Resistin / Fizz3 Expression in Relation to Obesity and Peroxisome Proliferator–Activated Receptor-γ Action in Humans

Abstract

Recent studies in murine models suggest that resistin (also called Fizz3 [1]), a novel cysteine-rich protein secreted by adipocytes, may represent the long-sought link between obesity and insulin resistance (2). Furthermore, peroxisome proliferator-activated receptor-␥ (PPAR-␥) agonists appear to inhibit resistin expression in murine adipocytes, providing a possible explanation for the mode of action of this class of insulin sensitizers (2). Using a fluorescent real-time reverse transcriptase-polymerase chain reaction-based assay, we found that resistin mRNA levels in whole adipose tissue samples were increased in morbidly obese humans compared with lean control subjects. However, in freshly isolated human adipocytes, resistin mRNA levels were very low and showed no correlation with BMI. Resistin mRNA was undetectable in preadipocytes, endothelial cells, and vascular smooth muscle cells, but it was readily detectable in circulating mononuclear cells. Although exposure of human mononuclear cells to PPAR-␥ agonists markedly upregulated fatty acid-binding protein-4 expression, these agents had no effect on mononuclear cell resistin expression. Finally, resistin mRNA was undetectable in adipocytes from a severely insulinresistant subject with a dominant-negative mutation in PPAR-␥ (3). We conclude that the recently described relationships of murine resistin/Fizz3 expression with obesity, insulin resistance, and PPAR-␥ action may not readily translate to humans. Further studies of this novel class of proteins are needed to clarify their roles in human metabolism. Diabetes 50:2199 -2202, 2001 S teppan et al. (2) recently reported a novel cysteine-rich secreted protein, which they termed resistin, the expression of which was markedly decreased by treatment of a murine adipocyte cell line with an agonist of the nuclear hormone receptor peroxisome proliferator-activated receptor-␥ (PPAR-␥). Serum levels of resistin were elevated in obese mice, and immunoneutralization of circulating resistin in these animals improved insulin sensitivity. Administration of recombinant resistin impaired insulin action in vivo in mice and ex vivo in an adipocyte cell line. These observations led the authors to conclude that resistin might represent an adipocyte-derived mediator of the link between obesity and insulin resistance. They also suggested that the suppression of resistin expression by PPAR-␥ agonists might explain the beneficial effects of these compounds in insulin-resistant states. Contrasting conclusions were reached by Way et al. (4), who found reduced resistin mRNA levels in white adipose tissue (WAT) of several obese rodent models. Furthermore, treating these animals with PPAR-␥ agonists increased resistin mRNA levels in WAT. These discrepant observations are difficult to reconcile and indicate the need for further studies. We developed a real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR)-based assay for human resistin using primers based in exons 1 and 2 of the human gene and used it to examine ...

Functional expression of glucose-dependent insulinotropic polypeptide receptors is coupled to differentiation in a human adipocyte model

“…Unlike rodents, most previous reports of human adipocytes, including differentiated SGBS cells, have found no conclusive evidence of resistin expression or secretion. 16,[36][37][38] Consequently, it is unlikely that GIP regulates fat accumulation in human adipocytes by activating lipoprotein lipase through a mechanism involving GIP-mediated secretion of resistin. Further investigation into the functional effects of GIP on differentiated SGBS cells could help towards understanding exactly how GIP regulates the fat accumulation in human adipocytes.…”

Regulation of human resistin gene expression in cell systems: an important role of stimulatory protein 1 interaction with a common promoter polymorphic site

“…In contrast, some reports demonstrate that a high level of resistin is not related to obesity or insulin resistance [6][7][8]. In particular, several studies with human resistin do not show any association between resistin expression and insulin resistance [9,10]. Levels of resistin expression are similar in normal, insulin-resistant and type 2 diabetic individuals [9].…”

Association between adipocytokines and insulin resistance in Indian hypertensive patients

“…7,8,16,17 Resistin, a novel cysteine-rich protein secreted by adipocytes, has been proposed to serve as a link between obesity and IR in rodents, but this has remained controversial. [18][19][20][21] Very few studies have been carried out to find the role of resistin in essential HT, but results are inconsistent. 11 All these adipocytokines such as leptin, adiponectin, and resistin have been associated with HT in either crosssectional or longitudinal studies.…”