Bauche Isabelle B, Ait El Mkadem Samira, Rezsohazy René, Funahashi Tohru, Maeda Norikazu, Miranda Lisa Miranda, Brichard Sonia M
Endocrinology and Metabolism Unit, University of Louvain, Faculty of Medicine, Brussels, Belgium.
Biochem Biophys Res Commun. 2006 Jul 14;345(4):1414-24. doi: 10.1016/j.bbrc.2006.05.033. Epub 2006 May 15.
Adiponectin (ApN) is an adipokine whose expression and plasma levels are inversely related to obesity and insulin-resistant states. The in vivo effects of a chronic expression of exogenous ApN restricted to adipose tissue are unclear. Moreover, the regulatory effects of ApN on its own expression and on that of its receptors are still unknown. In this study, we generated transgenic (Tg) mice with moderate expression of exogenous ApN targeted to adipose tissue (native full-length ApN being placed under control of the adipocyte promoter aP2). After a transient overexpression of ApN in young pups, we intriguingly observed a reduction of ApN mRNA levels and protein content in fat depots, together with a decrease of circulating ApN in adult mice. As a result, the phenotype of these adult mice included glucose intolerance, insulin resistance, and increased adiposity. Reduced expression of ApN in fat tissue was associated with diminished expression of uncoupling protein 2 involved in energy dissipation, and higher expression of fatty acid synthase, a key enzyme of lipogenesis, and of TNFalpha implicated in insulin resistance. Concomitantly, the expression of the ApN receptor AdipoR2 that mediates action of full-length ApN was downregulated, while that of AdipoR1 was unaffected. In agreement with the in vivo studies, recombinant ApN added to the culture medium of 3T3-F442A adipocytes caused a decrease in AdipoR2 and ApN mRNA levels. This treatment did not affect the expression of AdipoR1. Eventually, we demonstrated a contrario that AdipoR2 (but not R1) was specifically upregulated in fat of ApN(-/-) mice. Our in vivo and in vitro data provide evidence for a novel regulatory feedback loop by which ApN downregulates its own production and the expression of its AdipoR2 receptor.
脂联素（ApN）是一种脂肪因子，其表达和血浆水平与肥胖及胰岛素抵抗状态呈负相关。局限于脂肪组织的外源性ApN慢性表达的体内效应尚不清楚。此外，ApN对其自身表达及其受体表达的调节作用仍不明确。在本研究中，我们构建了转基因（Tg）小鼠，其外源性ApN的适度表达靶向脂肪组织（天然全长ApN置于脂肪细胞启动子aP2的控制之下）。在幼崽中外源性ApN短暂过表达后，我们有趣地观察到成年小鼠脂肪库中ApN mRNA水平和蛋白质含量降低，同时循环ApN减少。结果，这些成年小鼠的表型包括葡萄糖不耐受、胰岛素抵抗和肥胖增加。脂肪组织中ApN表达降低与参与能量消耗的解偶联蛋白2表达减少以及脂肪酸合成酶（脂肪生成的关键酶）和与胰岛素抵抗有关的肿瘤坏死因子α表达增加有关。同时，介导全长ApN作用的ApN受体AdipoR2的表达下调，而AdipoR1的表达未受影响。与体内研究一致，添加到3T3-F442A脂肪细胞培养基中的重组ApN导致AdipoR2和ApN mRNA水平降低。这种处理不影响AdipoR1的表达。最终，我们通过反证法证明AdipoR2（而非R1）在ApN基因敲除小鼠的脂肪中特异性上调。我们的体内和体外数据为一种新的调节反馈环提供了证据，通过该反馈环ApN下调其自身产生及其AdipoR2受体的表达。
