Obesity-Induced Increase in Cystatin C Alleviates Tissue Inflammation

Abstract

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<i> Hif1α</i> as well as <i>IL-6</i> mRNA expression. Moreover, healthy (i.e. insulin-sensitive) subjects with obesity depicted significantly higher mRNA expression of <i>CysC</i> 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.