Expression of inflammatory and insulin signaling genes in acute and chronic stress

The acute surgical stress response induces a short-term inflammatory and insulin resistant condition, commonly producing hyperglycemia, which is strongly associated to morbidity and mortality in postsurgical patients. The chronic state of renal insufficiency, on the other hand, represents a long-term stress associated with alarmingly high mortality rates, primarily due to cardiovascular complications, and is similarly related to chronic inflammation, oxidative stress, and insulin resistance. The underlying mechanisms are however incompletely understood.

A growing wealth of data emphasizes how mutual relationships between immunity and metabolism may contribute to disease, as well as the intrinsic properties of metabolically active organs, such as adipose tissue and skeletal muscle. Hence, in this translational study, we aimed to identify inflammatory and metabolic mediators being dysregulated and potentially contributing to homeostatic disturbances after surgery and in chronic kidney disease (CKD) patients.

In paper I, we evaluated the expression changes of 45 inflammatory and insulin signaling genes in skeletal muscle during major abdominal surgery of eight non-diabetic patients. In paper II, mRNA measurements of 21 genes were performed in 12 patients undergoing surgery on two separate adipose tissue depots: abdominal subcutaneous and omental adipose tissue. Overall, although some tissue specific alterations were observed, striking similarities were noted between the tissues. For example, we observed significantly increased mRNA levels of inflammatory signaling genes (e.g. interleukin 6 (IL6), suppressor of cytokine signaling 3 (SOCS3) and nicotinamide phosphoribosyltransferase (NAMPT)) in all tissues examined, but tumor necrosis factor (TNF) was only up-regulated in skeletal muscle. Insulin signaling pathway genes (e.g. insulin receptor substrate 1 (IRS1) and glucose transporter 4 (SLC2A4)), were only significantly affected in the adipose tissue depots.

Paper III and IV focused on abdominal subcutaneous adipose tissue. Gene expression levels were compared between CKD stage 5 patients and non-uremic controls to reveal uremic specific alterations. In accordance with surgical patients, adipose tissue from CKD patients showed a significant up-regulation of inflammatory pathway genes such as IL6 and SOCS3. Additionally, leptin and the oxidative stress-related genes uncoupling protein-2 (UCP2) and cytochrome b-245, alpha polypeptide (CYBA) were found to be down-regulated in relation to controls. Interestingly, we found reduced mRNA levels of the bone-associated factor osteoprotegerin (OPG), with reported implications for inflammation, vascular diseases and mortality, in uremic adipose tissue as compared to control tissue, despite higher OPG serum protein concentrations in patients and no apparent immunohistochemical differences. These observations suggest that aberrant gene expression of inflammatory and oxidative stress genes, as well as genes implicated in the control of vascular calcification, may be important features of the uremic adipose tissue, which may have significant effects on the uremic phenotype.

In summary, these studies contribute to our understanding of human gene expression alterations in association to clinical conditions producing acute and chronic stress, respectively, which may have implications for inflammatory and metabolic complications observed after surgery and in CKD. These results may also be relevant for other disorders in which pronounced inflammation and metabolic disturbances exacerbate the disease state, such as obesity and diabetes.

List of scientific papers

I. Witasp A, Nordfors L, Schalling M, Nygren J, Ljungqvist O, Thorell A (2009). "Increased expression of inflammatory pathway genes in skeletal muscle during surgery." Clin Nutr 28(3): 291-8. Epub 2009 Apr 5
https://pubmed.ncbi.nlm.nih.gov/19346035

II. Witasp A, Nordfors L, Schalling M, Nygren J, Ljungqvist O, Thorell A (2010). "Expression of Inflammatory and Insulin Signaling Genes in Adipose Tissue in Response to Elective Surgery." J Clin Endocrinol Metab May 5: Epub ahead of print
https://pubmed.ncbi.nlm.nih.gov/20444921

III. Witasp A, Carrero JJ, Heimbürger O, Lindholm B, Hammarqvist F, Stenvinkel P, Nordfors L (2010). "Increased expression of pro-inflammatory genes in abdominal subcutaneous fat in chronic kidney disease stage 5 patients." (Submitted)

IV. Witasp A, Carrero JJ, Hammarqvist F, Qureshi AR, Heimbürger O, Schalling M, Lindholm B, Nordfors L, Stenvinkel P (2010). "Expression of osteoprotegerin in human fat tissue; implications for chronic kidney disease." (Submitted)