(1/446) A family of tissue-specific resistin-like molecules.
We have identified a family of resistin-like molecules (RELMs) in rodents and humans. Resistin is a hormone produced by fat cells. RELMalpha is a secreted protein that has a restricted tissue distribution with highest levels in adipose tissue. Another family member, RELMbeta, is a secreted protein expressed only in the gastrointestinal tract, particularly the colon, in both mouse and human. RELMbeta gene expression is highest in proliferative epithelial cells and is markedly increased in tumors, suggesting a role in intestinal proliferation. Resistin and the RELMs share a cysteine composition and other signature features. Thus, the RELMs together with resistin comprise a class of tissue-specific signaling molecules. (+info)
(2/446) A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation.
A 12.5-kDa cysteine-rich adipose tissue-specific secretory factor (ADSF/resistin) is a novel secreted protein rich in serine and cysteine residues with a unique cysteine repeat motif of CX(12)CX(8)CXCX(3)CX(10)CXCXCX(9)CC. A single 0.8-kilobase mRNA coding for this protein was found in various murine white adipose tissues including inguinal and epididymal fats and also in brown adipose tissue but not in any other tissues examined. Two species of mRNAs with sizes of 1.4 and 0.8 kilobases were found in rat adipose tissue. Sequence analysis indicates that this is because of two polyadenylation signals, the proximal one with the sequence AATACA with a single base mismatch from murine AATAAA and the distal consensus sequence AATAAA. The mRNA level was markedly increased during 3T3-L1 and primary preadipocyte differentiation into adipocytes. Its expression in adipose tissue is under tight nutritional and hormonal regulation; the mRNA level was very low during fasting and increased 25-fold when fasted mice were refed a high carbohydrate diet. It was also very low in adipose tissue of streptozotocin-diabetes and increased 23-fold upon insulin administration. Upon treatment with the conditioned medium from COS cells transfected with the expression vector, conversion of 3T3-L1 cells to adipocytes was inhibited by 80%. The regulated expression pattern suggesting this factor as an adipose sensor for the nutritional state of the animals and the inhibitory effect on adipocyte differentiation implicate its function as a feedback regulator of adipogenesis. (+info)
(3/446) Dimerization of resistin and resistin-like molecules is determined by a single cysteine.
Resistin is a peptide hormone secreted by adipocytes. Cysteine residues comprise 11 of 94 (12%) amino acids in resistin. The arrangement of these cysteines is unique to resistin and its recently discovered family of tissue-specific secreted proteins, which have been independently termed resistin-like molecules (RELMs) and the FIZZ (found in inflammatory zone) family. Here we show that resistin is a disulfide-linked homodimer that can be converted to a monomer by reducing conditions. The intestine-specific RELM beta has similar characteristics. Remarkably, however, the adipose-enriched RELM alpha is a monomer under non-reducing conditions. We note that RELM alpha lacks a cysteine residue, closest to the cleaved N terminus, that is present in resistin and RELM beta in multiple species. Conversion of this cysteine to alanine abolishes dimerization of resistin. Thus, a single disulfide bond is necessary to connect two resistin subunits in a homodimer. The additional 10 cysteines most likely participate in intramolecular disulfide bonds that define the conserved structure of the family members. The monomeric nature of RELM alpha suggests structural and potentially functional divergence between resistin and this close family member. (+info)
(4/446) Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists.
Elevated levels of the hormone resistin, which is secreted by fat cells, are proposed to cause insulin resistance and to serve as a link between obesity and type 2 diabetes. In this report we show that resistin expression is significantly decreased in the white adipose tissue of several different models of obesity including the ob/ob, db/db, tub/tub, and KKA(y) mice compared with their lean counterparts. Furthermore, in response to several different classes of antidiabetic peroxisome proliferator-activated receptor gamma agonists, adipose tissue resistin expression is increased in both ob/ob mice and Zucker diabetic fatty rats. These data demonstrate that experimental obesity in rodents is associated with severely defective resistin expression, and decreases in resistin expression are not required for the antidiabetic actions of peroxisome proliferator-activated receptor gamma agonists. (+info)
(5/446) Isoproterenol inhibits resistin gene expression through a G(S)-protein-coupled pathway in 3T3-L1 adipocytes.
