Assessment of circulating Wnt1 inducible signalling pathway protein 1 (WISP-1)/CCN4 as a novel biomarker of obesity
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WNT1 inducible signaling pathway protein 1 (WISP-1/CCN4) is a novel adipokine, which is upregulated in obesity, and induces a pro-inflammatory response in macrophages in-vitro. Preclinical observations suggested WISP-1/CCN4 as a potential candidate for novel obesity therapy targeting adipose tissue inflammation. Whether circulating levels of WISP-1/CCN4 in humans are altered in obesity and/or type 2 diabetes (T2DM) and in the postprandial state, however, is unknown. This study assessed circulating WISP-1/CCN4 levels in a) paired liquid meal tests and hyperinsulinemic- euglycemic clamps (cohort I, n = 26), b) healthy individuals (cohort II, n = 207) and c) individuals with different stages of obesity and glucose tolerance (cohort III, n = 253). Circulating plasma and serum WISP-1/CCN4 concentrations were measured using a commercially available ELISA. WISP-1/CCN4 levels were not influenced by changes in insulin and/or glucose during the tests. In healthy individuals, WISP-1/CCN4 was detectable in 13% of plasma samples with the intraclass correlation coefficient of 0.93 (95% CI: 0.84–0.96) and in 58.1% of the serum samples in cohort III. Circulating WISP-1/CCN4 positively correlated with body mass index, body fat percentage, leptin and triglyceride levels, hip circumference and fatty liver index. No differences in WISP-1/CCN4 levels between individuals with normal glucose tolerance, impaired glucose tolerance and T2DM were found. The circulating concentrations of WISP-1/CCN4 showed no acute regulation in postprandial state and correlated with anthropometrical obesity markers and lipid profiles. In healthy individuals, WISP-1/CCN4 levels are more often below the detection limit. Thus, serum WISP-1/CCN4 levels may be used as a suitable biomarker of obesity.
KeywordsCCN proteins Insulin resistance Obesity WISP-1/CCN4
CTGF/Cyr61/Nov) family proteins
European Prospective Investigation into Cancer and Nutrition
Fatty Liver Index
Homeostatic model assessment insulin resistance
Hyperinsulinemic euglycemic clamp
Impaired fasting glucose
Impaired glucose tolerance
Intrahepatic liver fat
Liquid meal challenges tests
Normal glucose tolerance
Type 2 diabetes mellitus
Visceral adipose tissue
WNT-inducible signaling pathway protein-1
We thank all study participants for their cooperation. We thank the Human Study Centre at the DIfE for data collection and biological sample logistics. We express thanks to Dr. Manuela Bergmann for her contribution by leading the underlying processes of data generation, as well as to Silke Navia Fruth and Herbert Piechot for their valuable assistance with biosamples management. Particular thanks are given to the EPIC Potsdam data manager - Ellen Kohlsdorf. We gratefully acknowledge the excellent technical assistance of Katrin Sprengel, and Tanja Ahrens. We thank Stephanie Sucher for her extensive advice regarding nutritional counselling and June Inderthal for reading and correcting the manuscript.
Study concept and design: AFHP, OP, and NR. Acquisition of data: CT, KA, TH, MK, SH, CG and SK. Analysis and interpretation of data: CT, KA, DMO, VM, MM, CG, MR, DMO, TH, MOW, HB, AFHP, OP, and NR. Drafting of the manuscript: CT, AFHP, OP, and NR. Critical revision of the manuscript: CT, KA, MR, VM, MM, MK, SH, UK, CH, SK, TH, DMO, MOW, HB, AFHP, OP and NR. Obtained funding: DMO and NR. All authors contributed to and approved the final version of the manuscript. AFHP, OP, and NR are the guarantors of this work and as such had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
This work was financially supported by grant from German Diabetes Center (DZD) (NR, DMO) and grant of European Foundation for Study of Diabetes (EFSD) (NR, DMO). The funding source had no role in study design, data collection, analysis or interpretation, report writing, or the decision to submit this paper for publication.
Compliance with ethical standards
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
Conflict of interest
The authors declare no conflict of interest.
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