Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):240-5. doi: 10.1073/pnas.0905310107. Epub 2009 Dec 10.
Lipodystrophy and obesity are opposites in terms of a deficiency versus excess of adipose tissue mass, yet these conditions are accompanied by similar metabolic consequences, including insulin resistance, dyslipidemia, hepatic steatosis, and increased risk for diabetes and atherosclerosis. Hepatic and myocellular steatosis likely contribute to metabolic dysregulation in both states. Inflammation and macrophage infiltration into adipose tissue also appear to participate in the pathogenesis of obesity-induced insulin resistance, but their contributions to lipodystrophy-induced insulin resistance have not been evaluated. We used aP2-nSREBP-1c transgenic (Tg) mice, an established model of lipodystrophy, to ask this question. Circulating cytokine elevations suggested systemic inflammation but even more dramatic was the number of infiltrating macrophages in all white and brown adipose tissue depots of the Tg mice; in contrast, there was no evidence of inflammatory infiltrates or responses in any other tissue including liver. Despite there being overt evidence of adipose tissue inflammation, antiinflammatory strategies including salicylate treatment and genetic suppression of myeloid NF-kappaB signaling that correct insulin resistance in obesity were ineffective in the lipodystrophic mice. We further showed that adipose tissue macrophages (ATMs) in lipodystrophy and obesity are very different in terms of activation state, gene expression patterns, and response to lipopolysaccharide. Although ATMs are even more abundant in lipodystrophy than in obesity, they have distinct phenotypes and likely roles in tissue remodeling, but do not appear to be involved in the pathogenesis of insulin resistance.
脂肪营养不良和肥胖在脂肪组织质量的缺乏与过剩方面是相反的，但这些情况伴随着相似的代谢后果，包括胰岛素抵抗、血脂异常、肝脂肪变性，以及糖尿病和动脉粥样硬化风险增加。肝和肌细胞脂肪变性可能导致这两种状态的代谢失调。炎症和巨噬细胞浸润到脂肪组织中似乎也参与了肥胖引起的胰岛素抵抗的发病机制，但它们对脂肪营养不良引起的胰岛素抵抗的贡献尚未得到评估。我们使用 aP2-nSREBP-1c 转基因（Tg）小鼠，一种脂肪营养不良的既定模型，来提出这个问题。循环细胞因子的升高表明存在全身炎症，但更明显的是 Tg 小鼠所有白色和棕色脂肪组织中的浸润巨噬细胞数量；相比之下，在其他任何组织（包括肝脏）中都没有炎症浸润或反应的证据。尽管有明显的脂肪组织炎症证据，但抗炎策略，包括水杨酸盐治疗和骨髓 NF-κB 信号的遗传抑制，这些策略在肥胖症中纠正胰岛素抵抗的策略，在脂肪营养不良的小鼠中无效。我们进一步表明，脂肪组织中的巨噬细胞（ATMs）在脂肪营养不良和肥胖症中在激活状态、基因表达模式和对脂多糖的反应方面有很大的不同。尽管 ATMs 在脂肪营养不良中比在肥胖症中更为丰富，但它们具有不同的表型和可能在组织重塑中发挥作用，但似乎不参与胰岛素抵抗的发病机制。
