Fatty acid binding protein expression in different adipose tissue depots from lean and obese individuals

Aims/hypothesis: This study investigated the expression of adipose tissue fatty acid binding proteins (FABPs) in subcutaneous and visceral human adipose tissue depots from lean and obese individuals. Methods: Adipocyte lipid binding protein (ALBP) and keratinocyte lipid binding protein (KLBP) expression was quantified by western blot in subcutaneous and omental adipose tissue from 20 obese and 9 lean individuals. RNA expression was quantified by Northern blot in the obese subjects. Results: In the obese subjects, ALBP protein and RNA expression was higher in subcutaneous compared with omental adipose tissue (increases of 31 ± 14 % and 40 ± 13 % respectively, both p < 0.05), whereas in the lean group, KLBP protein levels were 32 ± 9 % lower in subcutaneous fat (p < 0.03). However, the ALBP/KLBP ratio was greater in subcutaneous compared to omental adipose tissue from both lean and obese subjects: increases of 187 ± 71 % (p = 0.01) and 52 ± 23 % (p = 0.17) respectively for the protein ratio, and 21 ± 6 % for RNA (p = 0.01, obese individuals). In lean subjects, insulin concentrations correlated positively with the ALBP/KLBP protein ratio in both depots (both p≤ 0.03). Conclusion/interpretation: There are regional differences in adipose tissue FABP expression, which could be influenced by obesity. However, the ALBP/KLBP ratio is greater in subcutaneous than visceral adipose tissue in lean as well as in obese subjects. Investigation of adipose tissue FABPs could further our understanding of the role of fatty acids in the insulin resistance syndrome. [Diabetologia (2001) 44: 1268–1273] Received: 1 February 2001 and in revised form: 25 June 2001     

失血性贫血小鼠骨髓间充质干细胞向成骨成脂分化的变化简

本研究旨在检测骨髓间充质干细胞（multipotent mesenchymal stem cells,MSC）向成骨、成脂分化的变化,探讨骨髓间充质干细胞的分化状态对骨髓造血功能的影响.先对实验小鼠每隔1-2d行内眦静脉取血0.3 ml,4周构建贫血模型,通过检测贫血小鼠外周血常规指标、网织红细胞比例、骨髓细胞造血集落形成以验证小鼠模型.通过检测贫血模型小鼠成纤维细胞集落形成、骨髓细胞和脂肪细胞的数量,并用实时定量PCR的方法检测骨髓成骨、成脂分化相关基因的表达来研究骨髓MSC分化潜能的改变.结果显示,与对照组相比,贫血小鼠红细胞数量和血红蛋白水平明显下降,网织红细胞比例增高,骨髓细胞造血集落形成单位数量增多;骨髓造血细胞增多,脂肪细胞减少;骨髓成纤维细胞集落形成单位增多并显著向成骨细胞分化;骨髓成骨分化相关基因Runx2和OSX的表达明显升高,而成脂相关基因aP2、PPARγ2的表达明显降低.结论：在骨髓造血功能活跃期小鼠骨髓间充质干细胞向成骨细胞分化能力增强,向脂肪细胞分化能力减弱.     

8周跑台运动对高脂膳食大鼠脂肪细胞分化和胰岛素敏感性的影响

目的:探讨大鼠经高脂膳食复制胰岛素抵抗模型后,运动对其的改善作用及脂肪细胞分化在其中的影响。方法:SD纯系雄性大鼠40只,随机分为对照组(C)、高脂组(H)、高脂运动组(HE)和普通膳食运动组(E),各运动组进行8周跑台训练,对比各组的胰岛素敏感性指标和脂肪细胞分化各指标。结果:8周高脂膳食成功复制大鼠胰岛素抵抗模型。大鼠脂肪细胞分化各指标变化:PPARγ在E组高于C组(P<0.01),H组高于C组;C/EBPα在H组高于其他各组(P<0.01),E组高于C组,HE组低于H组;E组脂肪细胞分化程度最高(P<0.01);C组增殖指数最高,与H组和E组相比具有显著性差异(P<0.01;P<0.05),HE组高于H组和E组(P<0.05);E组脂肪细胞体积小于C组(P<0.01),细胞数量高于C组;H组细胞体积小于C组(P<0.01),数量也增加(P<0.01),HE组与H组相比脂肪细胞体积较大(P<0.01),且数量减少。脂肪细胞分化指标与胰岛素抵抗指标间具有一定的相关关系。结论:8周跑台运动可以改善由高脂膳食喂养引起的大鼠胰岛素抵抗现象,具体机制可能与其脂肪细胞分化的变化相关。     

Regional differences in cellular mechanisms of adipose tissue gain with overfeeding

