Wu Dayong, Ren Zhihong, Pae Munkyong, Guo Weimin, Cui Xuelin, Merrill Alfred H, Meydani Simin Nikbin
Nutritional Immunology Laboratory, Jean Mayer Unites States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA.
J Immunol. 2007 Oct 1;179(7):4829-39. doi: 10.4049/jimmunol.179.7.4829.
Obesity is a leading risk factor for type 2 diabetes (T2D). Aging is associated with an increase in T2D incidence, which is not totally explained by the much lower prevalence of obesity in the elderly. Low-grade inflammation in adipose tissue (AT) contributes to insulin resistance and T2D. Thus, we determined whether inflammatory responses are up-regulated with age in AT. The results showed that visceral AT from old C57BL mice had significantly higher mRNA expression of the proinflammatory cytokines IL-1beta, IL-6, TNF-alpha, and COX-2 and lower expression of anti-inflammatory PPAR-gamma than those of young mice. We further showed that adipocytes (AD) and not stromal vascular cells including macrophages (Mphi) were the cells responsible for this higher inflammatory state of the aged AT, suggesting that the age-associated increase in AT inflammation is distinguished from that seen in obesity, in which Mphi are the main contributors. However, peritoneal Mphi of either age (young or old) produced more TNF-alpha and IL-6 after incubation in old AD-conditioned medium compared with young AD-conditioned medium. This suggests that in addition to producing more inflammatory cytokines, AD from old mice induce a higher inflammatory response in other cells. Sphingolipid ceramide was higher in old compared with young AD. Reducing ceramide levels or inhibiting NF-kappaB activation decreased cytokine production, whereas the addition of ceramide increased cytokine production in young AD to a level comparable to that seen in old AD, suggesting that ceramide-induced activation of NF-kappaB plays a key role in AT inflammation.
肥胖是2型糖尿病（T2D）的主要风险因素。衰老与T2D发病率增加相关，而老年人肥胖患病率低得多并不能完全解释这一现象。脂肪组织（AT）中的低度炎症会导致胰岛素抵抗和T2D。因此，我们确定了AT中的炎症反应是否随年龄上调。结果显示，老年C57BL小鼠的内脏AT中促炎细胞因子IL-1β、IL-6、TNF-α和COX-2的mRNA表达显著高于年轻小鼠，而抗炎性PPAR-γ的表达则较低。我们进一步表明，脂肪细胞（AD）而非包括巨噬细胞（Mphi）在内的基质血管细胞是导致老年AT这种更高炎症状态的细胞，这表明与年龄相关的AT炎症增加与肥胖中所见的情况不同，在肥胖中Mphi是主要促成因素。然而，与年轻AD条件培养基相比，无论年龄大小（年轻或年老）的腹膜Mphi在老AD条件培养基中孵育后产生的TNF-α和IL-6更多。这表明，除了产生更多炎症细胞因子外，老年小鼠的AD还会在其他细胞中诱导更高的炎症反应。与年轻AD相比，老年AD中的鞘脂神经酰胺含量更高。降低神经酰胺水平或抑制NF-κB激活可减少细胞因子产生，而添加神经酰胺可使年轻AD中的细胞因子产生增加至与老年AD相当的水平，这表明神经酰胺诱导的NF-κB激活在AT炎症中起关键作用。
