Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain.
Diabetologia. 2012 Nov;55(11):3038-50. doi: 10.1007/s00125-012-2671-5. Epub 2012 Aug 7.
AIMS/HYPOTHESIS: Proinflammatory and proapoptotic cytokines such as TNF-α are upregulated in human obesity. We evaluated the association between ghrelin isoforms (acylated and desacyl ghrelin) and TNF-α in obesity and obesity-associated type 2 diabetes, as well as the potential role of ghrelin in the control of apoptosis and autophagy in human adipocytes.
Plasma concentrations of the ghrelin isoforms and TNF-α were measured in 194 participants. Ghrelin and ghrelin O-acyltransferase (GOAT) levels were analysed by western-blot, immunohistochemistry and real-time PCR in 53 biopsies of human omental adipose tissue. We also determined the effect of acylated and desacyl ghrelin (10 to 1,000 pmol/l) on TNF-α-induced apoptosis and autophagy-related molecules in omental adipocytes.
Circulating concentrations of acylated ghrelin and TNF-α were increased, whereas desacyl ghrelin levels were decreased in obesity-associated type 2 diabetes. Ghrelin and GOAT were produced in omental and subcutaneous adipose tissue. Visceral adipose tissue from obese patients with type 2 diabetes showed higher levels of GOAT, increased adipocyte apoptosis and increased expression of the autophagy-related genes ATG5, BECN1 and ATG7. In differentiating human omental adipocytes, incubation with acylated and desacyl ghrelin reduced TNF-α-induced activation of caspase-8 and caspase-3, and cell death. In addition, acylated ghrelin reduced the basal expression of the autophagy-related genes ATG5 and ATG7, while desacyl ghrelin inhibited the TNF-α-induced increase of ATG5, BECN1 and ATG7 expression.
CONCLUSIONS/INTERPRETATION: Apoptosis and autophagy are upregulated in human visceral adipose tissue of patients with type 2 diabetes. Acylated and desacyl ghrelin reduce TNF-α-induced apoptosis and autophagy in human visceral adipocytes.
目的/假设：促炎和促凋亡细胞因子，如 TNF-α，在人类肥胖中上调。我们评估了肥胖和肥胖相关 2 型糖尿病中胃饥饿素同工型（酰化和去酰化胃饥饿素）与 TNF-α之间的关联，以及胃饥饿素在控制人类脂肪细胞凋亡和自噬中的潜在作用。
在 194 名参与者中测量了胃饥饿素同工型和 TNF-α的血浆浓度。通过 Western-blot、免疫组织化学和实时 PCR 分析了 53 个人腹部脂肪组织活检中的胃饥饿素和胃饥饿素 O-酰基转移酶（GOAT）水平。我们还测定了酰化和去酰化胃饥饿素（10 至 1000 pmol/L）对网膜脂肪细胞中 TNF-α诱导的凋亡和自噬相关分子的影响。
与肥胖相关的 2 型糖尿病患者中，循环中酰化胃饥饿素和 TNF-α的浓度增加，而去酰化胃饥饿素的水平降低。胃饥饿素和 GOAT 在腹部和皮下脂肪组织中产生。肥胖 2 型糖尿病患者的内脏脂肪组织中 GOAT 水平较高，脂肪细胞凋亡增加，自噬相关基因 ATG5、BECN1 和 ATG7 的表达增加。在分化的人网膜脂肪细胞中，酰化和去酰化胃饥饿素孵育可降低 TNF-α诱导的半胱天冬酶-8 和半胱天冬酶-3的激活和细胞死亡。此外，酰化胃饥饿素降低了自噬相关基因 ATG5 和 ATG7 的基础表达，而去酰化胃饥饿素抑制了 TNF-α诱导的 ATG5、BECN1 和 ATG7 表达增加。
结论/解释：2 型糖尿病患者的人内脏脂肪组织中凋亡和自噬增加。酰化和去酰化胃饥饿素可减少人内脏脂肪细胞中 TNF-α诱导的凋亡和自噬。
