Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA.
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
Cells. 2023 May 18;12(10):1424. doi: 10.3390/cells12101424.
Aging and obesity are the two prominent driving forces of metabolic dysfunction, yet the common underlying mechanisms remain elusive. PPARγ, a central metabolic regulator and primary drug target combatting insulin resistance, is hyperacetylated in both aging and obesity. By employing a unique adipocyte-specific PPARγ acetylation-mimetic mutant knock-in mouse model, namely aKQ, we demonstrate that these mice develop worsened obesity, insulin resistance, dyslipidemia, and glucose intolerance as they age, and these metabolic deregulations are resistant to intervention by intermittent fasting. Interestingly, aKQ mice show a whitening phenotype of brown adipose tissue (BAT) manifested in lipid filling and suppressed BAT markers. Diet-induced obese aKQ mice retain an expected response to thiazolidinedione (TZD) treatment, while BAT function remains impaired. This BAT whitening phenotype persists even with the activation of SirT1 through resveratrol treatment. Moreover, the adverse effect of TZDs on bone loss is exacerbated in aKQ mice and is potentially mediated by their increased Adipsin levels. Our results collectively suggest pathogenic implications of adipocyte PPARγ acetylation, contributing to metabolic dysfunction in aging and thus posing as a potential therapeutic target.
衰老和肥胖是代谢功能障碍的两个突出驱动因素，但共同的潜在机制仍难以捉摸。PPARγ 是一种中央代谢调节剂和主要的药物靶点，可对抗胰岛素抵抗，在衰老和肥胖中都被高度乙酰化。通过使用一种独特的脂肪细胞特异性 PPARγ 乙酰化模拟突变体敲入小鼠模型，即 aKQ，我们证明这些小鼠随着年龄的增长会发展出更严重的肥胖、胰岛素抵抗、血脂异常和葡萄糖不耐受，并且这些代谢失调对间歇性禁食的干预具有抗性。有趣的是，aKQ 小鼠表现出棕色脂肪组织（BAT）的白化表型，表现为脂质填充和抑制 BAT 标志物。饮食诱导肥胖的 aKQ 小鼠对噻唑烷二酮（TZD）治疗仍保持预期的反应，而 BAT 功能仍然受损。即使通过白藜芦醇治疗激活 SirT1，这种 BAT 白化表型也仍然存在。此外，TZD 对骨丢失的不良影响在 aKQ 小鼠中加剧，并且可能是通过其增加的 Adipsin 水平介导的。我们的研究结果表明脂肪细胞 PPARγ 乙酰化具有致病性意义，导致衰老时代谢功能障碍，因此可能成为一个潜在的治疗靶点。
