Kim Kee-Hong, Zhao Ling, Moon Yangsoo, Kang Chulho, Sul Hei Sook
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA.
Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6780-5. doi: 10.1073/pnas.0305905101. Epub 2004 Apr 16.
Adipocyte-specific secretory factor (ADSF)/resistin is a small cysteine-rich 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 IgGgamma constant region (hFc). ADSF-hFc not only homodimerizes but heterooligomerizes with ADSF/resistin and prevents ADSF/resistin 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.
脂肪细胞特异性分泌因子（ADSF）/抵抗素是一种从脂肪组织分泌的富含半胱氨酸的小蛋白，属于在炎症区发现的基因家族（FIZZ）或抵抗素样分子（RELM）家族。ADSF与脂肪生成和胰岛素抵抗的调节有关。为了研究ADSF在脂肪生成和葡萄糖稳态中的长期功能，我们通过将ADSF与人IgGγ恒定区（hFc）融合构建了一种显性抑制形式的ADSF表达载体。ADSF-hFc不仅能同二聚化，还能与ADSF/抵抗素异源寡聚化，并以显性负性方式阻止ADSF/抵抗素对3T3-L1细胞脂肪细胞分化的抑制作用。在脂肪组织中过表达ADSF-hFc的转基因小鼠表现出肥胖增加，脂肪细胞标志物表达升高，脂肪细胞大小增大。这一发现清楚地在体内证明了ADSF在脂肪生成中的抑制作用。ADSF功能受损的ADSF-hFc转基因小鼠在正常饮食或高脂饮食下均表现出改善的葡萄糖耐量和胰岛素敏感性。由于脂肪细胞分化增强，ADSF-hFc转基因小鼠脂肪组织中瘦素和脂联素的表达增加。这些脂肪细胞衍生激素的循环水平升高，同时血浆甘油三酯和游离脂肪酸水平降低，这可能解释了这些转基因小鼠葡萄糖和胰岛素耐受性的改善。
