Characterising metabolically healthy obesity in weight-discordant monozygotic twins

Naukkarinen, Jussi; Heinonen, Sini; Hakkarainen, Antti; Lundbom, Jesper; Vuolteenaho, Katriina; Saarinen, Lilli; Hautaniemi, Sampsa; Rodrı́guez, Amaia; Frühbeck, Gema; Pajunen, Pia; Hyötyläinen, Tuulia; Orešič, Matej; Moilanen, Eeva; Suomalainen, Anu; Lundbom, Nina; Kaprio, Jaakko; Rissanen, A.; Pietiläinen, Kirsi H.

doi:10.1007/s00125-013-3066-y

Cited by 129 publications

(152 citation statements)

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“…In contrast, obese patients exhibiting insulin resistance, increased blood pressure, and dyslipidemia are considered as having metabolically abnormal obesity (MAO) (6). The lack of consensus criteria to define MHO does not allow the accurate estimation of the prevalence of the MHO and MAO phenotypes, making the comparison between different studies difficult (4,7). In this sense, the reported prevalence of MHO varies widely, ranging from 3 to 57% of obese patients, depending on the method used to define this condition (5,(8)(9)(10).…”

Section: Discussionmentioning

confidence: 99%

Increased Cardiometabolic Risk Factors and Inflammation in Adipose Tissue in Obese Subjects Classified as Metabolically Healthy

et al. 2014

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OBJECTIVEIt has been suggested that individuals with the condition known as metabolically healthy obesity (MHO) may not have the same increased risk for the development of metabolic abnormalities as their non-metabolically healthy counterparts. However, the validity of this concept has recently been challenged, since it may not translate into lower morbidity and mortality. The aim of the current study was to compare the cardiometabolic/inflammatory profile and the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes (T2D) in patients categorized as having MHO or metabolically abnormal obesity (MAO). RESEARCH DESIGN AND METHODSWe performed a cross-sectional analysis to compare the cardiometabolic/inflammatory profile of 222 MHO and 222 MAO patients (62% women) matched by age, including 255 lean subjects as reference (cohort 1). In a second cohort, we analyzed the adipokine profile and the expression of genes involved in inflammation and extracellular matrix remodeling in visceral adipose tissue (VAT; n = 82) and liver (n = 55). RESULTSThe cardiometabolic and inflammatory profiles (CRP, fibrinogen, uric acid, leukocyte count, and hepatic enzymes) were similarly increased in MHO and MAO in both cohorts. Moreover, above 30% of patients classified as MHO according to fasting plasma glucose exhibited IGT or T2D. The profile of classic (leptin, adiponectin, resistin) as well as novel (serum amyloid A and matrix metallopeptidase 9) adipokines was almost identical in MHO and MAO groups in cohort 2. Expression of genes involved in inflammation and tissue remodeling in VAT and liver showed a similar alteration pattern in MHO and MAO individuals. CONCLUSIONSThe current study provides evidence for the existence of a comparable adverse cardiometabolic profile in MHO and MAO patients; thus the MHO concept should be applied with caution. A better identification of the obesity phenotypes and a more precise diagnosis are needed for improving the management of obese individuals.

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Section: Discussionmentioning

confidence: 99%

Increased Cardiometabolic Risk Factors and Inflammation in Adipose Tissue in Obese Subjects Classified as Metabolically Healthy

et al. 2014

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“…In subcutaneous and visceral adipose tissue obtained during surgery, essential amino acids, leucine, glutamine and serine and 2-ketoisocaproic acid differed significantly between obese and lean subjects [41]. In our earlier study of MZ twin pairs discordant for obesity, serum levels of insulin secretionenhancing BCAA were increased in obese male co-twins and adipose tissue transcription profiles exposed significant down-regulation of genes involved with mitochondrial BCAA catabolism [3,42] indicating that the increase in plasma BCAA levels may be due to their decreased oxidation in the peripheral tissues. Our finding of an inverse association between glutamine and insulin resistance is in accordance with previously published data from the Framingham Heart Study and the Malmö Diet and Cancer Study [43].…”

Section: Discussionmentioning

confidence: 82%

“…Although body mass index (BMI) predicts the incidence of diabetes and coronary heart disease [1], it cannot by itself identify obese individuals who remain metabolically healthy and normal weight individuals who present disturbed lipid or glucose metabolism and increased cardiovascular risk [2,3]. The assessment of body fat distribution can further improve the evaluation of the subject's metabolic risk.…”

Section: Introductionmentioning

confidence: 99%

“…The assessment of body fat distribution can further improve the evaluation of the subject's metabolic risk. Indeed, observational studies have shown that abdominal obesity, especially excess visceral [4,5], together with liver fat [3] accumulation is the main driver of cardiometabolic risk factors and disease independently of BMI. Traditionally, serum lipids, glucose and insulin were used as markers of cardiovascular risk.…”

