Serum Cystatin C Concentrations Are Increased in Human Obesity in Relation to Over-Production by the Adipose Tissue
Article first published online: 17 OCT 2012
2012 North American Association for the Study of Obesity (NAASO)
Volume 20, Issue 9, page 1755, September 2012
How to Cite
Guerre-Millo, M. (2012), Serum Cystatin C Concentrations Are Increased in Human Obesity in Relation to Over-Production by the Adipose Tissue. Obesity, 20: 1755. doi: 10.1038/oby.2012.21
- Issue published online: 17 OCT 2012
- Article first published online: 17 OCT 2012
TO THE EDITOR: In our study “Potential Contribution of Adipose Tissue to Elevated Serum Cystatin C in Human Obesity” (1) published in 2009, we attempted to investigate the contribution of adipose tissue to serum cystatin C. Our previous observation showing that human preadipocytes release cystatin C in vitro (2) was the rationale for this study. Cystatin C is a small circulating protein produced by several cell types that has been proposed as a surrogate marker of renal filtration. In our study, we measured cystatin C in a large population of lean and obese subjects and, as clearly stated in our paper, we did no attempt to characterize the stage of kidney disease in this population. We used creatinine-based estimated glomerular filtration rate (eGFR) to compare cystatin C levels in lean and obese subjects within a similar range of eGFR. Although, we were very well aware that eGFR might be a biased estimate of GFR, the observation that serum cystatin C was higher in subjects with reduced eGFR than in those with high eGFR was reassuring. Several key points have to be emphasized: (i) the amount of increase of cystatin C between high and low eGFR groups was similar in lean and obese subjects, indicating that serum cystatin C raised with reduced eGFR independently of BMI, at least in the range of eGFR found in our explored population, (ii) serum cystatin C values were systematically higher in obese than in lean subjects in each eGFR tertile, as well as in the whole population after adjustment for age and other confounding factors and, (iii) while serum creatinine also increased with reduced eGFR, as expected, it was not affected by obesity in sharp contrast with cystatin C. Thus, in this population, we did find a specific elevation of cystatin C in obese participants. Moreover, explant experiments demonstrated that adipose tissue from obese subjects produces cystatin C in higher amounts than lean adipose tissue. These in vitro data demonstrate that adipose tissue is a source of cystatin C in a way that is not related to eGFR but to the status of adipose tissue itself, including enlarged adipocytes, hypoxia, proinflammatory cytokines production, increased number of macrophages, and probably other cellular and molecular alterations known to occur in obesity. In that, we agree with Salgado et al. that obesity-induced alterations in adipose tissue explain the link with serum cystatin C, although the exact mechanism of cystatin C upregulation was not investigated in our study. Moreover, considering the fact that the amount of adipose tissue is increased in obese subjects, our data suggest that the production rate of cystatin C in vivo by the adipose tissue is much higher in obese than in lean individuals.
Increased body fat mass is not the sole determinant of serum cystatin C in obese subjects and this might explain the discrepancies found in the literature regarding correlation with BMI. Care was taken in our paper to indicate that elevated serum cystatin C might or might not apply to more obese subjects (i.e., with BMI >40 kg/m2) and/or to subjects with more advanced kidney disease. In this study, we excluded three subjects with eGFR <30 ml/min/1.73m2, who were clearly discordant from the rest of the population. We apologize for the mistake noted by Salgado et al. in the legend of Figure 1, in which the third tertile of eGFR should be: (30.0–64.3 ml/min/1.73m2). Finally, we did not measure “body fat composition” in our study participants. Thus, we did not state that “cystatin C may be dependent of body fat composition”, as suggested by Salgado et al.
We believe that our data bring evidence that circulating cystatin C is elevated in obese as compared to lean individuals at least in the range of BMI and eGFR of the study population, and that this elevation that is likely to arise at least in part from adipose tissue. As indicated in the discussion, this opens new avenues to establish whether or not BMI has to be taken into account to adjust the cystatin C reference intervals (similar to male gender for creatinine), in large clinical studies including direct measurement of GFR.