Downregulation of Electron Transport Chain Genes in Visceral Adipose Tissue in Type 2 Diabetes Independent of Obesity and Possibly Involving Tumor Necrosis Factor-α

Abstract

Impaired oxidative phosphorylation is suggested as a factor behind insulin resistance of skeletal muscle in type 2 diabetes. The role of oxidative phosphorylation in adipose tissue was elucidated from results of Affymetrix gene profiling in subcutaneous and visceral adipose tissue of eight nonobese healthy, eight obese healthy, and eight obese type 2 diabetic women. Downregulation of several genes in the electron transport chain was the most prominent finding in visceral fat of type 2 diabetic women independent of obesity, but the gene pattern was distinct from that previously reported in skeletal muscle in type 2 diabetes. A similar but much weaker effect was observed in subcutaneous fat. Tumor necrosis factor-␣ (TNF-␣) is a major factor behind inflammation and insulin resistance in adipose tissue. TNF-␣ treatment decreased mRNA expression of electron transport chain genes and also inhibited fatty acid oxidation when differentiated human preadipocytes were treated with the cytokine for 48 h. Thus, type 2 diabetes is associated with a tissue-and region-specific downregulation of oxidative phosphorylation genes that is independent of obesity and at least in part mediated by TNF-␣, suggesting that impaired oxidative phosphorylation of visceral adipose tissue has pathogenic importance for development of type 2 diabetes. Diabetes 55:1792-1799, 2006

Adipose tissue pathways involved in weight loss of cancer cachexia

“…Under normal circumstances the rate of FA oxidation is low in fat cells, but can increase under catabolic conditions (Wang et al, 2003). The findings are opposite to those observed in the adipose tissue of obese and type-2 diabetic subjects (Dahlman et al, 2006;Henegar et al, 2008).…”

“…Gene expression profiling is a useful tool to identify pivotal regulatory pathways for altered function of adipose tissue (Clement et al, 2004;Dahlman et al, 2006). In this study we used global gene expression profiling to identify molecular pathways associated with weight loss in cancer cachexia.…”

Lipodystrophy in HIV 1-infected patients: lessons for obesity research

“…26 Other authors found a downregulation of expression of mitochondrial electron transport (OXPHOS) genes preferentially in visceral adipose tissue of obese patients developing type 2 diabetes. 27 In mice, weight gain has been associated with the downregulation of OXPHOS genes in visceral adipose tissue, 28 and in ob/ob mice, an animal model of obesity, there is reduced mtDNA in visceral adipose tissue. 29 Experimental modification of the respiratory chain system in adipose tissue through genetically-driven overexpression of mitochondrial uncoupling protein-1 (UCP1) in white adipose tissue protects mice from genetic or dietary-driven obesity, in association with enhanced mitochondrial biogenesis in white fat.…”

“…In summary, mitochondrial alterations are evident in adipose tissue from HALS patients and there is also evidence of mitochondrial dysfunction in type 2 diabetes associated with obesity. 27,34 However, it is also apparent that simple impairment of metabolic energy production by mitochondria in adipose tissue, which makes only a small contribution to overall energy expenditure, is not sufficient to explain the complexities of HALS or the overall metabolic syndrome associated with obesity. Recently recognized signaling properties of mitochondrial function for multiple aspects of adipocyte biology are likely to be the basis of these complex alterations, and mitochondrial activity could influence the myriad of adipokines and signaling molecules released by adipose tissue, thus influencing systemic metabolism.…”

BNIP3 is essential for mitochondrial bioenergetics during adipocyte remodelling in mice

“…Within adipocytes, mitochondria show robust changes in density and morphology under pathophysiological conditions [2,3]. Excess mitochondria occur with myopathy or cancer [4] and reduced mitochondria number and/or function is associated with obesity [5][6][7]. This suggests that tight quality control of the mitochondria may be critical for maintaining adipocyte function during adipocyte remodelling.…”