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 Hif1 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, obesityassociated deterioration of glucose metabolism.

Serum Cystatin C Levels Are Associated With Obesity in Adolescents Aged 14–17 Years

“…However, in our study, no relationship between eGFR and obesity was found. The present study showed that the elevated circulating cystatin C levels in study participants with obesity may be to counteract obesity-related inflammation (27). Elevated cystatin C levels in adolescence were also associated with lipid metabolic dysregulation and cardiometabolic risk (28).…”

Assessment of kidney function: clinical indications for measured GFR

“…Creatinine-based equations may overestimate GFR when used in individuals with a BMI >30 kg/m 2 due to variable body composition, including reduced muscle mass [ 40 ]. In contrast, cystatin C synthesis has been shown to be upregulated in adipose tissue in obese individuals and to counteract inflammation of peripheral insulin-sensitive tissues [ 41 ]. Recently it has been shown that in severely obese subjects enrolled in medical weight loss programmes, cystatin C–based eGFR and indexation to actual body surface area (BSA) instead of 1.73 m 2 may provide the most accurate estimate of kidney function [ 42 ].…”

Prognostic Value of Pretreatment Serum Cystatin C Level in Nasopharyngeal Carcinoma Patients in the Intensity-modulated Radiotherapy Era

“…Serum cystatin C is a cysteine protease inhibitor and has been reported to be a significant predictor to carry prognostic or diagnostic information in human diseases, including various malignant cancers. [17][18][19][20][21][22][23][24][25][26] However, a study regarding the predictive value of serum cystatin C on NPC patients treated with IMRT has not been reported yet.…”

“…15 Cystatin C affects protein catabolism, antigen presentation, bone resorption, and hormone processing, and it can couple to cleavage of membrane and extracellular matrix proteins during tissue remodeling irregularly, and its homeostasis imbalance can lead to disease, including cancer. 16 Previous studies have shown that serum cystatin C level plays important roles in diagnosing and predicting human diseases, such as cirrhosis, 17 inflammation, 18 Parkinson's disease, 19 kidney disease, 20 and cardiovascular disease. 21 Many studies have reported that cystatin C plays important roles in predicting the prognosis and effect of clinical therapy of various cancers, such as myeloma, 22, esophageal cancer, 23 renal carcinoma, 24 upper tract urothelial carcinoma, 25 non-Hodgkin's B-cell lymphoma, 26 and so on.…”