Section: Introductionmentioning

confidence: 99%

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Abdominal obesity and circulating metabolites: A twin study approach

et al. 2016

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Objective. To investigate how obesity, insulin resistance and low-grade inflammation link to circulating metabolites, and whether the connections are due to genetic or environmental factors.Subjects and methods. Circulating serum metabolites were determined by proton NMR spectroscopy. Data from 1368 (531 monozygotic (MZ) and 837 dizygotic (DZ)) twins were used for bivariate twin modeling to derive the genetic (r g ) and environmental (r e ) correlations between waist circumference (WC) and serum metabolites. Detailed examination of the associations between fat distribution (DEXA) and metabolic health (HOMA-IR, CRP) was performed among 286 twins including 33 BMI-discordant MZ pairs. Results. Fat, especially in the abdominal area (i.e. WC, android fat % and android to gynoid fat ratio), together with HOMA-IR and CRP correlated significantly with an atherogenic lipoprotein profile, higher levels of branched-chain (BCAA) and aromatic amino acids, higher levels of glycoprotein, and a more saturated fatty acid profile. In contrast, a higher proportion of gynoid to total fat associated with a favorable metabolite profile. There was a significant genetic overlap between WC and several metabolites, most strongly with phenylalanine (r g = 0.40), glycoprotein (r g = 0.37), serum triglycerides (r g = 0.36), BCAAs (r g = 0.30-0.40), HDL Keywords:Twin study Bivariate twin model 2 0 1 6 ) 1 1 Conclusions. A wide range of unfavorable alterations in the serum metabolome was associated with abdominal obesity, insulin resistance and low-grade inflammation. Twin modeling and obesity-discordant twin analysis suggest that these associations are partly explained by shared genes but also reflect mechanisms independent of genetic liability. Genetic correlation Serum metabolites Obesity measures M E T A B O L I S M C L I N I C A L A N D E X P E R I M E N T A L 6 5 (

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“…Lipids with higher UFAs are generally associated with improved cellular maintenance. 57 In hibernating animals, fatty acid composition of stored lipids affects the depth and duration of torpor. Diets rich in MUFAs and PUFAs have a beneficial impact on mammalian torpor, whereas diets rich in SFAs have a negative effect.…”

Section: The Coordination Of Disparate Lipid-metabolic Pathways By Nhmentioning

confidence: 99%

Nuclear hormone receptors as mediators of metabolic adaptability following reproductive perturbations

Ratnappan

Ward

Ghazi

2016

Worm

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Previously, we identified a group of nuclear hormone receptors (NHRs) that promote longevity in the nematode Caenorhabditis elegans following germline-stem cell (GSC) loss. This group included NHR-49, the worm protein that performs functions similar to vertebrate PPARa, a key regulator of lipid metabolism. We showed that NHR-49/PPARa enhances mitochondrial b-oxidation and fatty acid desaturation upon germline removal, and through the coordinated enhancement of these processes allows the animal to retain lipid homeostasis and undergo lifespan extension. NHR-49/ PPARa expression is elevated in GSC-ablated animals, in part, by DAF-16/FOXO3A and TCER-1/ TCERG1, two other conserved, pro-longevity transcriptional regulators that are essential for germline-less longevity. In exploring the roles of the other pro-longevity NHRs, we discovered that one of them, NHR-71/HNF4, physically interacted with NHR-49/PPARa. NHR-71/HNF4 did not have a broad impact on the expression of b-oxidation and desaturation targets of NHR-49/PPARa. But, both NHR-49/PPARa and NHR-71/HNF4 were essential for the increased expression of DAF-16/ FOXO3A-and TCER-1/TCERG1-downstream target genes. In addition, nhr-49 inactivation caused a striking membrane localization of KRI-1, the only known common upstream regulator of DAF-16/ FOXO3A and TCER-1/TCERG1, suggesting that it may operate in a positive feedback loop to potentiate the activity of this pathway. These data underscore how selective interactions between NHRs that function as nodes in metabolic networks, confer functional specificity in response to different physiological stimuli.

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Characterising metabolically healthy obesity in weight-discordant monozygotic twins

Abstract: Our results suggest that maintenance of high mitochondrial transcription and lack of inflammation in SAT are associated with low liver fat and MHO.

Cited by 129 publications

References 54 publications

Increased Cardiometabolic Risk Factors and Inflammation in Adipose Tissue in Obese Subjects Classified as Metabolically Healthy

Increased Cardiometabolic Risk Factors and Inflammation in Adipose Tissue in Obese Subjects Classified as Metabolically Healthy

Abdominal obesity and circulating metabolites: A twin study approach

Nuclear hormone receptors as mediators of metabolic adaptability following reproductive perturbations

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