posted on 2020-07-02, 14:00authored byAda AdminAda 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.
Funding
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).