Dulloo A G
Division of Physiology, Department of Medicine, University of Fribourg, Fribourg, Switzerland.
Acta Physiol Scand. 2005 Aug;184(4):295-307. doi: 10.1111/j.1365-201X.2005.01466.x.
An impressive body of epidemiological evidence suggests that a history of large perturbations in body weight earlier in life, independently of excess weight, is a risk factor for later development of insulin-related complications, namely central obesity, type 2 diabetes and cardiovascular disease. Such an increased risk has been reported in men and women who in young adulthood experienced weight fluctuations that involved weight recovery after weight loss caused by disease, famine or voluntary 'yoyo' dieting, and is particularly strong when the weight fluctuations occurred much earlier in life and are characterized by catch-up growth after foetal and/or neonatal growth retardation. As the phase of weight recovery/catch-up growth is associated with both hyperinsulinaemia and an accelerated rate for recovering fat mass (i.e. catch-up fat), the questions arise as to whether, why and how processes that regulate catch-up fat might predispose to hyperinsulinaemia and to insulin-related diseases. In addressing these issues, this paper first reviews evidence for the existence of an adipose-specific control of thermogenesis, whose suppression contributes to the phenomenon of catch-up fat during weight recovery/catch-up growth. It subsequently concentrates upon recent findings suggesting that: (i) such suppression of thermogenesis directed at catch-up fat is accompanied by a redistribution of glucose from skeletal muscle to white adipose tissue, and (ii) substrate cycling between de novo lipogenesis and lipid oxidation can operate as a thermogenic effector in skeletal muscle in response to signalling interactions between leptin and insulin - two key 'adiposity' hormones implicated in the peripheral control of substrate metabolism. These new findings are integrated into the proposal that, in its 'evolutionary adaptive' role to spare glucose for rapid rebuilding of the fat stores, suppressed thermogenesis in skeletal muscle - via inhibition of substrate cycling between de novo lipogenesis and lipid oxidation - confers to the phase of weight recovery/catch-up growth its high sensitivity towards the development of insulin resistance and hyperinsulinaemia, and hence towards diseases that are clustered around the insulin resistance syndrome.
大量令人瞩目的流行病学证据表明，早年体重曾出现大幅波动，无论体重是否超标，都是日后发生胰岛素相关并发症（即中心性肥胖、2型糖尿病和心血管疾病）的危险因素。在青年时期经历过体重波动（包括因疾病、饥荒或自愿“溜溜球”节食导致体重下降后又恢复体重）的男性和女性中，都报告了这种风险增加的情况。当体重波动发生在生命早期且以胎儿和/或新生儿生长迟缓后的追赶生长为特征时，这种风险尤其高。由于体重恢复/追赶生长阶段与高胰岛素血症以及脂肪量恢复加快（即追赶性脂肪）相关，因此就出现了以下问题：调节追赶性脂肪的过程是否、为何以及如何可能导致高胰岛素血症和胰岛素相关疾病。在探讨这些问题时，本文首先回顾了存在脂肪特异性产热控制的证据，这种控制的抑制导致了体重恢复/追赶生长期间的追赶性脂肪现象。随后，本文集中讨论了最近的研究结果，这些结果表明：（i）针对追赶性脂肪的产热抑制伴随着葡萄糖从骨骼肌向白色脂肪组织的重新分配，以及（ii）从头脂肪生成和脂质氧化之间的底物循环可作为骨骼肌中的产热效应器，以响应瘦素和胰岛素之间的信号相互作用，这两种关键的“肥胖”激素参与了底物代谢的外周控制。这些新发现被整合到以下提议中：在其“进化适应性”作用中，为快速重建脂肪储备而节省葡萄糖，骨骼肌中产热抑制通过抑制从头脂肪生成和脂质氧化之间的底物循环，使体重恢复/追赶生长阶段对胰岛素抵抗和高胰岛素血症的发展具有高度敏感性，从而对围绕胰岛素抵抗综合征聚集的疾病也具有高度敏感性。
