Endotrophin is associated with chronic multimorbidity and all-cause mortality in a cohort of elderly women

Abstract

Background: The signalling peptide endotrophin is derived through proteolytic cleavage of the carboxyl-terminal during formation of type VI collagen. It is expressed by most descendants of the mesenchymal stem cells lineage, including adipocytes and fibroblasts, and have been proposed to be a central extracellular matrix hormone associated with several age-related diseases. We aimed to assess the association of endotrophin with chronic disease incidence and death in older women. Methods: 5,602 elderly Danish women from the observational, prospective cohort: The Prospective Epidemiological Risk Factor (PERF) study were included in the analysis which covered baseline (BL) and follow-up (FU) 14 years later. An elastic net was used to investigate the relative importance of 58 variables to serum endotrophin-levels. 20 chronic diseases were defined on the basis of clinical variables available along with diagnoses extracted from both the National Patient Register, the National Diabetes Register and the Danish Cancer Registry. The cross-sectional associations between endotrophin-levels and these 17 chronic agerelated diseases were investigated using logistic regression and a set-analysis explored disease-combinations within multimorbidity. The association of endotrophin with mortality was assessed by Cox proportional hazard models. Findings: Formation of type III collagen (PRO-C3), age and creatine-levels were the most influential variables of endotrophin-levels. Several chronic diseases were significantly associated with endotrophin-levels independent of age and BMI including chronic kidney disease (BL OR=3.7, p < 0.001; FU OR = 7.9 p < 0.001), diabetes (BL OR = 1.5, p = 0.0015, FU OR=1.6, p = 0.004) and peripheral arterial disease (BL OR = 1.3, p = 0.029; FU OR=2.4, p < 0.001). Lastly, endotrophin-levels were significantly rising with number of morbidities (p < 0.001) and a predictor of death after adjusting for age and BMI (BL HR=1.95; FU HR = 2.00). Interpretation: Endotrophin was associated with death and increased with number of morbidities. Endotrophin may be a central hormone of fibroblast that warrant investigation and possible targeted intervention in several chronic diseases.

COL6A3-derived endotrophin mediates the effect of obesity on coronary artery disease: an integrative proteogenomics analysis

“…The major finding of this study is the mediating role of endotrophin in the effect of obesity on CAD in humans. Previous studies reported endotrophin as an important hormone that induces metabolic dysfunction, fibrosis, and inflammation in rodent models [40][41][42]57 , and cross-sectional studies in humans have found that increased circulating endotrophin level was observationally associated with cardiovascular events and all-cause mortality [43][44][45]58 . However, cross-sectional observational studies cannot disentangle cause and consequence.…”

“…Endotrophin is produced in multiple tissues, including adipose tissue 40,41 . Endotrophin strongly induces fibrosis and inflammation, and recent evidence suggests that it is involved in obesity-induced metabolic dysfunction [40][41][42][43][44][45] (Fig 4a).…”

Endotrophin neutralization through targeted antibody treatment protects from renal fibrosis in a podocyte ablation model

“…Endotrophin is a cleavage product of the α3 chain of collagen VI [ 10 ]. Since its first identification as a tumor promoting factor [ 11 , 12 ], more and more observations have linked endotrophin to various fibro-inflammatory conditions, including CKD [ [13] , [14] , [15] ]. Serum endotrophin levels independently correlate with mortality in CKD, suggesting that the accumulation of collagen VI and its cleavage product, endotrophin, promote mortality risk associated with CKD [ 13 ].…”

“…Recently, Karsdal et al. analyzed the association between serum endotrophin levels and various chronic diseases, and discovered that CKD mortality shows the strongest correlation with circulating endotrophin levels [ 15 ]. All the above evidence prompted us to propose endotrophin as a novel target for treatment of CKD.…”

Endotrophin: Nominated for best supporting actor in the fibro-inflammatory saga

“…In an article in EBioMedicine [1], Morten Karsdal and colleagues report the association of circulating levels of a recently described collagen VI cleavage product, referred to as endotrophin, with chronic disease incidence and death in an observational, prospective cohort of elderly Danish women. Participants in this Prospective Epidemiological Risk Factor Study provided fasting blood samples at baseline (n=5,602) and at follow-up (2,094) timepoints.…”