Body fat distribution is an important predictor of the metabolic consequences of obesity, but the cellular mechanisms regulating regional fat accumulation are unknown. We assessed the changes in adipocyte size (photomicrographs) and number in response to overfeeding in upper- and lower-body s.c. fat depots of 28 healthy, normal weight adults (15 men) age 29 ± 2 y. We analyzed how these changes relate to regional fat gain (dual energy X-ray absorptiometry and computed tomography) and baseline preadipocyte proliferation, differentiation [peroxisome proliferator-activated receptor-γ2 (PPARγ2) and CCAAT/enhancer binding protein-α (C/EBPα) mRNA]), and apoptotic response to TNF-α. Fat mass increased by 1.9 ± 0.2 kg in the upper body and 1.6 ± 0.1 kg in the lower body. Average abdominal s.c. adipocyte size increased by 0.16 ± 0.06 μg lipid per cell and correlated with relative upper-body fat gain (r = 0.74, P < 0.0001). However, lower-body fat responded to overfeeding by fat-cell hyperplasia, with adipocyte number increasing by 2.6 ± 0.9 × 10(9) cells (P < 0.01). We found no depot-differences in preadipocyte replication or apoptosis that would explain lower-body adipocyte hyperplasia and abdominal s.c. adipocyte hypertrophy. However, baseline PPARγ2 and C/EBPα mRNA were higher in abdominal than femoral s.c. preadipocytes (P < 0.005 and P < 0.03, respectively), consistent with the ability of abdominal s.c. adipocytes to achieve a larger size. Inherent differences in preadipocyte cell dynamics may contribute to the distinct responses of different fat depots to overfeeding, and fat-cell number increases in certain depots in adults after only 8 wk of increased food intake.     

Down regulation of peroxisome proliferator-activated receptorγ expression by inflammatory cytokines and its reversal by thiazolidinediones

Aims/hypothesis. Previous studies show that inflammatory cytokines play a part in the development of insulin resistance. Thiazolidinediones were developed as insulin-sensitizing drugs and are ligands for the peroxisome proliferator-activated receptorγ (PPARγ). We hypothesized that the anti-diabetic mechanism of thiazolidinediones depends on the quantity of PPARγ in the insulin resistant state in which inflammatory cytokines play a part. Methods. We isolated rat PPARγ1 and γ2 cDNAs and examined effects of various cytokines and thiazolidinediones on PPARγ mRNA expression in rat mature adipocytes. Results. Various inflammatory cytokines, such as tumour necrosis factor-α (TNF-α), interleukin-1α (IL-1α), IL-1β, IL-6 and leukaemia inhibitory factor decreased PPARγ mRNA expression. In addition, hydrogen peroxide, lysophosphatidylcholine or phorbol 12-myristate 13-acetate also decreased the expression of PPARγ. The suppression of PPARγ mRNA expression caused by 10 nmol/l of TNF-α was reversed 60 % and 55 % by treatment with 10^–4 mol/l of troglitazone and 10^–4 mol/l of pioglitazone, respectively. The suppression of glucose transporter 4 mRNA expression caused by TNF-α was also reversed by thiazolidinediones. Associated with the change of PPARγ mRNA expression, troglitazone improved glucose uptake suppressed by TNF-α. Conclusion/interpretation. Our study suggests that inflammatory cytokines could be factors that regulate PPARγ expression for possible modulation of insulin resistance. In addition, we speculate that the regulation of PPARγ mRNA expression may contribute to the anti-diabetic mechanism of thiazolidinediones. [Diabetologia (1999) 42: 702–710] Received: 11 August 1998 and in final revised form: 12 February 1999     

Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ

The endocrine hormone fibroblast growth factor 21 (FGF21) is a powerful modulator of glucose and lipid metabolism and a promising drug for type 2 diabetes. Here we identify FGF21 as a potent regulator of skeletal homeostasis. Both genetic and pharmacologic FGF21 gain of function lead to a striking decrease in bone mass. In contrast, FGF21 loss of function leads to a reciprocal high-bone-mass phenotype. Mechanistically, FGF21 inhibits osteoblastogenesis and stimulates adipogenesis from bone marrow mesenchymal stem cells by potentiating the activity of peroxisome proliferator-activated receptor γ (PPAR-γ). Consequently, FGF21 deletion prevents the deleterious bone loss side effect of the PPAR-γ agonist rosiglitazone. Therefore, FGF21 is a critical rheostat for bone turnover and a key integrator of bone and energy metabolism. These results reveal that skeletal fragility may be an undesirable consequence of chronic FGF21 administration.     

Identification of plant extracts with potential antidiabetic properties: effect on human peroxisome proliferator‐activated receptor (PPAR), adipocyte differentiation and insulin‐stimulated glucose uptake

Thiazolidinediones (TZDs) are insulin sensitizing drugs used to treat type 2 diabetes. The primary target of the TZDs is the peroxisome proliferator‐activated receptor (PPAR) γ, a key regulator of adipogenesis and glucose homeostasis. Currently prescribed TZDs are full PPARγ agonists, and their use is associated with several side effects. Partial PPARγ agonists appear to be associated with fewer side effects but may still confer the desired insulin sensitizing action. Extracts from common medicinal/food plants were tested in a screening platform comprising a series of bioassays, including tests for PPARγ, α and δ transactivation, adipocyte differentiation and insulin‐stimulated glucose uptake, allowing identification of plants containing potentially interesting PPAR agonists. Twenty‐two plant extracts out of 133 were found to increase insulin‐stimulated glucose uptake and 18 extracts were found to activate PPARγ, 3 to activate PPARα and γ, 6 to activate PPARδ and γ, and 9 to activate PPARγ, α and δ. Among the 24 different plant species tested in the platform, 50% were shown to contain compounds capable of activating PPARγ and stimulating insulin‐dependent glucose uptake with no or little effect on adipocyte differentiation warranting further studies and characterization. Copyright © 2009 John Wiley & Sons, Ltd.