Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus
Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus
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DOI：
10.1038/sj.ijo.0802853
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发表时间：
2004-12-01
影响因子：
4.9
通讯作者：
Ravussin, E
中科院分区：
文献类型：
--
作者：
Heilbronn, L;Smith, SR;Ravussin, E
背景：人们普遍认为，肥胖增加与胰岛素抵抗和II型糖尿病风险增加有关。用于解释这种联系的主要范式是门户/内脏假说。这一假说认为，肥胖增加，特别是在内脏储存库，会导致胰岛素敏感组织中游离脂肪酸流量增加，并通过Randle效应抑制胰岛素作用。目的：在这篇综述中，将讨论这一范式的局限性，并提出另外两种可能解释肥胖与胰岛素抵抗/糖尿病之间已建立联系的范式。(A)异位脂肪储存综合征。有三条证据支持这一概念。首先，不能形成足够的脂肪组织块(也称为“脂肪营养不良症”)会导致严重的胰岛素抵抗和糖尿病。这被认为是脂肪异位储存到肝脏、骨骼肌和胰腺分泌胰岛素的β细胞的结果。其次，大多数肥胖患者还会将脂肪分流到骨骼肌、肝脏，可能还有β细胞。几项研究证明了这一发现的重要性，这些研究表明，骨骼肌和肝脏的脂质渗透程度与胰岛素抵抗高度相关。第三，脂肪细胞体积增大与胰岛素抵抗和糖尿病的发生密切相关。脂肪细胞大小的增加可能代表脂肪组织块无法膨胀，从而无法适应能量流入的增加。综上所述，这些观察结果支持“获得性脂肪营养不良”假说，认为肥胖和胰岛素抵抗之间存在联系。因此，异位脂肪沉积是相加或协同作用的结果，包括增加饮食摄入量，减少脂肪氧化和阻碍脂肪生成。(B)内分泌模式。这一概念是与“异位脂肪储存综合征”假说同时发展起来的。脂肪组织分泌多种内分泌激素，如瘦素、白介素6、血管紧张素II、脂联素和抵抗素。从这一观点来看，脂肪组织作为内分泌腺起着至关重要的作用，它分泌多种对远端组织的代谢有强大影响的因子。结论：异位脂肪和脂肪细胞作为内分泌器官的新范式可能会构成一个新的框架，研究我们的自然环境与糖尿病发病风险之间的联系。
BACKGROUND: It is widely accepted that increasing adiposity is associated with insulin resistance and increased risk of type II diabetes. The predominant paradigm used to explain this link is the portal/visceral hypothesis. This hypothesis proposes that increased adiposity, particularly in the visceral depots, leads to increased free-fatty acid flux and inhibition of insulin-action via Randle's effect in insulin-sensitive tissues.OBJECTIVES: In this review, limitations of this paradigm will be discussed and two other paradigms that may explain established links between adiposity and insulin resistance/diabetes will be presented. ( a) Ectopic fat storage syndrome. Three lines of evidence support this concept. Firstly, failure to develop adequate adipose tissue mass ( also known as 'lipodystrophy') results in severe insulin resistance and diabetes. This is thought to be the result of ectopic storage of lipid into liver, skeletal muscle and the pancreatic insulin-secreting beta cell. Secondly, most obese patients also shunt lipid into the skeletal muscle, the liver and probably the beta cell. The importance of this finding is exemplified by several studies demonstrating that the degree of lipid infiltration into skeletal muscle and liver highly correlates with insulin resistance. Thirdly, increased fat cell size is highly associated with insulin resistance and the development of diabetes. Increased fat cell size may represent the failure of the adipose tissue mass to expand and therefore to accommodate an increased energy influx. Taken together, these observations support the 'acquired lipodystrophy' hypothesis as a link between adiposity and insulin resistance. Ectopic fat deposition is therefore the result of additive or synergistic effects including increased dietary intake, decreased fat oxidation and impaired adipogenesis. (b) Endocrine paradigm. This concept was developed in parallel with the 'ectopic fat storage syndrome' hypothesis. Adipose tissue secretes a variety of endocrine hormones such as leptin, interleukin-6, angiotensin II, adiponectin and resistin. From this viewpoint, adipose tissue plays a critical role as an endocrine gland, secreting numerous factors with potent effects on the metabolism of distant tissues.CONCLUSIONS: The novel paradigms of ectopic fat and fat cell as an endocrine organ probably will constitute a new framework for the study of the links between our obesigenic environment and the risk of developing diabetes.