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

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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 hyerinsulinemia in the face of normoglycemia, hypertrigly ceridemia 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 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 manipulations, glucose preference tests and intraperitoneal injections with glucose. Hyperinsulinemia and hypertrigly ceridemia 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 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 these 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 changed also appear on several different types of diet and persist with fasting. The latter does not reduce insulin sensitivity of VMN rat tissues, whereas it does so in normal rats. Mature VMN rats develop 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. Glucose transport across cell membranes does not appear to be a critical step in the enhanced glucose activity and increased glycolysis. However, pyruvate metabolism does not appear to be enhanced in weanling VMN rat tissue. Enhanced gluconeogenesis is suggested by increased ureagenesis, bicarbonate incorporation into plasma glucose and liver glycogen and greater alanine incorporation. The weanling rat ventromedial syndrome appears to be the result of a hypothalamic-autonomic nervous system disturbance rather than due to a disruption of „classic”︁ neuroendocrine mechanisms.