We investigated whether (1) subcutaneous adipose tissue (SAT) mitochondrial capacity predicts weight loss success and (2) weight loss ameliorates obesity-related SAT mitochondrial abnormalities.
SAT biopsies were obtained from 19 clinically healthy obese subjects (body mass index (BMI) 34.6±2.7 kg m–2) during a weight loss intervention (0, 5 and 12 months) and from 19 lean reference subjects (BMI 22.7±1.1 kg m–2) at baseline. Based on 1-year weight loss outcome, the subjects were divided into two groups: continuous weight losers (WL, n=6) and weight regainers (WR, n=13). Main outcome measures included SAT mitochondrial pathways from transcriptomics, mitochondrial amount (mitochondrial DNA (mtDNA), Porin protein levels), mtDNA-encoded transcripts, oxidative phosphorylation (OXPHOS) proteins, and plasma metabolites of the mitochondrial branched-chain amino-acid catabolism (BCAA) pathway. SAT and visceral adipose tissue (VAT) glucose uptake was measured with positron emission tomography.
Despite similar baseline clinical characteristics, SAT in the WL group exhibited higher gene expression level of nuclear-encoded mitochondrial pathways (P=0.0224 OXPHOS, P=0.0086 tricarboxylic acid cycle, P=0.0074 fatty acid beta-oxidation and P=0.0122 BCAA), mtDNA transcript COX1 (P=0.0229) and protein level of Porin (P=0.0462) than the WR group. Many baseline mitochondrial parameters correlated with WL success, and with SAT and VAT glucose uptake. During WL, the nuclear-encoded mitochondrial pathways were downregulated, together with increased plasma metabolite levels of BCAAs in both groups. MtDNA copy number increased in the WR group at 5 months (P=0.012), but decreased to baseline level between 5 and 12 months (P=0.015). The only significant change in the WL group for mtDNA was a reduction between 5 and 12 months (P=0.004). The levels of Porin did not change in either group upon WL.
Higher mitochondrial capacity in SAT predicts good long-term WL success. WL does not ameliorate SAT mitochondrial downregulation and based on pathway expression, may paradoxically further reduce it.
The transcriptomics data generated in this study have been deposited to the Gene Expression Omnibus public repository, accession number GSE103769.
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Identification of TBX15 as an adipose master trans regulator of abdominal obesity genes
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We thank the study participants for their contribution to this research. We thank Professor Jaakko Kaprio for contributions in collecting the study participants. We acknowledge Laura Suojanen (MSc) for managing the WL intervention, Sari Räsänen (MSc) for analyzing the food diary data, Juha Rantanen, Mia Urjansson and Antti Muranen (MSc) for their technical expertise in the laboratory, and Biomedicum Functional Genomics Unit (FuGU) for their services. The study was supported by grants from the Academy of Finland (grant numbers 272376, 266286, 285963 and 265240), the Novo Nordisk Foundation, Finnish Diabetes Research Foundation, Gyllenberg Foundation, Jalmari and Rauha Ahokas Foundation, Finnish Foundation for Cardiovascular Research, Sigrid Jusélius Foundation, Biocentrum Helsinki, University of Helsinki, Maud Kuistila Foundation, Biomedicum Helsinki Foundation, Paulo Foundation, Finnish Medical Foundation and Emil Aaltonen Foundation, the donation from Paavo and Eila Salonen to Central Finland Hospital District of Central Finland, Turku University Hospital Research Funds and Helsinki University Hospital Research Funds.
RJ performed experiments, analyzed and collected the data, and wrote the manuscript. RR-T and ER performed experiments and analyzed data. KHP, SK and SH collected the material and data. LS performed the whole-genome transcriptomics analyses. RJ, MM and SJ analyzed data. AP and VV performed the metabolite analysis. KAV measured and analyzed the PET data. EP designed and supervised laboratory analyses. KHP, KAV and AR designed the study. KHP supervised the study and analyzed data. All authors participated in the writing and revision of the manuscript.
The authors declare no conflict of interest.
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Jokinen, R., Rinnankoski-Tuikka, R., Kaye, S. et al. Adipose tissue mitochondrial capacity associates with long-term weight loss success. Int J Obes 42, 817–825 (2018). https://doi.org/10.1038/ijo.2017.299
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