Centre for Endocrine and Diabetes Sciences, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
Int J Obes (Lond). 2012 Mar;36(3):397-406. doi: 10.1038/ijo.2011.129. Epub 2011 Jul 5.
Adenosine mediates its actions through four G protein-coupled receptors, A1, A2a, A2b and A3. The A1 receptor (A1R) is dominant in adipocytes where it mediates many actions that include inhibition of lipolysis, stimulation of leptin secretion and protection against obesity-related insulin resistance.
The objective of this study is to investigate whether induced expression of A1Rs stimulates adipogenesis, or whether A1R expression is a consequence of cells having an adipocyte phenotype.
Human A1R and A2b receptors (A2bRs) were stably transfected into a murine osteoblast precursor cell line, 7F2. Adipogenesis was determined by lipid accumulation and expression of adipocyte and osteoblast marker molecules. Adenosine receptor expression and activation of associated signal molecules were also evaluated as 7F2 cells were induced to differentiate to adipocytes.
7F2 cells transfected with the A1R showed increased adipocyte marker mRNA expression; lipoprotein lipase and glycerol-3-phosphate dehydrogenase were both upregulated, whereas the osteoblast marker alkaline phosphatase (ALP) was downregulated. When cultured in adipocyte differentiating media, such cells also showed increased adipogenesis as judged by lipid accumulation. Conversely, A2bR transfection stimulated osteocalcin and ALP expression, and in addition, adipogenesis was inhibited in the presence of adipocyte differentiation media. Adipogenic differentiation of naive 7F2 cells also resulted in increased expression of the A1R and reduced or modified expression of the A2a and A2bR. The loss of A2 receptors after adipogenic differentiation was accompanied by a loss of cyclic adenosine monophosphate and ERK1/2 signalling.
These data show that expression of A1Rs induced adipocyte differentiation, whereas A2bR expression inhibited adipogenesis and stimulated an osteoblastic phenotype. These data suggest that targeting A1 and A2bR could be considered in the management of obesity and diabetes. Targeting adenosine signal pathways may be useful in treatment strategies for diseases in which there is an imbalance between osteoblasts and adipocytes.
腺苷通过四种 G 蛋白偶联受体（A1、A2a、A2b 和 A3）发挥作用。A1 受体（A1R）在脂肪细胞中占主导地位，介导包括抑制脂肪分解、刺激瘦素分泌和防止肥胖相关胰岛素抵抗等多种作用。
本研究旨在探讨 A1R 的诱导表达是否会刺激脂肪生成，或者 A1R 表达是否是细胞具有脂肪细胞表型的结果。
将人 A1R 和 A2b 受体（A2bRs）稳定转染到鼠成骨细胞前体细胞系 7F2 中。通过脂质积累和脂肪细胞和成骨细胞标记分子的表达来确定脂肪生成。还评估了腺苷受体表达和相关信号分子的激活，因为 7F2 细胞被诱导分化为脂肪细胞。
转染 A1R 的 7F2 细胞显示出增加的脂肪细胞标记物 mRNA 表达；脂蛋白脂肪酶和甘油-3-磷酸脱氢酶均上调，而成骨细胞标记物碱性磷酸酶（ALP）下调。当在脂肪细胞分化培养基中培养时，如通过脂质积累判断，此类细胞也显示出增加的脂肪生成。相反，A2bR 转染刺激骨钙素和 ALP 的表达，并且在存在脂肪细胞分化培养基的情况下抑制脂肪生成。未分化的 7F2 细胞的脂肪生成分化也导致 A1R 的表达增加，并且 A2a 和 A2bR 的表达减少或改变。脂肪生成分化后 A2 受体的丧失伴随着环腺苷酸和 ERK1/2 信号的丧失。
这些数据表明，A1R 的表达诱导脂肪细胞分化，而 A2bR 的表达抑制脂肪生成并刺激成骨细胞表型。这些数据表明，针对 A1 和 A2bR 的治疗可能在肥胖症和糖尿病的管理中被考虑。靶向腺苷信号通路可能在骨细胞和脂肪细胞之间失衡的疾病的治疗策略中有用。
