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. 2019 Sep 1;110(3):605-616.
doi: 10.1093/ajcn/nqz144.

Persistent low body weight in humans is associated with higher mitochondrial activity in white adipose tissue

Yiin Ling  1   2 , Jérôme Carayol  3 , Bogdan Galusca  1   2 , Carles Canto  3 , Christophe Montaurier  4 , Alice Matone  5 , Irene Vassallo  6 , Kaori Minehira  3 , Virginie Alexandre  3 , Ornella Cominetti  7 , Antonio Núñez Galindo  7 , John Corthésy  7 , Loïc Dayon  7 , Aline Charpagne  8 , Sylviane Métairon  8 , Frédéric Raymond  8 , Patrick Descombes  8 , François Casteillo  9 , Michel Peoc'h  9 , Radu Palaghiu  10 , Léonard Féasson  11 , Yves Boirie  4 , Bruno Estour  1   2 , Jörg Hager  3 , Natacha Germain  1   2 , Nele Gheldof  3
Affiliations

Persistent low body weight in humans is associated with higher mitochondrial activity in white adipose tissue

Yiin Ling et al. Am J Clin Nutr. .

Abstract

Background: Constitutional thinness (CT) is a state of low but stable body weight (BMI ≤18 kg/m2). CT subjects have normal-range hormonal profiles and food intake but exhibit resistance to weight gain despite living in the modern world's obesogenic environment.

Objective: The goal of this study is to identify molecular mechanisms underlying this protective phenotype against weight gain.

Methods: We conducted a clinical overfeeding study on 30 CT subjects and 30 controls (BMI 20-25 kg/m2) matched for age and sex. We performed clinical and integrative molecular and transcriptomic analyses on white adipose and muscle tissues.

Results: Our results demonstrate that adipocytes were markedly smaller in CT individuals (mean ± SEM: 2174 ± 142 μm 2) compared with controls (3586 ± 216 μm2) (P < 0.01). The mitochondrial respiratory capacity was higher in CT adipose tissue, particularly at the level of complex II of the electron transport chain (2.2-fold increase; P < 0.01). This higher activity was paralleled by an increase in mitochondrial number (CT compared with control: 784 ± 27 compared with 675 ± 30 mitochondrial DNA molecules per cell; P < 0.05). No evidence for uncoupled respiration or "browning" of the white adipose tissue was found. In accordance with the mitochondrial differences, CT subjects had a distinct adipose transcriptomic profile [62 differentially expressed genes (false discovery rate of 0.1 and log fold change >0.75)], with many differentially expressed genes associating with positive metabolic outcomes. Pathway analyses revealed an increase in fatty acid oxidation ( P = 3 × 10-04) but also triglyceride biosynthesis (P = 3.6 × 10-04). No differential response to the overfeeding was observed in the 2 groups.

Conclusions: The distinct molecular signature of the adipose tissue in CT individuals suggests the presence of augm ented futile lipid cycling, rather than mitochondrial uncoupling, as a way to increase energy expenditure in CT individuals. We propose that increased mitochondrial function in adipose tissue is an important mediator in sustaining the low body weight in CT individuals. This knowledge could ultimately allow more targeted approaches for weight management treatment strategies. This trial was registered at clinicaltrials.gov as NCT02004821.

Keywords: constitutional thinness; futile lipid cycling; mitochondria; proteomics; respiration; transcriptome analysis; white adipose tissue.

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Figures

FIGURE 1
FIGURE 1
Distinct differences in adipose tissue in constitutional thinness (CT). (A) Adipocyte area (μm2) measured by histological analysis. Values are expressed as mean and SEM. Mean values are from at least 10 pictures per slide (capturing more than 1000 cells per sample). Black bars correspond to CT individuals ( n = 29, 15 females and 14 males), while white bars correspond to the controls (n = 29, 15 females and 14 males). (B) Respirometry analyses in subcutaneous white adipose tissue (sWAT) using high-resolution respirometry. Values are expressed as mean and SEM from 10 CT individuals (5 females, 5 males; black bars) and 13 controls (9 females, 4 males; white bars) before and after overfeeding (OF; dashed bars). CI, complex I respiration; CI + CII, complex I and II respiration; CII, complex II activity alone; ETS, maximal electron transport system capacity. (C) Mitochondrial DNA content in sWAT at baseline in CT individuals ( n = 29) compared with controls (n = 29). Associations between CT status and variables were tested using a logistic regression adjusted on confounders (age and sex) at baseline and after intervention. Statistical significance level after correction for multiple testing when comparing CT versus controls is indicated by * for P < 0.05 and ** for P < 0.01, while # indicates a significance level at P < 0.05 of the intervention (before vs after intervention).
FIGURE 2
FIGURE 2
Transcriptomic analyses of adipose tissue at baseline. (A) Volcano plot showing differential expression of constitutional thinness (CT) (n = 30) compared with control (n = 30) individuals. Dashed lines correspond to the log2 fold change (FC) and false discovery rate (FDR) of 10%. The top differentially expressed hits are represented by orange dots, the significant hits but not strongly differentially expressed are represented by dark blue dots, and the nonsignificant hits not selected are represented by light blue dots. Differential expression was tested by using a logistic regression model correcting for age and sex followed by a Wald test to assess the statistical significance of the coefficient of interest. As no sex interaction was found, association was evaluated without interaction term. Benjamini–Hochberg multiple testing correction was applied within the fitted model on the derived P values (FDR). (B) Correlation is shown between RNA sequencing (RNA-seq) and Nanostring gene expression analysis of top 65 differentially expressed genes, tested using a nonparametric Spearman correlation (Spearman's r = 0.8926; 95% CI: 0.82, 0.94; P < 0.0001). (C) Ingenuity Pathway Analysis showing the top 5 significantly affected pathways. Genes that passed the FDR-adjusted P value < 10% were used as input data (orange and dark blue dots in the volcano plot, corresponding to 753 genes). Percentage overlap with the corresponding pathway is shown, as well as the number of hits compared with total number of genes in the pathway in parentheses.
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