Online_Appendix_Dedual_et_al_Revision_2.pdf (349.02 kB)

Obesity-Induced Increase in Cystatin C Alleviates Tissue Inflammation

Download (349.02 kB)
posted on 02.07.2020 by Ada Admin, Mara A. Dedual, Stephan Wueest, Tenagne D. Challa, Fabrizio C. Lucchini, Tim R. J. Aeppli, Marcela Borsigova, Andrea A. Mauracher, Stefano Vavassori, Jana Pachlopnik Schmid, Matthias Blüher, Daniel Konrad
We recently demonstrated that removal of one kidney (uninephrectomy; UniNx) in mice reduced high fat-diet (HFD)-induced adipose tissue inflammation thereby improving adipose tissue and hepatic insulin sensitivity. Of note, circulating cystatin C (CysC) levels were increased in UniNx compared to sham-operated mice. Importantly, CysC may have anti-inflammatory properties, and circulating CysC levels were reported to positively correlate with obesity in humans and as shown herein in HFD-fed mice. However, the causal relationship of such observation remains unclear. HFD feeding of CysC-deficient (CysC KO) mice deteriorated obesity-associated adipose tissue inflammation and dysfunction, as assessed by pro-inflammatory macrophage accumulation. In addition, mRNA expression of pro-inflammatory mediators was increased, whereas markers of adipocyte differentiation were decreased. Similarly to findings in adipose tissue, expression of pro-inflammatory cytokines was increased in liver and skeletal muscle of CysC KO mice. In line, HFD-induced hepatic insulin resistance and impairment of glucose tolerance were further aggravated in knockout mice. Consistently, chow-fed CysC KO mice were more susceptible to lipopolysaccharide (LPS)-induced adipose tissue inflammation. In people with obesity, circulating CysC levels correlated negatively with adipose tissue Hif1α as well as IL-6 mRNA expression. Moreover, healthy (i.e. insulin-sensitive) subjects with obesity depicted significantly higher mRNA expression of CysC in white adipose tissue. In conclusion, CysC is upregulated under obesity conditions and thereby counteracts inflammation of peripheral insulin-sensitive tissues and, thus, obesity-associated deterioration of glucose metabolism.


This work was supported by grants from the Wolfermann-Nägeli Foundation, the Children’s Research Centre, University Children’s Hospital Zurich, and the Forschungskredit “candoc”, University of Zurich (#FK-18-027) (all to MAD) as well as from the Swiss National Science Foundation (#310030-160129 and #310030-179344 to DK).



Logo branding