金属蛋白酶及其组织抑制剂在脂肪组织重塑和全身脂质分布中的作用：一项横断面临床研究。

The role of metalloproteinases and their tissue inhibitors in adipose tissue remodelling and whole-body lipid distribution: a cross-sectional clinical study.

机构信息

Norwich Medical School, University of East Anglia, Norwich, UK.

School of Biological Sciences, University of East Anglia, Norwich, UK.

出版信息

Lancet. 2015 Feb 26;385 Suppl 1:S36. doi: 10.1016/S0140-6736(15)60351-8.

DOI:10.1016/S0140-6736(15)60351-8

PMID:26312858

Abstract

BACKGROUND

Metabolically unhealthy obesity is associated with insulin resistance. Dysfunctional adipose tissue remodelling might explain features of this disorder, such as chronic white adipose tissue inflammation, adipocyte hypertrophy, and ectopic lipid deposition. Metalloproteinases and their tissue inhibitors (TIMPs) have been implicated in human adipose tissue remodelling. In a cross-sectional study, we investigated the association of adipose metalloproteinase and TIMP expression with whole-body lipid distribution and insulin resistance.

METHODS

Healthy women undergoing elective surgery donated fasting blood samples (for calculation of homoeostasis model assessment of insulin resistance [HOMA2-IR], the primary outcome). At operation 2 cm(3) biopsy samples of subcutaneous and visceral adipose tissue were obtained. 1 cm(3) was fixed, paraffin-embedded, and stained for adipocyte size quantification, and RNA was extracted from the remaining tissue for quantitative RT-PCR analysis. The women also underwent whole-body MRI for analysis of fat distribution.

FINDINGS

26 women were recruited (mean age 50·3 years, SD 13·1) into five body-mass index categories (18·5-24·9 kg/m(2) [n=12, 46·1%], 25-29·9 [n=6, 23·1%], 30-34·9 [n=3, 11·5%], 35-39·9 [n=3, 11·5%], >40 [n=2, 7·8%]). Mean fasting glucose was 5·29 mmol/L (SD 0·66), mean fasting insulin 71·29 pmol/L (47·72), and mean HOMA2-IR 1·35 (0·91). HOMA2-IR correlated with body-mass index (r=0·73, p<0·0001), subcutaneous and visceral adipose tissue volumes (r=0·94 and r=0·87, respectively; both p<0·0001), and hepatic fat fraction (r=0·57, p=0·013). Visceral adipose tissue MMP14 expression correlated strongly with hepatic fat fraction (r=0·944, p<0·0001), HOMA2-IR (r=0·74, p=0·01), and visceral adipose tissue volume (r=0·74, p=0·036). Subcutaneous adipose tissue TIMP3 expression correlated with subcutaneous adipocyte area (r=0·72, p=0·029), but not with HOMA2-IR (r=-0·53, p=0·062).

INTERPRETATION

The results suggest that metalloproteinases and TIMPs regulate adipose tissue remodelling and distribution. MMP14 has been implicated in collagen turnover in pre-adipocyte differentiation, whereas TIMP3 may modulate the shedding of DLK1, a regulator of adipogenesis. In our concurrent in-vitro study, we have shown that human adipocytes express metalloproteinases and TIMPs, and that their expression varies with inflammatory stimulation. These proteins might therefore integrate inflammatory signals with dysregulated adipose remodelling in metabolically unhealthy obesity.

FUNDING

British Heart Foundation, Diabetes Research & Wellness Foundation Open Funding 2011.

摘要

背景

代谢不健康的肥胖与胰岛素抵抗有关。功能失调的脂肪组织重塑可能解释了这种疾病的一些特征，如慢性白色脂肪组织炎症、脂肪细胞肥大和异位脂质沉积。金属蛋白酶及其组织抑制剂（TIMPs）已被认为与人类脂肪组织重塑有关。在一项横断面研究中，我们研究了脂肪金属蛋白酶和 TIMP 表达与全身脂质分布和胰岛素抵抗的关系。

方法

接受择期手术的健康女性捐献空腹血样（用于计算稳态模型评估的胰岛素抵抗[HOMA2-IR]，这是主要结果）。在手术过程中，从皮下和内脏脂肪组织中获得 2cm3 的活检样本。1cm3 被固定、石蜡包埋并染色以量化脂肪细胞大小，剩余组织的 RNA 被提取用于定量 RT-PCR 分析。这些女性还接受了全身 MRI 分析脂肪分布。

结果

共招募了 26 名女性（平均年龄 50.3 岁，SD 13.1），分为五个体重指数类别（18.5-24.9kg/m2[n=12，46.1%]，25-29.9[n=6，23.1%]，30-34.9[n=3，11.5%]，35-39.9[n=3，11.5%]，>40[n=2，7.8%]）。空腹血糖平均为 5.29mmol/L（SD 0.66），空腹胰岛素平均为 71.29pmol/L（47.72），HOMA2-IR 平均为 1.35（0.91）。HOMA2-IR 与体重指数（r=0.73，p<0.0001）、皮下和内脏脂肪组织体积（r=0.94 和 r=0.87，均 p<0.0001）和肝脂肪分数（r=0.57，p=0.013）相关。内脏脂肪组织 MMP14 表达与肝脂肪分数（r=0.944，p<0.0001）、HOMA2-IR（r=0.74，p=0.01）和内脏脂肪组织体积（r=0.74，p=0.036）强烈相关。皮下脂肪组织 TIMP3 表达与皮下脂肪细胞面积（r=0.72，p=0.029）相关，但与 HOMA2-IR 无关（r=-0.53，p=0.062）。

结论

结果表明，金属蛋白酶和 TIMPs 调节脂肪组织重塑和分布。MMP14 已被牵连到前脂肪细胞分化中的胶原蛋白转化中，而 TIMP3 可能调节 DLK1 的脱落，DLK1 是脂肪生成的调节剂。在我们同时进行的体外研究中，我们已经表明人类脂肪细胞表达金属蛋白酶和 TIMPs，并且它们的表达随炎症刺激而变化。因此，这些蛋白质可能将炎症信号与代谢不健康肥胖中的失调脂肪重塑整合在一起。