Mitochondria-related transcriptional signature is downregulated in adipocytes in obesity: a study of young healthy MZ twins
Artikel i vetenskaplig tidskrift, 2017

Low mitochondrial activity in adipose tissue is suggested to be an underlying factor in obesity and its metabolic complications. We aimed to find out whether mitochondrial measures are downregulated in obesity also in isolated adipocytes. We studied young adult monozygotic (MZ) twin pairs discordant (n = 14, intrapair difference Delta BMI ae 3 kg/m(2)) and concordant (n = 5, Delta BMI < 3 kg/m(2)) for BMI, identified from ten birth cohorts of 22- to 36-year-old Finnish twins. Abdominal body fat distribution (MRI), liver fat content (magnetic resonance spectroscopy), insulin sensitivity (OGTT), high-sensitivity C-reactive protein, serum lipids and adipokines were measured. Subcutaneous abdominal adipose tissue biopsies were obtained to analyse the transcriptomics patterns of the isolated adipocytes as well as of the whole adipose tissue. Mitochondrial DNA transcript levels in adipocytes were measured by quantitative real-time PCR. Western blots of oxidative phosphorylation (OXPHOS) protein levels in adipocytes were performed in obese and lean unrelated individuals. The heavier (BMI 29.9 +/- 1.0 kg/m(2)) co-twins of the discordant twin pairs had more subcutaneous, intra-abdominal and liver fat and were more insulin resistant (p < 0.01 for all measures) than the lighter (24.1 +/- 0.9 kg/m(2)) co-twins. Altogether, 2538 genes in adipocytes and 2135 in adipose tissue were significantly differentially expressed (nominal p < 0.05) between the co-twins. Pathway analysis of these transcripts in both isolated adipocytes and adipose tissue revealed that the heavier co-twins displayed reduced expression of genes relating to mitochondrial pathways, a result that was replicated when analysing the pathways behind the most consistently downregulated genes in the heavier co-twins (in at least 12 out of 14 pairs). Consistently upregulated genes in adipocytes were related to inflammation. We confirmed that mitochondrial DNA transcript levels (12S RNA, 16S RNA, COX1, ND5, CYTB), expression of mitochondrial ribosomal protein transcripts and a major mitochondrial regulator PGC-1 alpha (also known as PPARGC1A) were reduced in the heavier co-twins' adipocytes (p < 0.05). OXPHOS protein levels of complexes I and III in adipocytes were lower in obese than in lean individuals. Subcutaneous abdominal adipocytes in obesity show global expressional downregulation of oxidative pathways, mitochondrial transcripts and OXPHOS protein levels and upregulation of inflammatory pathways. The datasets analysed and generated during the current study are available in the figshare repository.

acquired obesity

human adipose-tissue

Endocrinology & Metabolism

tumor-necrosis-factor

biogenesis

Adipocytes

insulin-resistance

factor-alpha

Mitochondria

mice

Twins

expression

Gene expression

in-vivo

Obesity

fat-cell size

Författare

S. Heinonen

Helsingin Yliopisto

M. Muniandy

Helsingin Yliopisto

J. Buzkova

Helsingin Yliopisto

Adil Mardinoglu

Chalmers, Biologi och bioteknik, Systembiologi

A. Rodriguez

Instituto de Salud Carlos III

Universidad de Navarra

G. Fruhbeck

Instituto de Salud Carlos III

Universidad de Navarra

A. Hakkarainen

Helsinki University Central Hospital

J. Lundbom

Helsinki University Central Hospital

Heinrich Heine Universitat

N. Lundbom

Helsinki University Central Hospital

J. Kaprio

Helsingin Yliopisto

National Institute for Health and Welfare

A. Rissanen

Helsinki University Central Hospital

Helsingin Yliopisto

K. H. Pietilainen

Helsingin Yliopisto

Helsinki University Central Hospital

Diabetologia

0012-186X (ISSN) 1432-0428 (eISSN)

Vol. 60 169-181

Ämneskategorier

Medicinsk genetik

Genetik

Styrkeområden

Livsvetenskaper och teknik

DOI

10.1007/s00125-016-4121-2