Department of Internal Medicine, Assisi Hospital, Via Valentin Muller 1, Assisi, Perugia, Italy.
Biochimie. 2013 Mar;95(3):585-94. doi: 10.1016/j.biochi.2012.12.014. Epub 2012 Dec 26.
Obesity has been proposed as an energy balance disorder in which the expansion of adipose tissue (AT) leads to unfavorable health outcomes. Even though adiposity represents the most powerful driving force for the development of insulin resistance (IR) and type 2 diabetes, mounting evidence points to "adipose dysregulation", rather than fat mass accrual per se, as a key pathophysiological trigger of the obesity-linked metabolic complications. The dysfunctional fat, besides hypertrophic adipose cells and inflammatory cues, displays a reduced ability to form new adipocytes from the undifferentiated precursor cells (ie, the preadipocytes). The failure of adipogenesis poses a "diabetogenic" milieu either by promoting the ectopic overflow/deposition of lipids in non-adipose targets (lipotoxicity) or by inducing a dysregulated secretion of different adipose-derived hormones (ie, adipokines and lipokines). This novel and provocative paradigm ("expandability hypothesis") further extends current "adipocentric view" implicating a reduced adipogenic capacity as a missing link between "unhealthy" fat expansion and impairment of metabolic homeostasis. Hitherto, reactive oxygen species have been implicated in multiple forms of IR. However, the effects of stress on adipogenesis remain controversial. Compelling circumstantial data indicate that lipid peroxidation by-products (ie, oxysterols and 4-hydrononenal) may detrimentally affect adipose homeostasis partly by impairing (pre)adipocyte differentiation. In this scenario, it is tempting to speculate that a fine tuning of the adipose redox status may provide new mechanistic insights at the interface between fat dysregulation and development of metabolic dysfunctions. Yet, in humans, the molecular "signatures" of oxidative stress in the dysregulated fat as well as the pathophysiological effects of adipose (per)oxidation on glucose homeostasis remain poorly investigated. In this review we will summarize the potential mechanisms by which increased oxidative stress in fat may impair (pre)adipocyte differentiation and promote the adipose dysfunction. We will also attempt to highlight the conundrum with the adipose redox changes and the regulation of glucose homeostasis. Finally, we will briefly discuss the scientific rationale for proposing the adipose redox state as a potential target for novel therapeutic strategies to curb/prevent adiposity-linked insulin resistance.
肥胖被认为是一种能量平衡紊乱，其中脂肪组织（AT）的扩张导致不利的健康结果。尽管肥胖是导致胰岛素抵抗（IR）和 2 型糖尿病发展的最强大驱动力，但越来越多的证据表明，“脂肪失调”而不是脂肪质量的积累本身，是肥胖相关代谢并发症的关键病理生理触发因素。功能失调的脂肪，除了肥大的脂肪细胞和炎症线索外，还显示出从未分化的前体细胞（即前脂肪细胞）形成新的脂肪细胞的能力降低。脂肪生成的失败构成了一种“糖尿病生成”的环境，要么通过促进脂质在非脂肪靶标中的异位溢出/沉积（脂毒性），要么通过诱导不同脂肪衍生激素（即脂肪因子和脂素）的失调分泌。这种新的和有争议的范式（“可扩展性假说”）进一步扩展了当前的“脂肪中心观点”，暗示脂肪生成能力的降低是“不健康”脂肪扩张和代谢稳态受损之间缺失的联系。迄今为止，活性氧已被牵连到多种形式的 IR 中。然而，应激对脂肪生成的影响仍然存在争议。令人信服的间接证据表明，脂质过氧化产物（即氧化固醇和 4-羟壬烯醛）可能通过损害（前）脂肪细胞分化，对脂肪稳态产生不利影响。在这种情况下，人们不禁推测，精细调节脂肪的氧化还原状态可能为脂肪失调和代谢功能障碍的发展之间的机制提供新的见解。然而，在人类中，失调脂肪中氧化应激的分子“特征”以及脂肪（过）氧化对葡萄糖稳态的病理生理影响仍未得到充分研究。在这篇综述中，我们将总结增加脂肪中的氧化应激如何损害（前）脂肪细胞分化并促进脂肪功能障碍的潜在机制。我们还将尝试突出脂肪氧化还原变化与葡萄糖稳态调节之间的难题。最后，我们将简要讨论将脂肪氧化还原状态作为一种潜在的治疗策略靶点的科学依据，以遏制/预防肥胖相关的胰岛素抵抗。
