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

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.

Identification of ALK in Thinness

“…We next asked whether increased sympathetic tone to the adipose tissue also exists in constitutionally thin humans. We took advantage of the availability of fat tissue samples from a previously described clinical study on 30 well-characterized constitutionally thin individuals (Ling et al, 2019). Paralleling our findings in mice, we indeed found markedly increased NE levels in the WAT of constitutionally thin subjects compared to their age-and sex-matched controls (Figure 6B).…”

The unidentified hormonal defense against weight gain

“…This phenotype has been termed persistent thinness [38] or constitutional thinness [39] and is defined by a body mass index of �17.5 kg/m 2 but being otherwise healthy. One intriguing characteristic of these individuals is their desire to gain weight and their self-reported difficulties in doing so [39,40]. Interpreting this phenotype in light of the dual-intervention point model, it can be rationalized that the upper intervention point in constitutionally lean subjects must be under narrow biological control and that the homeostatic defense mechanisms against fatness are engaged even upon very small increases in adipose mass.…”

Invited Letter to Editor in response to: Constitutional thinness: body fat metabolism and skeletal muscle are important factors

“…We would like here to thank Dr Maffetone for his encouraging and constructive comment and collectively agree that body fat is a highly important criterion to consider in CT, especially given the recent study that showed smaller adipocytes but higher mitochondrial respiratory capacities in adipose tissue of CT participants (3) . Our systematic review, which exclusively focused on the inclusion criteria used in available publications, identified only two studies that considered body fat percentage in their inclusion criteriaenrolling participants with a body fat below 20 %.…”

“…Our conclusions and the constructive comment from Dr Maffetone call for further physiological and functional investigations of both adipose and muscle tissues in individuals with CT, to better understand and diagnose this condition and hopefully propose appropriate and effective intervention strategies favouring weight gain in this population. Mélina Bailly 1,2 , Natacha Germain 2,3 , Bogdan Galusca 2,3 , Daniel Courteix 1 , David Thivel 1 and Julien Verney 1…”