Circulating resistin in lean, obese, and insulin-resistant mouse models: lack of association with insulinemia and glycemia

Abstract

.-Resistin is an adipocyte-secreted hormone proposed to link obesity with insulin resistance and diabetes, but no previous study has performed a joint quantitative evaluation of white adipose tissue (WAT) resistin mRNA expression and serum levels in relation to insulinemia and glycemia in mice. We have thus comparatively assessed WAT resistin mRNA expression and serum resistin levels in lean C57BL/6J mice and various mouse models of obesity, including diet-induced obese (DIO) C57BL/6J mice, high fat-fed TNF-␣ Ϫ/Ϫ mice, and brown adipose tissue (BAT)-deficient uncoupling proteindiphtheria toxin A chain (UCP1-DTA) mice. We also studied whether treatment with the weight-reducing and insulin-sensitizing compounds, MTII, an ␣-melanocyte-stimulating hormone analog, or CNTFAx15, a ciliary neurotrophic factor analog, alters resistin mRNA expression and/or circulating levels in lean and DIO C57BL/6J mice. We find that resistin mRNA expression is similar in DIO and lean C57BL/6J mice, as well as in TNF-␣ Ϫ/Ϫ and wild-type (WT) mice. Circulating resistin levels, however, are higher in DIO C57BL/6J, high fat-fed TNF-␣ Ϫ/Ϫ , and UCP1-DTA mice compared with lean controls. Moreover, although resistin mRNA expression is upregulated by MTII treatment for 24 h and downregulated by CNTFAx15 treatment for 3 or 7 days, circulating resistin levels are not altered by MTII or CNTFAx15 treatment. In addition, serum resistin levels, but not resistin mRNA expression levels, are correlated with body weight, and neither resistin mRNA expression nor serum resistin levels are correlated with serum insulin or glucose levels. We conclude that transcriptional regulation of resistin in WAT does not correlate with circulating resistin levels and that circulating resistin is unlikely to play a major endocrine role in insulin resistance or glycemia in mice.obesity; diet-induced obesity; MTII; ciliary neurotrophic factor analog; uncoupling protein-diphtheria toxin A chain; tumor necrosis factor-␣; RESISTIN is a 12.5-kda cysteine-rich protein secreted by adipocytes, which has been proposed to link obesity with insulin resistance and diabetes (14,17,38). Initial studies in mice suggested that resistin induces insulin resistance, but subsequent animal studies revealed conflicting data regarding whether resistin expression is increased (38, 39) or decreased (16, 19, 25, 26, 43) in obesity, and decreased (12, 27, 36, 38, 39) or increased (8, 43) by thiazolidinediones (TZDs), drugs known to improve insulin resistance. Moreover, although serum resistin levels measured by Western blot appeared to be elevated in genetic (ob/ob and db/db) and diet-induced models of obesity and decreased after TZD treatment or fasting (38), only a limited number of mice were studied, and thus no statistical evaluation of this difference could be performed. Furthermore, data from another study showed decreased serum resistin levels in obese mice by use of an ELISA with low accuracy and sensitivity (22). Thus the relevance and physiological role of circulating resistin in mice ...

Evidence that oestrogen receptor-α plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver

“…The sensitivity of the assay was 0.8 ng/ml and the CV was <8.2% at both low and high levels. Plasma resistin levels were measured by doubleantibody RIA kit (Linco Research) [19], using 125 I-labelled murine resistin, a mouse resistin rabbit antiserum and mouse resistin as standard. The sensitivity was 0.78 ng/ml with an intra-assay CV of 3.6%.…”

Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin

“…Plasma resistin levels are increased in ob/ob, db/db and diet-induced obese mice [6], although, concomitantly, resistin mRNA levels in obese rodents are often found to be decreased [7][8][9]. It is now appreciated that there is often a discrepancy between the circulating protein levels of resistin and the mRNA content in adipocytes [10,11].…”

Adipocytokines in Particular Pregnancy Disorders

“…Megia et al reported lower resistin levels in GDM. Other investigators have documented elevated maternal resistin levels in GDM, supporting the status of insulin resistance [94,95].…”

“…Higher maternal resistin levels have been demonstrated in PE, although placental gene expression of resistin was found to be unchanged [94]. Recent evidence suggests that circulating resistin levels increases with the progressive decline of renal function and depends on glomerular filtration rates [95].…”