Ventromedial hypothalamic obesity: a reexamination of the irritative hypothesis

The basic assumption of brain research utilizing lesions is that any observed changes in behavior or physiological responses must be the result of tissue destruction. Reynolds suggested 25 years ago that in the case of electrolytic ventromedial hypothalamic lesions, the observed hyperphagia and obesity were due instead to metallic ion deposits from the electrode tip irritating adjacent tissue. His "irritative hypothesis" was largely ignored after others reported obesity in rats given nonirritative (i.e., no deposits) VMH lesions. However, recent studies have shown that the experimental observations by both Reynolds and his critics were correct and that the early discrepancies were largely due to the sex of the animals used in the experiments. Obesity can be produced with nonirritative VMH lesions, but the weight gain is only about 60% of that observed with irritative VMH lesions and the animals do not display the characteristic lesion-induced elevations in basal insulin levels. A new combination ablation-irritative hypothesis is proposed in which electrolytic VMH lesion obesity is attributed in part to tissue ablation and in part to metallic ion deposits stimulating (rather than disinhibiting) vagally mediated insulin responses.