Origin of endocrine‐metabolic changes in the weanling rat ventromedial syndrome

Abstract

Destruction of the ventromedial hypothalamic nuclei (VMN) in the weanling rat without injury to the median eminence results in a series of somatic, endocrine, and metabolic changes that are characterized by normal food and water intake but decreased linear growth, normal body weight but increased carcass fat and reduced carcass protein, lean body mass, and water. The endocrine alterations comprise hyperinsulinemia in the face of normoglycemia, hypertriglyceridemia and hypercholesterolemia and reduced growth hormone levels. The metabolic changes include greater oxidation of glucose and incorporation into lipid and reduced palmitate oxidation but increased incorporation into lipid. Weanling rats with VMN lesions are normophagic in absolute terms, relative to body weight and per metabolic unit, but their nocturnal feeding and weight gain cycles are disrupted and their locomotor activity is reduced. The VMN are involved in the long-term control of feeding - as in the mature rat - as shown by intragastric preloading studies and dietary density manipulation, glucose preference tests and intraperitoneal injections with glucose. Hyperinsulinemia and hypertriglyceridemia are present four days after the VMN operation in the presence of subnormal food intake and plasma glucose levels. Manipulations of the fat content of the diet revealed that the hyperlipidemia is of both endogenous and exogenous origin and that lipoprotein lipase is increased; a 48-hour fast reduced the hyperlipidemia to control levels, however. This suggests that weanling VMN rat tissue may have an impaired ability to take up circulating lipid. An increased incorporation of glycerol into lipid may be due to induction of glycerokinase by hyperinsulinemia. Adipose tissue of weanling VMN rats showed glycerokinase by hyperinsulinemia. Adipose tissue of weanling VMN rats showed neither depressed lipolysis nor diminished lipolytic activity per milligram of tissue protein. Glucose oxidation and incorporation into adipose tissue is increased in several tissues in vitro and there is enhanced glucose disappearance from plasma and incorporation into tissue lipids in vivo. These changes develop within a short time after lesion production and persist at least partially up to six months: glucose utilization in liver increases already four hours after the operation whereas it takes 72 hours to commence in adipose tissue. Insulin resistance is not apparent either in vivo or in vitro. The decreased growth hormone levels are not critical to the metabolic changes, nor is the hyperinsulinemia totally necessary. The metabolic changes also appear on several different types of diet and persist with fasting. The latter does not reduce insulin sensitivity of VMN rat tissues, wheras it does so in normal rats. Mature rats developed the same metabolic changes even in the absence of hyperphagia. The metabolic alterations can be blocked by pharmacologic doses of glucocorticoids, but are enhanced by the administration of estrogen...

Ventromedial Hypothalamic Lesions and the Mobilization of Fatty Acids

“…Thev are coonsistenit with this hypothesis and suggest that the ventromiie(lial hypothalamus may modulate lipid storage aindI releatse in m11an1 (4) and aniimals (5). Modulation of lipid mobilization coul(d have profounid effects on storage ofbl)odv f:at.…”

“…FFA and glycerol rose after 8 4 Effects ofexercise in control and VMIH-lesioned rats. The rise in FFA was significantly less in the VMH-lesioned rats than in the sham-operated animals, but unexercised animals from both groups showed comparable levels.…”

“…Modulation of lipid mobilization coul(d have profounid effects on storage ofbl)odv f:at. It has long been knowni that bilateral lesionis of the ventromedial hypothalanmus result in obesity (4,5,36,37). Ou)r uncderstancdin g of the organiizationi of'the v7entromedial hypothalamus has been extendedl by the anatoniict oi)servations of Ban (6,7) antd by the stutdies with electrical stimiiulation published by Frohimiani andl Bernardis (38) and by Shiniazu and his colleaguies (39)(40)(41).…”

“…Diminished activity of the sympathetic nervous system might be involved in the hyperinsulinemia characteristic of this syndrome in both animals and man (4,5). Reduced sympathetic activity might also account for the lower concentrations of glucagon and the smaller salivary glands that have been reported to follow ventromedial hypothalamic injury and obesity in experimental animals (9).…”

“…Most of the increase in body weight can be accounted for by an increase in the size of pre-existing fat cells (5). Hyperphagia, hypometabolism, and abnormalities of endocrine function are frequent features of both the human and experimental syndromes (4,5).…”