Impaired Mitochondrial Biogenesis in Adipose Tissue in Acquired Obesity

Abstract

Low mitochondrial number and activity have been suggested as underlying factors in obesity, type 2 diabetes, and metabolic syndrome. However, the stage at which mitochondrial dysfunction manifests in adipose tissue after the onset of obesity remains unknown. Here we examined subcutaneous adipose tissue (SAT) samples from healthy monozygotic twin pairs, 22.8-36.2 years of age, who were discordant (ΔBMI >3 kg/m(2), mean length of discordance 6.3 ± 0.3 years, n = 26) and concordant (ΔBMI <3 kg/m(2), n = 14) for body weight, and assessed their detailed mitochondrial metabolic characteristics: mitochondrial-related transcriptomes with dysregulated pathways, mitochondrial DNA (mtDNA) amount, mtDNA-encoded transcripts, and mitochondrial oxidative phosphorylation (OXPHOS) protein levels. We report global expressional downregulation of mitochondrial oxidative pathways with concomitant downregulation of mtDNA amount, mtDNA-dependent translation system, and protein levels of the OXPHOS machinery in the obese compared with the lean co-twins. Pathway analysis indicated downshifting of fatty acid oxidation, ketone body production and breakdown, and the tricarboxylic acid cycle, which inversely correlated with adiposity, insulin resistance, and inflammatory cytokines. Our results suggest that mitochondrial biogenesis, oxidative metabolic pathways, and OXPHOS proteins in SAT are downregulated in acquired obesity, and are associated with metabolic disturbances already at the preclinical stage.

Gene expression profile of subcutaneous adipose tissue in BMI-discordant monozygotic twin pairs unravels molecular and clinical changes associated with sub-types of obesity

“…16 The participants have been described previously as has the targeted analysis of genes regulating the mitochondria. 11,12 In brief, the mean BMI difference within the twin pairs was 6 kg m − 2 , and mean age 30.2 years at the time of clinical study. The twins were healthy, with the exception of one obese twin with inactive ulcerative colitis (treated with mesalazine and azathioprine), and another obese twin with T2DM (treated with metformin and insulin).…”

“…17 We also recorded nutritional intake with a 3-day food diary, physical activity by Baecke indices. 12,20 Current daily smoking status for the twins was assessed by questionnaire.…”

“…We used the RNeasy Lipid Tissue Mini Kit (Qiagen, Redwood City, CA, USA) to extract SAT RNA, 12 treated it with DNase I (Qiagen) and hybridised 250 ng to Affymetrix U133Plus2.0 microarray (Affymetrix, www.affymetrix. com) to detect gene expression.…”

“…[3][4][5][6] Changes include an increase in number and size of adipocytes, infiltration of adipose tissue (AT) by immune cells and relative rarefaction of blood vessels and neural structures. [3][4][5][6] Whole-genome scale SAT transcriptomics studies have revealed various genes and pathways associated with upregulation of inflammation [7][8][9][10][11] and immune response, 7,8 and downregulation of mitochondrial pathways, 8,10,12 insulin-signalling 13 and lipid metabolism 8 in obesity. Further, targeted SAT transcriptomics studies comparing metabolically (MHO) healthy and unhealthy (MUO) obese individuals have found more downregulation of branched chain amino acid (BCAA) degradation in MUO than in MHO group.…”

Mitochondrial Actions for Fat Browning and Energy Expenditure in White Adipose Tissue

“…This paper is under submission. A recent study with human twins showed that adiposity is correlated with downshifting of fatty acid oxidation and that, indeed, mitochondrial biogenesis, oxidative metabolic pathways and OXPHOS proteins in subcutaneous adipose tissue are down regulated in acquired obesity [89]. Thus, WAT FAO stimulation can be considered a target to develop therapies for prevention and treatment of obesity, insulin resistance and related pathologies via energy expenditure augmentation and fat loss.…”