Gagnon A, Dods P, Roustan-Delatour N, Chen C S, Sorisky A
The Departments of Medicine and Biochemistry, Microbiology & Immunology, Loeb Health Research Institute, Ottawa Hospital, University of Ottawa, Ottawa, Canada.
Endocrinology. 2001 Jan;142(1):205-12. doi: 10.1210/endo.142.1.7902.
Adipocyte number, a determinant of adipose tissue mass, reflects the balance between the rates of proliferation/differentiation vs. apoptosis of preadipocytes. The percentage of 3T3-L1 preadipocytes undergoing cell death following serum deprivation was reduced by 10 nM insulin-like growth factor (IGF)-1 (from 50.0 +/- 0.7% for control starved cells to 27.5 +/- 3.1%). TUNEL staining confirmed the apoptotic nature of the cell death. The protective effect of IGF-1 was blocked by phosphoinositide 3-kinase (PI3K) inhibitors, wortmannin, and LY294002, but was unaffected by rapamycin, PD98059, or SB203580, which inhibit mammalian target of rapamycin (mTOR), ERK kinase (MEK1), and p38 MAPK respectively. Exogenous PI(3,4,5)P3 (10 microM), the principal product of IGF-1-stimulated PI3K in 3T3-L1 preadipocytes, had a modest survival effect on its own, reducing cell death from 47.9 +/- 3.4% to 35.6 +/- 3.5%. When added to the combination of IGF-1 and LY294002, PI(3,4,5)P3 reversed most of the inhibitory effect of LY294002 on IGF-1-dependent cell survival, protein kinase B/Akt phosphorylation, and caspase-3 activity. Taken together, these results implicate PI(3,4,5)P3 as a necessary signal for the anti-apoptotic action of IGF-1 on 3T3-L1 preadipocytes.
脂肪细胞数量是脂肪组织质量的一个决定因素，反映了前脂肪细胞增殖/分化速率与凋亡速率之间的平衡。血清剥夺后发生细胞死亡的3T3-L1前脂肪细胞百分比，在添加10 nM胰岛素样生长因子（IGF）-1后降低（从饥饿对照细胞的50.0±0.7%降至27.5±3.1%）。TUNEL染色证实了细胞死亡的凋亡性质。IGF-1的保护作用被磷酸肌醇3-激酶（PI3K）抑制剂渥曼青霉素和LY294002阻断，但不受雷帕霉素、PD98059或SB203580的影响，它们分别抑制雷帕霉素哺乳动物靶点（mTOR）、ERK激酶（MEK1）和p38丝裂原活化蛋白激酶（MAPK）。外源性PI(3,4,5)P3（10 microM）是IGF-1刺激3T3-L1前脂肪细胞中PI3K的主要产物，其自身具有适度的存活作用，将细胞死亡从47.9±3.4%降至35.6±3.5%。当添加到IGF-1和LY294002的组合中时，PI(3,4,5)P3逆转了LY294002对IGF-1依赖性细胞存活、蛋白激酶B/Akt磷酸化和半胱天冬酶-3活性的大部分抑制作用。综上所述，这些结果表明PI(3,4,5)P3是IGF-1对3T3-L1前脂肪细胞抗凋亡作用的必要信号。
