Zhu Min, Lee Garrick D, Ding Liusong, Hu Jingping, Qiu Guang, de Cabo Rafa, Bernier Michel, Ingram Donald K, Zou Sige
Laboratory of Experimental Gerontology, National Institute on Aging, 6200 Seaforth Street, Baltimore, MD 21224, USA.
Exp Gerontol. 2007 Aug;42(8):733-44. doi: 10.1016/j.exger.2007.05.011. Epub 2007 Jun 6.
Alterations in adipogenesis could have significant impact on several aging processes. We previously reported that calorie restriction (CR) in rats significantly increases the level of circulating adiponectin, a distinctive marker of differentiated adipocytes, leading to a concerted modulation in the expression of key transcription target genes and, as a result, to increased fatty acid oxidation and reduced deleterious lipid accumulation in other tissues. These findings led us to investigate further the effects of aging on adipocytes and to determine how CR modulates adipogenic signaling in vivo. CR for 2 and 25 months, significantly increased the expression of PPARgamma, C/EBPbeta and Cdk-4, and partially attenuated age-related decline in C/EBPalpha expression relative to rats fed ad libitum (AL). As a result, adiponectin was upregulated at both mRNA and protein levels, resulting in activation of target genes involved in fatty acid oxidation and fatty acid synthesis, and greater responsiveness of adipose tissue to insulin. Moreover, CR significantly decreased the ratio of C/EBPbeta isoforms LAP/LIP, suggesting the suppression of gene transcription associated with terminal differentiation while facilitating preadipocytes proliferation. Morphometric analysis revealed a greater number of small adipocytes in CR relative to AL feeding. Immunostaining confirmed that small adipocytes were more strongly positive for adiponectin than the large ones. Overall these results suggest that CR increased the expression of adipogenic factors, and maintained the differentiated state of adipocytes, which is critically important for adiponectin biosynthesis and insulin sensitivity.
脂肪生成的改变可能会对多个衰老过程产生重大影响。我们之前报道过，大鼠的热量限制（CR）显著提高了循环脂联素的水平，脂联素是分化脂肪细胞的一个独特标志物，导致关键转录靶基因的表达协同调节，结果是脂肪酸氧化增加，其他组织中有害脂质积累减少。这些发现促使我们进一步研究衰老对脂肪细胞的影响，并确定CR如何在体内调节脂肪生成信号。与自由采食（AL）的大鼠相比，2个月和25个月的CR显著增加了PPARγ、C/EBPβ和Cdk-4的表达，并部分减弱了与年龄相关的C/EBPα表达下降。结果，脂联素在mRNA和蛋白质水平均上调，导致参与脂肪酸氧化和脂肪酸合成的靶基因激活，以及脂肪组织对胰岛素的反应性增强。此外，CR显著降低了C/EBPβ亚型LAP/LIP的比例，表明在促进前脂肪细胞增殖的同时，抑制了与终末分化相关的基因转录。形态计量分析显示，与AL喂养相比，CR组中有更多的小脂肪细胞。免疫染色证实，小脂肪细胞比大脂肪细胞对脂联素的阳性反应更强。总体而言，这些结果表明，CR增加了脂肪生成因子的表达，并维持了脂肪细胞的分化状态，这对脂联素的生物合成和胰岛素敏感性至关重要。
