Tomlinson J W, Moore J, Cooper M S, Bujalska I, Shahmanesh M, Burt C, Strain A, Hewison M, Stewart P M
Division of Medical Sciences, Queen Elizabeth Hospital, University of Birmingham, Birmingham, United Kingdom B15 2TH.
Endocrinology. 2001 May;142(5):1982-9. doi: 10.1210/endo.142.5.8168.
Patients with glucocorticoid excess develop central obesity, yet in simple obesity, circulating glucocorticoid levels are normal. We have suggested that the increased activity and expression of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) generating active cortisol from cortisone within adipose tissue may be crucial in the pathogenesis of obesity. In this study primary cultures of human hepatocytes and adipose stromal cells (ASC) were used as in vitro models to investigate the tissue-specific regulation of 11betaHSD1 expression and activity. Treatment with tumor necrosis factor-alpha (TNFalpha) caused a dose-dependent increase in 11betaHSD1 activity in primary cultures of both sc [1743.1 +/- 1015.4% (TNFalpha, 10 ng/ml); P < 0.05 vs. control (100%)] and omental [375.8 +/- 57.0% (TNFalpha, 10 ng/ml); P < 0.01 vs. control (100%)] ASC, but had no effect on activity in human hepatocytes [90.2 +/- 2.8% (TNFalpha, 10 ng/ml); P = NS vs. control (100%)]. Insulin-like growth factor I (IGF-I) caused a dose-dependent inhibition of 11betaHSD1 activity in sc [49.7 +/- 15.0% (IGF-I, 100 ng/ml]; P < 0.05 vs. control (100%)] and omental [71.6 +/- 7.5 (IGF-I, 100 ng/ml); P < 0.01 vs. control (100%)] stromal cells, but not in human hepatocytes [101.8 +/- 15.7% (IGF-I, 100 ng/ml); P = NS vs. control (100%)]. Leptin treatment did not alter 11betaHSD1 activity in human hepatocytes, but increased activity in omental ASC [135.8 +/- 14.1% (leptin, 100 ng/ml); P = 0.08 vs. control (100%)]. Treatment with interleukin-1beta induced 11betaHSD1 activity and expression in sc and omental ASC in a time- and dose-dependent manner. 15-Deoxy-12,14-PGJ2, the putative endogenous ligand of the orphan nuclear receptor peroxisome proliferator-gamma, significantly increased 11betaHSD1 activity in omental cells [179.7 +/- 29.6% (1 microM); P < 0.05 vs. control (100%)] and sc [185.3 +/- 12.6% (1 microM); P < 0.01 vs. control (100%)] ASC, and it is possible that expression of this ligand may ensure continued cortisol generation to permit adipocyte differentiation. Protease inhibitors used in the treatment of human immunodeficiency virus infection are known to cause a lipodystrophic syndrome and central obesity, but saquinavir, indinavir, and neflinavir caused a dose-dependent inhibition of 11betaHSD1 activity in primary cultures of human omental ASC. 11betaHSD1 expression is increased in human adipose tissue by TNFalpha, interleukin-1beta, leptin, and orphan nuclear receptor peroxisome proliferator-gamma agonists, but is inhibited by IGF-I. This autocrine and/or paracrine regulation is tissue specific and explains recent clinical data and animal studies evaluating cortisol metabolism in obesity. Tissue-specific 11betaHSD1 regulation offers the potential for selective enzyme inhibition within adipose tissue as a novel therapy for visceral obesity.
糖皮质激素过多的患者会出现向心性肥胖，而在单纯性肥胖患者中，循环糖皮质激素水平正常。我们曾提出，脂肪组织中由可的松生成活性皮质醇的11β-羟基类固醇脱氢酶1型（11βHSD1）的活性和表达增加可能在肥胖发病机制中起关键作用。在本研究中，人肝细胞和脂肪基质细胞（ASC）的原代培养物被用作体外模型，以研究11βHSD1表达和活性的组织特异性调节。用肿瘤坏死因子-α（TNFα）处理导致皮下[1743.1±1015.4%（TNFα，10 ng/ml）；与对照（100%）相比，P<0.05]和网膜[375.8±57.0%（TNFα，10 ng/ml）；与对照（100%）相比，P<0.01]ASC原代培养物中11βHSD1活性呈剂量依赖性增加，但对人肝细胞活性无影响[90.2±2.8%（TNFα，10 ng/ml）；与对照（100%）相比，P=无显著差异]。胰岛素样生长因子I（IGF-I）导致皮下[49.7±15.0%（IGF-I，100 ng/ml）；与对照（100%）相比，P<0.05]和网膜[71.6±7.5（IGF-I，100 ng/ml）；与对照（100%）相比，P<0.01]基质细胞中11βHSD1活性呈剂量依赖性抑制，但对人肝细胞无影响[101.8±15.7%（IGF-I，100 ng/ml）；与对照（100%）相比，P=无显著差异]。瘦素处理未改变人肝细胞中11βHSD1活性，但增加了网膜ASC中的活性[135.8±14.1%（瘦素，100 ng/ml）；与对照（100%）相比，P=0.08]。用白细胞介素-1β处理以时间和剂量依赖性方式诱导皮下和网膜ASC中11βHSD1活性和表达。15-脱氧-12,14-前列腺素J2，孤儿核受体过氧化物酶体增殖物-γ的假定内源性配体，显著增加网膜细胞[179.7±29.6%（1μM）；与对照（100%）相比，P<0.05]和皮下[185.3±12.6%（1μM）；与对照（100%）相比，P<0.01]ASC中11βHSD1活性，并且该配体的表达可能确保持续生成皮质醇以允许脂肪细胞分化。已知用于治疗人类免疫缺陷病毒感染的蛋白酶抑制剂会导致脂肪营养不良综合征和向心性肥胖，但沙奎那韦、茚地那韦和奈非那韦在人网膜ASC原代培养物中导致11βHSD1活性呈剂量依赖性抑制。TNFα、白细胞介素-1β、瘦素和孤儿核受体过氧化物酶体增殖物-γ激动剂可增加人脂肪组织中11βHSD1表达，但被IGF-I抑制。这种自分泌和/或旁分泌调节具有组织特异性，并解释了最近评估肥胖中皮质醇代谢的临床数据和动物研究。组织特异性11βHSD1调节为在脂肪组织内选择性抑制该酶提供了潜力，作为治疗内脏肥胖的一种新疗法。
