Dominant inhibitory adipocyte-specific secretory factor (ADSF)/resistin enhances adipogenesis and improves insulin sensitivity

Abstract

Adipocyte-specific secretory factor (ADSF)͞resistin is a small cysteinerich protein secreted from adipose tissue that belongs to a gene family found in inflammatory zone (FIZZ) or found in resistin-like molecule (RELM). ADSF has been implicated in modulating adipogenesis and insulin resistance. To examine the long-term function of ADSF in adipogenesis and glucose homeostasis, we constructed an expression vector for a dominant inhibitory form of ADSF by fusing it to the human IgG␥ constant region (hFc). ADSF-hFc not only homodimerizes but heterooligomerizes with ADSF͞resistin and prevents ADSF͞resis-tin inhibition of adipocyte differentiation of 3T3-L1 cells in a dominant negative manner. Transgenic mice overexpressing ADSF-hFc in adipose tissue show increased adiposity with elevated expression of adipocyte markers as well as enlarged adipocyte size. This finding clearly demonstrates in vivo the inhibitory role of ADSF in adipogenesis. ADSF-hFc transgenic mice with impaired ADSF function exhibit improved glucose tolerance and insulin sensitivity either on chow or high-fat diets. Because of the enhanced adipocyte differentiation, the ADSF-hFc transgenic mice show increased expression of leptin and adiponectin in adipose tissue. The elevated circulating levels for these adipocyte-derived hormones with decreased plasma triglyceride and free fatty acid levels may account for the improved glucose and insulin tolerance in these transgenic mice.O besity is a prevalent health hazard in industrialized countries and is closely associated with insulin resistance and type 2 diabetes. Obesity arises from increased size of adipocytes caused by lipid accumulation and from an increased number of adipocytes arising from differentiation of adipose precursor cells to mature adipocytes under the appropriate nutritional and hormonal conditions (1). Gene expression studies during adipocyte differentiation have firmly established that peroxisome proliferator-activated receptor ␥ (PPAR␥) and the CCAAT enhancer-binding protein (C͞EBP) family of transcription factors play central roles in adipocyte differentiation (2, 3). However, various factors in cell-cell and cell-matrix communications govern expression of the adipocyte transcription factors and therefore regulate conversion of preadipocytes to adipocytes (4). Although adipose tissue serves as the major energy reservoir in higher eukaryotes, the role of adipose tissue as a secretory organ has emerged through the discovery of leptin (5). In addition to leptin, other secretory factors including adiponectin and tumor necrosis factor ␣, as well as preadipocytespecific preadipocyte factor 1 (Pref-1) are known to be secreted from adipose tissue (6-8). These factors are involved in regulating a variety of physiological functions including satiety and energy metabolism, as well as adipocyte differentiation. In this regard, we have shown that Pref-1, which is secreted specifically by preadipocytes, inhibits adipocyte differentiation (8-10).We previously identified adipocyte-specific secretory ...

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

“…Considerable debate exists regarding the role of resistin in the pathophysiology of insulin resistance in humans and animals and as to whether resistin acts primarily in muscle, liver or fat [2,3,5,[29][30][31][32]. However, several studies provide convincing evidence for an effect of resistin in skeletal muscle.…”

“…Resistin caused insulin resistance at the level of both skeletal muscle (decreased insulin-stimulated glucose infusion during clamp) and liver (attenuation of suppression of hepatic glucose output) [31]. Furthermore, preventing resistin action in transgenic mice expressing a dominant inhibitory version of the protein improved insulin sensitivity and glucose tolerance in mice [5]. A recent elegant study where adipocytes transfected in vitro to express resistin were surgically inserted into mice showed that these mice then exhibited high plasma resistin levels [32].…”

“…Several years of capricious interest in the link between resistin and diabetes [1] have been enhanced by recent developments such as the generation of mice lacking or overexpressing resistin [2][3][4][5]. Resistin was discovered by virtue of its altered gene expression in mouse adipocytes in response to the peroxisome proliferator-activated receptor-γ ligands known as thiazolidinediones [6].…”

Brain Adipocytokine Action and Metabolic Regulation

“…Conversely, ablation of the retn gene or reduction in resistin protein through antisense oligonucleotide treatment improves insulin sensitivity through AMPK activation (86,87). Resistin inhibits adipogenesis, whereas the loss of resistin function increases body weight and fat and enhances insulin sensitivity (88,89). Thus, resistin has significant roles in energy and glucose homeostasis.…”

Identification and functional characterization of a missense mutation in resistin in two patients with severe obesity and insulin resistance

“…Neutralization of endogenous resistin by antibodies improved insulin sensitivity in mice with diet-induced obesity (1). An inhibitory effect of resistin on adipose conversion could also be demonstrated in vitro (3,4). In addition, it was also suggested that resistin may be involved in inflammation due to its homology to FIZZ1 (2).…”