed lipidomic analyses of adipose tissue in twin pairs discordant for obesity but still metabolically compensated. In parallel we studied more evolved states of obesity by investigating a separated set of individuals considered to be morbidly obese. Despite lower dietary polyunsaturated fatty acid intake, the obese twin individuals had increased proportions of palmitoleic and arachidonic acids in their adipose tissue, including increased levels of ethanolamine plasmalogens containing arachidonic acid. Information gathered from these experimental groups was used for molecular dynamics simulations of lipid bilayers combined with dependency network analysis of combined clinical, lipidomics, and gene expression data. The simulations suggested that the observed lipid remodeling maintains the biophysical properties of lipid membranes, at the price, however, of increasing their vulnerability to inflammation. Conversely, in morbidly obese subjects, the proportion of plasmalogens containing arachidonic acid in the adipose tissue was markedly decreased. We also show by in vitro Elovl6 knockdown that the lipid network regulating the observed remodeling may be amenable to genetic modulation. Together, our novel approach suggests a physiological mechanism by which adaptation of adipocyte membranes to adipose tissue expansion associates with positive energy balance, potentially leading to higher vulnerability to inflammation in acquired obesity. Further studies will be needed to determine the cause of this effect.
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| 12. |
- Pietiläinen, Kirsi H., et al.
(författare)
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Global transcript profiles of fat in monozygotic twins discordant for BMI : pathways behind acquired obesity
- 2008
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 5:3
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The acquired component of complex traits is difficult to dissect in humans. Obesity represents such a trait, in which the metabolic and molecular consequences emerge from complex interactions of genes and environment. With the substantial morbidity associated with obesity, a deeper understanding of the concurrent metabolic changes is of considerable importance. The goal of this study was to investigate this important acquired component and expose obesity-induced changes in biological pathways in an identical genetic background.METHODS AND FINDINGS: We used a special study design of "clonal controls," rare monozygotic twins discordant for obesity identified through a national registry of 2,453 young, healthy twin pairs. A total of 14 pairs were studied (eight male, six female; white), with a mean +/- standard deviation (SD) age 25.8 +/- 1.4 y and a body mass index (BMI) difference 5.2 +/- 1.8 kg/m(2). Sequence analyses of mitochondrial DNA (mtDNA) in subcutaneous fat and peripheral leukocytes revealed no aberrant heteroplasmy between the co-twins. However, mtDNA copy number was reduced by 47% in the obese co-twin's fat. In addition, novel pathway analyses of the adipose tissue transcription profiles exposed significant down-regulation of mitochondrial branched-chain amino acid (BCAA) catabolism (p < 0.0001). In line with this finding, serum levels of insulin secretion-enhancing BCAAs were increased in obese male co-twins (9% increase, p = 0.025). Lending clinical relevance to the findings, in both sexes the observed aberrations in mitochondrial amino acid metabolism pathways in fat correlated closely with liver fat accumulation, insulin resistance, and hyperinsulinemia, early aberrations of acquired obesity in these healthy young adults.CONCLUSIONS: Our findings emphasize a substantial role of mitochondrial energy- and amino acid metabolism in obesity and development of insulin resistance.
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| 13. |
- Sahebekhtiari, Navid, et al.
(författare)
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Plasma Proteomics Analysis Reveals Dysregulation of Complement Proteins and Inflammation in Acquired Obesity—A Study on Rare BMI-Discordant Monozygotic Twin Pairs
- 2019
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Ingår i: Proteomics - Clinical Applications. - : Wiley. - 1862-8354 .- 1862-8346. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The purpose of this study is to elucidate the effect of excess body weight and liver fat on the plasma proteome without interference from genetic variation. Experimental Design: The effect of excess body weight is assessed in young, healthy monozygotic twins from pairs discordant for body mass index (intrapair difference (Δ) in BMI > 3 kg m −2 , n = 26) with untargeted LC-MS proteomics quantification. The effect of liver fat is interrogated via subgroup analysis of the BMI-discordant twin cohort: liver fat discordant pairs (Δliver fat > 2%, n = 12) and liver fat concordant pairs (Δliver fat < 2%, n = 14), measured by magnetic resonance spectroscopy. Results: Seventy-five proteins are differentially expressed, with significant enrichment for complement and inflammatory response pathways in the heavier co-twins. The complement dysregulation is found in obesity in both the liver fat subgroups. The complement and inflammatory proteins are significantly associated with adiposity measures, insulin resistance and impaired lipids. Conclusions and Clinical Relevance: The early pathophysiological mechanisms in obesity are incompletely understood. It is shown that aberrant complement regulation in plasma is present in very early stages of clinically healthy obese persons, independently of liver fat and in the absence of genetic variation that typically confounds human studies.
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| 14. |
- Sevastianova, Ksenia, et al.
