Abstract
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 ΔBMI ≥ 3kg/m2) and concordant (n = 5, ΔBMI < 3kg/m2) 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 ± 1.0kg/m2) 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 ± 0.9kg/m2) 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-1α (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, https://dx.doi.org/10.6084/m9.figshare.3806286.v1.
Highlights
Adipose tissue is the most flexible organ of the body, readily adapting to changes in energy supply.Mitochondria are essential in these adaptations, as their molecular machinery governs the metabolic pathways by which nutrients are either oxidised or stored [1]
We demonstrated that mitochondria-related transcripts and pathways, mitochondrial DNA amount, mtDNA-encoded transcripts and oxidative phosphorylation (OXPHOS) protein levels are reduced in adipose tissue of obese vs lean monozygotic (MZ) co-twins [7]
This study of BMI-discordant MZ twin pairs shows that mitochondria-related transcriptional signature, at the nuclear and mitochondrial transcription level, is downregulated in adipocytes in the heavier co-twins
Summary
Adipose tissue is the most flexible organ of the body, readily adapting to changes in energy supply.Mitochondria are essential in these adaptations, as their molecular machinery governs the metabolic pathways by which nutrients are either oxidised or stored [1]. Adipose tissue is the most flexible organ of the body, readily adapting to changes in energy supply. The mitochondria’s own genome [2] and over 1500 genes from the nucleus [3] control the function and the energy adaptations of the mitochondria. We demonstrated that mitochondria-related transcripts and pathways, mitochondrial DNA (mtDNA) amount, mtDNA-encoded transcripts and oxidative phosphorylation (OXPHOS) protein levels are reduced in adipose tissue of obese vs lean monozygotic (MZ) co-twins [7]. Mitochondrial content measured by mtDNA copy-number [8, 9] and OXPHOS transcripts [9, 10] have been shown to be downregulated in adipose tissue in obesity, and basal oxygen consumption is lower in adipose tissue of obese compared with lean individuals [11]
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