Boucher J, Castan-Laurell I, Le Lay S, Grujic D, Sibrac D, Krief S, Lafontan M, Lowell B B, Dugail I, Saulnier-Blache J-S, Valet P
INSERM U317, Institut Louis Bugnard, CHU Rangueil, 31403 Toulouse cedex 4, France.
J Mol Endocrinol. 2002 Oct;29(2):251-64. doi: 10.1677/jme.0.0290251.
Catecholamines regulate white adipose tissue function and development by acting through beta- and alpha2-adrenergic receptors (ARs). Human adipocytes express mainly alpha 2A- but few or no beta 3-ARs while the reverse is true for rodent adipocytes. Our aim was to generate a mouse model with a human-like alpha2/beta-adrenergic balance in adipose tissue by creating transgenic mice harbouring the human alpha 2A-AR gene under the control of its own regulatory elements in a combined mouse beta 3-AR-/- and human beta 3-AR+/+ background. Transgenic mice exhibit functional human alpha 2A-ARs only in white fat cells. Interestingly, as in humans, subcutaneous adipocytes expressed higher levels of alpha2-AR than perigonadal fat cells, which are associated with a better antilipolytic response to epinephrine. High-fat-diet-induced obesity was observed in transgenic mice in the absence of fat cell size modifications. In addition, analysis of gene expression related to lipid metabolism in isolated adipocytes suggested reduced lipid mobilization and no changes in lipid storage capacity of transgenic mice fed a high-fat diet. Finally, the development of adipose tissue in these mice was not associated with significant modifications of glucose and insulin blood levels. Thus, these transgenic mice constitute an original model of diet-induced obesity for in vivo physiological and pharmacological studies with respect to the alpha2/beta-AR balance in adipose tissue.
儿茶酚胺通过作用于β-肾上腺素能受体（AR）和α2-肾上腺素能受体来调节白色脂肪组织的功能和发育。人类脂肪细胞主要表达α2A-肾上腺素能受体，但β3-肾上腺素能受体表达很少或不表达，而啮齿动物脂肪细胞的情况则相反。我们的目标是通过创建转基因小鼠来生成一种脂肪组织中具有类似人类α2/β-肾上腺素能平衡的小鼠模型，这些转基因小鼠在小鼠β3-AR基因敲除和人类β3-AR基因过表达的联合背景下，在其自身调控元件的控制下携带人类α2A-AR基因。转基因小鼠仅在白色脂肪细胞中表现出功能性人类α2A-肾上腺素能受体。有趣的是，与人类一样，皮下脂肪细胞中α2-肾上腺素能受体的表达水平高于性腺周围脂肪细胞，这与对肾上腺素更好的抗脂解反应相关。在转基因小鼠中观察到高脂饮食诱导的肥胖，且脂肪细胞大小无变化。此外，对分离的脂肪细胞中与脂质代谢相关的基因表达分析表明，高脂饮食喂养的转基因小鼠的脂质动员减少，脂质储存能力无变化。最后，这些小鼠脂肪组织的发育与血糖和胰岛素水平的显著变化无关。因此，这些转基因小鼠构成了一种用于体内生理学和药理学研究的饮食诱导肥胖的原始模型，该模型涉及脂肪组织中的α2/β-肾上腺素能平衡。
