Role of inflammatory and mitochondria genes in adipose tissue and obesity

Obesity is rapidly increasing in prevalence around the world together with its complications such as dyslipidemia, cardiovascular disease (CVD) and insulin resistance, which eventually may lead to type 2 diabetes (T2DM). The excess of adipose tissue, the hallmark of obesity, led us to study the adipose tissue as a contributor to obesity and insulin resistance. Both systemic and local, that is in adipose tissue, inflammation have in the recent years emerged as complications to obesity. This inflammation contributes to the infiltration of macrophages and to the insulin resistance in adipose tissue.

We investigated the role of inflammatory genes in the regulation of obesity in subcutaneous adipose tissue pieces. We found that several cytokines were significantly upregulated in obesity and this led us to investigate the secretion of the corresponding proteins. We found that monocyte chemoattractant protein 1 (MCP1) was the only upregulated chemokine on gene level to be secreted from both adipose tissue and isolated adipocytes. MCP1, since it is not secreted from the adipose tissue into the general circulation, seems to be a local inflammatory mediator. Other studies have shown its ability to induce insulin resistance in adipose tissue.

The gene arachidonate 5 lipoxygenase activating protein (ALOX5AP) was first implicated in CVD in men. We aimed to investigate its role in obesity in adipose tissue. We found the mRNA expression to be increased in obesity and strongly associate to insulin resistance measured as homeostasis model assessment (HOMA). The ALOX5AP protein FLAP, as well as its head enzyme 5-lipoxygenase (5-LO), were detected in adipocytes. We propose an increased synthesis of 5-LO products in adipose tissue in the obese, leading to an inflammatory profile and insulin resistance.

Mitochondrial dysfunction has recently emerged as being associated with insulin resistance, firstly in skeletal muscle and subsequently in human adipose tissue. We found a significant downregulation in the expression of several electron transport chain genes selectively in T2DM in the visceral fat depot. We suggested this downregulation to be mediated by TNF-alpha and found that the cytokine downregulated the electron transport chain genes as well as significantly decreased the fatty acid oxidation in differentiated primary human adipocytes. We next investigated the amount of mitochondrial DNA/cell in adipose tissue in relation to clinical and experimental parameters of insulin sensitivity. We found an association between mtDNA/cell and basal and insulin stimulated lipogenesis, suggesting that adipose tissue mitochondria are local regulators of lipid metabolism.

We suggest a causal relationship between the inflammation present in adipose tissue in obesity with the downregulation of mitochondrial genes. Also we have found a potential new role for mitochondria in human adipose tissue as regulators of adipocyte metabolism. These findings add to the knowledge of the role of human adipose tissue in obesity and development of insulin resistance.

List of scientific papers

I. Dahlman I, Kaaman M, Olsson T, Tan GD, Bickerton AS, Wåhlén K, Andersson J, Nordström EA, Blomqvist L, Sjögren A, Forsgren M, Attersand A, Arner P (2005). "A unique role of monocyte chemoattractant protein 1 among chemokines in adipose tissue of obese subjects." J Clin Endocrinol Metab 90(10): 5834-40.
https://doi.org/10.1210/jc.2005-0369

II. Kaaman M, Rydén M, Axelsson T, Nordström E, Sicard A, Bouloumié A, Langin D, Arner P, Dahlman I (2006). "ALOX5AP expression, but not gene haplotypes, is associated with obesity and insulin resistance." Int J Obes (Lond) 30(3): 447-52.
https://doi.org/10.1038/sj.ijo.0803147

III. Dahlman I, Forsgren M, Sjögren A, Nordström EA, Kaaman M, Näslund E, Attersand A, Arner P (2006). "Downregulation of electron transport chain genes in visceral adipose tissue in type 2 diabetes independent of obesity and possibly involving tumor necrosis factor-alpha." Diabetes 55(6): 1792-9.
https://doi.org/10.2337/db05-1421

IV. Kaaman M, Sparks LM, van Harmelen V, Smith SR, Sjölin E, Dahlman I, Arner P (2007). "Strong association between mitochondrial DNA copy number and lipogenesis in human white adipose tissue." Diabetologia. [Accepted]
https://doi.org/10.1007/s00125-007-0818-6