Zierath J R, Livingston J N, Thörne A, Bolinder J, Reynisdottir S, Lönnqvist F, Arner P
Department of Clinical Physiology, Karolinska Institute at Karolinska Hospital, Sweden.
Diabetologia. 1998 Nov;41(11):1343-54. doi: 10.1007/s001250051075.
Increased mobilization of non-esterified fatty acids (NEFA) from visceral as opposed to peripheral fat depots can lead to metabolic disturbances because of the direct portal link between visceral fat and the liver. Compared with peripheral fat, visceral fat shows a decreased response to insulin. The mechanisms behind these site variations were investigated by comparing insulin action on NEFA metabolism with insulin receptor signal transduction through the insulin receptor substrate-1 (IRS-1) pathway in omental (visceral) and subcutaneous human fat obtained during elective surgery. Insulin inhibited lipolysis and stimulated NEFA re-esterification. This was counteracted by wortmannin, an inhibitor of phosphaditylinositol (PI) 3-kinase. The effects of insulin on antilipolysis and NEFA re-esterification were greatly reduced in omental fat cells. Insulin receptor binding capacity, mRNA and protein expression did not differ between the cell types. Insulin was four times more effective in stimulating tyrosine phosphorylation of the insulin receptor in subcutaneous fat cells (p < 0.001). Similarly, insulin was two to three times more effective in stimulating tyrosine phosphorylation of IRS-1 in subcutaneous fat cells (p < 0.01). This finding could be explained by finding that IRS-1 protein expression was reduced by 50 +/- 8% in omental fat cells (p < 0.01). In omental fat cells, maximum insulin-stimulated association of the p85 kDa subunit of PI 3-kinase to phosphotyrosine proteins and phosphotyrosine associated PI 3-kinase activity were both reduced by 50% (p < 0.05 or better). Thus, the ability of insulin to induce antilipolysis and stimulate NEFA re-esterification is reduced in visceral adipocytes. This reduction can be explained by reduced insulin receptor autophosphorylation and signal transduction through an IRS-1 associated PI 3-kinase pathway in visceral adipocytes.
与外周脂肪库相比，内脏脂肪库中非酯化脂肪酸（NEFA）动员增加可导致代谢紊乱，因为内脏脂肪与肝脏之间存在直接的门静脉联系。与外周脂肪相比，内脏脂肪对胰岛素的反应降低。通过比较胰岛素对NEFA代谢的作用以及胰岛素通过胰岛素受体底物-1（IRS-1）途径在择期手术期间获取的网膜（内脏）和皮下人体脂肪中的胰岛素受体信号转导，研究了这些部位差异背后的机制。胰岛素抑制脂肪分解并刺激NEFA再酯化。这被磷脂酰肌醇（PI）3激酶抑制剂渥曼青霉素所抵消。胰岛素对网膜脂肪细胞中抗脂解和NEFA再酯化的作用大大降低。胰岛素受体结合能力、mRNA和蛋白质表达在不同细胞类型之间没有差异。胰岛素刺激皮下脂肪细胞中胰岛素受体酪氨酸磷酸化的效率高四倍（p<0.001）。同样，胰岛素刺激皮下脂肪细胞中IRS-1酪氨酸磷酸化的效率高两到三倍（p<0.01）。这一发现可以通过以下发现来解释：网膜脂肪细胞中IRS-1蛋白表达降低了50±8%（p<0.01）。在网膜脂肪细胞中，胰岛素刺激的PI 3激酶p85 kDa亚基与磷酸酪氨酸蛋白的最大结合以及磷酸酪氨酸相关的PI 3激酶活性均降低了50%（p<0.05或更佳）。因此，胰岛素在内脏脂肪细胞中诱导抗脂解和刺激NEFA再酯化的能力降低。这种降低可以通过内脏脂肪细胞中胰岛素受体自身磷酸化和通过IRS-1相关的PI 3激酶途径的信号转导减少来解释。