Resistin was recently identified as a hormone secreted by adipocytes which leads to insulin resistance in vivo and in vitro and might therefore be an important link between obesity and diabetes. To clarify the regulation of resistin gene expression, 3T3-L1 adipocytes were treated with various agents known to modulate insulin sensitivity, and resistin mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction. Interestingly, isoproterenol treatment reduced the level of resistin mRNA to 20% of non-treated control cells. This effect was dose-dependent with significant inhibition occurring at concentrations as low as 10 nM isoproterenol. Moreover, pretreatment of adipocytes with the beta-adrenergic antagonist propranolol almost completely reversed the inhibitory effect of isoproterenol, whereas addition of the alpha-adrenergic antagonist phentolamine did not have any effect. Furthermore, the effect of isoproterenol could be mimicked by activation of G(S)-proteins and adenylyl cyclase. Thus, both cholera toxin and forskolin decreased resistin mRNA expression in a dose-dependent fashion by up to 90% of control levels. Taken together, these results suggest that resistin gene expression is regulated by a protein kinase A-dependent pathway in 3T3-L1 adipocytes. (+info)
(6/446) Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans.
Recent studies in murine models suggest that resistin (also called Fizz3 ), 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-gamma (PPAR-gamma) 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-gamma 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 insulin-resistant subject with a dominant-negative mutation in PPAR-gamma (3). We conclude that the recently described relationships of murine resistin/Fizz3 expression with obesity, insulin resistance, and PPAR-gamma action may not readily translate to humans. Further studies of this novel class of proteins are needed to clarify their roles in human metabolism. (+info)
(7/446) Inhibition by insulin of resistin gene expression in 3T3-L1 adipocytes.
Expression of the gene encoding resistin, a low molecular weight protein secreted from adipose tissue postulated to link obesity and type II diabetes, was examined in 3T3-L1 adipocytes. Resistin mRNA was detected in 3T3-L1 cells by day 3 following induction of differentiation into adipocytes; by day 4 the level of resistin mRNA peaked and remained high. The PPARgamma activators, rosiglitazone or darglitazone, reduced the level of resistin mRNA. Dexamethasone upregulated resistin mRNA level, but no effect was observed with the beta(3)-adrenoceptor agonist, BRL 37344. A substantial reduction in resistin mRNA level was observed with insulin, which induced decreases at physiological concentrations. Insulin may be a major inhibitor of resistin production, and this does not support a role for resistin in insulin resistance. (+info)
(8/446) Increased resistin expression in the adipose tissue of male prolactin transgenic mice and in male mice with elevated androgen levels.
The aim of this study was to investigate the regulation of resistin, a recently identified adipocyte-secreted peptide, in the adipose tissue of prolactin (PRL)-transgenic (tg) mice using ribonuclease protection assay. The level of resistin mRNA increased 3.5-fold in the adipose tissue of untreated male PRL-tg mice compared to controls. However, there was no difference in resistin expression in the adipose tissue of female PRL-tg mice compared to control mice. PRL-tg male mice have elevated serum testosterone levels and we therefore analyzed the effects of testosterone alone on resistin mRNA expression. Furthermore, the effects of elevated androgen levels on PRL receptor (PRLR) mRNA expression in the adipose tissue were investigated. Resistin mRNA increased 2.6-fold in the adipose tissue of control male mice with elevated serum androgen levels. In addition, PRLR mRNA expression was increased in the adipose tissue of male mice with elevated testosterone. These results suggest testosterone to be a regulator of resistin and PRLR mRNA expression in the adipose tissue of male mice. (+info)