Jeanrenaud B
Metabolism. 1978 Dec;27(12 Suppl 2):1881-92. doi: 10.1016/s0026-0495(78)80006-7.
Animal models with genetic or experimentally produced (lesions of hypothalamus) obesities are numerous and unlikely to ever be reduced to a single pathophysiologic entity. However, obese animals have many similar traits in common. They are all hyperinsulinemic, an abnormality that occurs early in the development of these syndromes and appears to be of prime importance in producing most of the metabolic changes observed both in the early and late phases of the obesity syndromes. In all instances, obesity is an evolutional syndrome in which the early phase is different from the later one. The early phase is principally characterized by increased hepatic very low density lipoprotein (VLDL) output, increased adipose tissue lipogenesis and VLDL uptake, hence, increased fat accretion and fat cell size. These abnormalities are secondary to hyperinsulinemia and can be reversed toward normal by normalizing circulating insulin levels. The late phase is characterized by the continuation of the disorders of the early one plus a superimposed abnormality, the insulin resistance state, that is detectable particularly at the level of adipose and muscle tissues, and eventually brings about hyperglycemia. Insulin resistance is a multifactorial pathological condition that includes at least: (a) a decrease (more or less marked) in insulin binding to target tissues that is responsible for the decrease in tissue sensitivity to the hormone; (b) intracellular defects that are probably responsible for the decreased insulin responsiveness of target tissues. The origin of hyperinsulinemia in animal obesities is still ill-defined. Lesions of the ventromedial hypothalamus (VMH) produce rapid and lasting hyperinsulinemia. Such lesions produce, in addition, increased secretion of insulin and glucagon and changes in pancreatic insulin, glucagon, and somatostatin content in subsequently perfused pancreases. The locus responsible for these effects is not defined and may actually involve a series of interrelated loci. Whatever the latter may be, one of the routes of CNS influence upon endocrine pancreas is the vagus nerve, although a humoral factor has also been claimed. The etiology of hyperinsulinemia in genetically obese animals is unknown. Genetic inheritance could bear primarily upon some hypothalamic or other CNS sites, with secondary alterations in the endocrine pancreas function, or primarily on the islets of Langerhans with possible alteration in the respective function of the A, B, and D cells with resulting excessive insulin secretion.
具有遗传性或实验性（下丘脑损伤）肥胖的动物模型众多，不太可能归结为单一的病理生理实体。然而，肥胖动物有许多共同的相似特征。它们都存在高胰岛素血症，这种异常在这些综合征的早期就会出现，并且在肥胖综合征的早期和晚期所观察到的大多数代谢变化中似乎起着至关重要的作用。在所有情况下，肥胖都是一种渐进性综合征，其早期阶段与后期阶段不同。早期阶段的主要特征是肝脏极低密度脂蛋白（VLDL）输出增加、脂肪组织脂肪生成增加和VLDL摄取增加，因此脂肪堆积和脂肪细胞大小增加。这些异常是高胰岛素血症的继发结果，通过使循环胰岛素水平正常化可恢复正常。后期阶段的特征是早期紊乱持续存在，加上一种叠加的异常情况，即胰岛素抵抗状态，这种状态尤其在脂肪组织和肌肉组织水平可检测到，并最终导致高血糖。胰岛素抵抗是一种多因素病理状态，至少包括：（a）胰岛素与靶组织结合减少（或多或少明显），这导致组织对该激素的敏感性降低；（b）细胞内缺陷，这可能是靶组织胰岛素反应性降低的原因。动物肥胖中高胰岛素血症的起源仍不明确。腹内侧下丘脑（VMH）损伤会导致快速且持久的高胰岛素血症。此外，此类损伤会使胰岛素和胰高血糖素分泌增加，并使随后灌注的胰腺中胰岛素、胰高血糖素和生长抑素含量发生变化。导致这些效应的位点尚未明确，实际上可能涉及一系列相互关联的位点。无论后者是什么，中枢神经系统影响内分泌胰腺的途径之一是迷走神经，尽管也有人声称存在一种体液因子。遗传性肥胖动物中高胰岛素血症的病因尚不清楚。遗传因素可能主要影响某些下丘脑或其他中枢神经系统部位，继而导致内分泌胰腺功能改变，或者主要影响朗格汉斯岛，可能改变A、B和D细胞的各自功能，从而导致胰岛素分泌过多。