(författare)
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Genetic variation in PNPLA3 (adiponutrin) confers sensitivity to weight loss-induced decrease in liver fat in humans
- 2011
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 1938-3207 .- 0002-9165. ; 94:1, s. 104-111
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Tidskriftsartikel (refereegranskat)abstract
- Background: The rs738409 C -> G single nucleotide polymorphism in the patatin-like phospholipase domain-containing 3 (PNPLA3; adiponutrin) leads to a missense mutation (I148M), which is associated with increased liver fat but not insulin resistance. The I148M mutation impedes triglyceride hydrolysis in vitro, and its carriers have an increased risk of developing severe liver disease. Objective: We explored whether the rs738409 PNPLA3 G allele influences the ability of weight loss to decrease liver fat or change insulin sensitivity. Design: We recruited 8 subjects who were homozygous for the rs738409 PNPLA3 G allele (PNPLA3-148MM) and 10 who were homozygous for the rs738409 PNPLA3 C allele (PNPLA3-148II). To allow comparison of changes in liver fat, the groups were matched with respect to baseline age, sex, body mass index, and liver fat. The subjects were placed on a hypocaloric low-carbohydrate diet for 6 d. Liver fat content (proton magnetic resonance spectroscopy), whole-body insulin sensitivity of glucose metabolism (euglycemic clamp technique), and lipolysis ([H-2(5)] glycerol infusion) were measured before and after the diet. Results: At baseline, fasting serum insulin and C-peptide concentrations were significantly lower in the PNPLA3-148MM group than in the PNPLA3-148II group, as predicted by study design. Weight loss was not significantly different between groups (PNPLA3-148MM: -3.1 +/- 0.5 kg; PNPLA3-148II: -3.1 +/- 0.4 kg). Liver fat decreased by 45% in the PNPLA3-148MM group (P < 0.001) and by 18% in the PNPLA3-148II group (P < 0.01). Conclusion: Weight loss is effective in decreasing liver fat in subjects who are homozygous for the rs738409 PNPLA3 G or C allele. This trial was registered at www.hus.fi as 233775. Am J Clin Nutr 2011;94:104-11.
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| 15. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 16. |
- Suomalainen, Anu, et al.
(författare)
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FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study.
- 2011
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Ingår i: Lancet neurology. - 1474-4465. ; 10:9, s. 806-818
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Muscle biopsy is the gold standard for diagnosis of mitochondrial disorders because of the lack of sensitive biomarkers in serum. Fibroblast growth factor 21 (FGF-21) is a growth factor with regulatory roles in lipid metabolism and the starvation response, and concentrations are raised in skeletal muscle and serum in mice with mitochondrial respiratory chain deficiencies. We investigated in a retrospective diagnostic study whether FGF-21 could be a biomarker for human mitochondrial disorders. METHODS: We assessed samples from adults and children with mitochondrial disorders or non-mitochondrial neurological disorders (disease controls) from seven study centres in Europe and the USA, and recruited healthy volunteers (healthy controls), matched for age where possible, from the same centres. We used ELISA to measure FGF-21 concentrations in serum or plasma samples (abnormal values were defined as >200 pg/mL). We compared these concentrations with values for lactate, pyruvate, lactate-to-pyruvate ratio, and creatine kinase in serum or plasma and calculated sensitivity, specificity, and positive and negative predictive values for all biomarkers. FINDINGS: We analysed serum or plasma from 67 patients (41 adults and 26 children) with mitochondrial disorders, 34 disease controls (22 adults and 12 children), and 74 healthy controls. Mean FGF-21 concentrations in serum were 820 (SD 1151) pg/mL in adult and 1983 (1550) pg/mL in child patients with respiratory chain deficiencies and 76 (58) pg/mL in healthy controls. FGF-21 concentrations were high in patients with mitochondrial disorders affecting skeletal muscle but not in disease controls, including those with dystrophies. In patients with abnormal FGF-21 concentrations in serum, the odds ratio of having a muscle-manifesting mitochondrial disease was 132·0 (95% CI 38·7-450·3). For the identification of muscle-manifesting mitochondrial disease, the sensitivity was 92·3% (95% CI 81·5-97·9%) and specificity was 91·7% (84·8-96·1%). The positive and negative predictive values for FGF-21 were 84·2% (95% CI 72·1-92·5%) and 96·1 (90·4-98·9%). The accuracy of FGF-21 to correctly identify muscle-manifesting respiratory chain disorders was better than that for all conventional biomarkers. The area under the receiver-operating-characteristic curve for FGF-21 was 0·95; by comparison, the values for other biomarkers were 0·83 lactate (p=0·037, 0·83 for pyruvate (p=0·015), 0·72 for the lactate-to-pyruvate ratio (p=0·0002), and 0·77 for creatine kinase (p=0·013). INTERPRETATION: Measurement of FGF-21 concentrations in serum identified primary muscle-manifesting respiratory chain deficiencies in adults and children and might be feasible as a first-line diagnostic test for these disorders to reduce the need for muscle biopsy. FUNDING: Sigrid Jusélius Foundation, Jane and Aatos Erkko Foundation, Molecular Medicine Institute of Finland, University of Helsinki, Helsinki University Central Hospital, Academy of Finland, Novo Nordisk, Arvo and Lea Ylppö Foundation.
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| 17. |
- van der Kolk, Birgitta W., et al.
(författare)
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Molecular pathways behind acquired obesity : Adipose tissue and skeletal muscle multiomics in monozygotic twin pairs discordant for BMI
- 2021
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Ingår i: Cell Reports Medicine. - : Elsevier BV. - 2666-3791. ; 2:4, s. 100226-
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Tidskriftsartikel (refereegranskat)abstract
- Tissue-specific mechanisms prompting obesity-related development complications in humans remain unclear. We apply multiomics analyses of subcutaneous adipose tissue and skeletal muscle to examine the effects of acquired obesity among 49 BMI-discordant monozygotic twin pairs. Overall, adipose tissue appears to be more affected by excess body weight than skeletal muscle. In heavier co-twins, we observe a transcriptional pattern of downregulated mitochondrial pathways in both tissues and upregulated inflammatory pathways in adipose tissue. In adipose tissue, heavier co-twins exhibit lower creatine levels; in skeletal muscle, glycolysis- and redox stress-related protein and metabolite levels remain higher. Furthermore, metabolomics analyses in both tissues reveal that several proinflammatory lipids are higher and six of the same lipid derivatives are lower in acquired obesity. Finally, in adipose tissue, but not in skeletal muscle, mitochondrial downregulation and upregulated inflammation are associated with a fatty liver, insulin resistance, and dyslipidemia, suggesting that adipose tissue dominates in acquired obesity.
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