Jack K. Goldman

Effects of ventromedial hypothalamic destruction in rats: With preexisting streptozotocin-induced diabetes☆

Abstract This report describes the effects of electrolytic destruction of the ventromedial hypothalamic nuclei (VMN) in rats previously made diabetic by injection of streptozotocin. Results were compared to those obtained following VMN destruction in non-diabetic rats. Findings indicate that diabetes does not entirely prevent the obesity or changes in adipose tissue metabolism seen after VMN destruction, whereas it does prevent the development of hyperinsulinemia or significant increase in hypertriglyceridemia. Possible mechanisms are discussed.

Adipose tissue metabolism of weanling rats after destruction of ventromedial hypothalamic nuclei: Effect of hypophysectomy and growth hormone

Abstract This report describes the effects of hypophysectomy and growth hormone treatment on the endocrine-metabolic alterations associated with destruction of the ventromedial hypothalamic nuclei (VMN) in weanling rats. In addition to previously noted characteristics of the syndrome (increased plasma insulin and triglyceride levels without hyperphagia, normal plasma glucose, and decreased plasma growth hormone levels with impaired linear growth), changes in in vitro adipose tissue metabolism of glucose-U-C 14 and palmitate-1-C 14 were observed. Glucose oxidation and incorporation into lipid were markedly elevated, whereas palmitate oxidation was decreased in adipose tissue of VMN rats. Although hypophysectomy and growth hormone treatment alone or in combination produced effects in rats with or without VMN lesions, neither significantly modified the characteristic changes observed in untreated rats with VMN lesions.

Hypothalamic obesity in the weanling rat: Effect of diet upon hormonal and metabolic alterations

Abstract Weanling rats with ventromedial hypothalamic (VMN) lesions were studied on diets varying in carbohydrate and fat content and after 48 hr of starvation to determine dietary effects on the specific endocrine-metabolic alterations associated with this model of experimental obesity. Neither food intake nor the increased carcass fat of VMN rats was affected by diet, though with starvation VMN rats lost more fat and less lean tissue than did controls. Hyperinsulinemia in VMN rats persisted on all diets but disappeared after starvation, at which time moderate hypoglycemia developed. Hypertriglyceridemia was present in VMN rats on fat containing diets but not on a fat-free diet unless the animals were subsequently starved. Increased glucose oxidation and conversion to lipid by adipose tissue of VMN rats was independent of diet and persisted during starvation. The rate of glycogen synthesis was not increased. Palmitate oxidation by VMN adipose tissue was reduced in fed animals but increased in starved animals when compared to similarly treated controls. The observed dissociation of hyperinsulinemia and hypertriglyceridemia as a consequence of dietary alteration and starvation suggests independent pathogenetic mechanisms for these variables. Similarly, persistence of enhanced glucose utilization by adipose tissue during starvation, and selective enhancement of glucose oxidation and lipid but not glycogen synthesis from glucose suggests the presence of a primary defect in VMN adipose tissue metabolism, at least partly independent of hyperinsulinemia.

Growth and metabolic changes in weanling rats with lesions in the dorsomedial hypothalamic nuclei

SummaryWhen compared with sham-operated ad libitum-fed controls, weanling rats with lesions primarily destroying the dorsomedial hypothalamic nuclei (DMNL rats) showed reduced ponderal and linear growth and food intake, normal carcass fat but increased carcass protein. Among the metabolic parameters measured, DMNL rats showed only decreased incorporation of palmitate into epididymal fat pad phospholipid and triglyceride. When sham-operated controls were pair-fed with DMNL rats, they showed growth changes almost identical with those observed in lesioned rats. However, their carcass protein was lower than both that of the lesioned rats and the ad libitum-fed controls. Metabolically, the sham-operated, pair-fed controls showed decreased incorporation of palmitate into triglyceride of epididymal fat pads and decreased oxidation of glucose and increased incorporation into total lipid of the diaphragm. When previous data on growth hormone, insulin, triglyceride and cholesterol are compared with the present findings it is suggested that dorsomedial lesions cause a subcaloric-type dwarfism that does not involve adenohypophyseal secretions and their target organs affecting growth.

Sequential changes in glucose metabolism by adipose tissue and liver of rats after destruction of the ventromedial hypothalamic muclei: Effect of three dietary regimens

Abstract U- 14 C-glucose metabolism by adipose tissue and liver was studied in vitro at several time periods after destruction of the ventromedial hypothalamic nuclei (VMN) in weanling rats on three dietary regimens. In addition, plasma insulin and glucose, food intake, carcass composition, and weight gain were measured. The animals fed ad lib, comprising experimental series I, were sacrificed at varying intervals from 2 to 13 days after lesion placement. Results in rats with lesions showed: an initial depression in food intake by lesioned animals; hyperinsulinemia and increased lipogenesis by liver and adipose tissue during a period of hypophagia; a delay of several days before increased glucose oxidation became apparent; and difference between the responses of liver and adipose tissue to lesioning. Animals in experimental series II were tube fed a quantity of diet inadequate to maintain body weight (semistarvation). This suppressed all metabolic and hormonal alterations that normally accompany VMN destruction. In experimental series III, all animals were tube fed a sufficient quantity of diet to insure weight gain in an attempt to standardize food intake and feeding pattern. Rats with lesions demonstrated: an increase in fatty acid labeling by liver 24 hr postoperatively, accompanied by hyperinsulinemia and hyperglycemia; asynchronous enhancement of glucose utilization, such that liver glucose oxidation was not elevated until 24 hr after an increase in liver lipogenesis; and delay in the increase in adipose tissue glucose utilization until 72 hr after the elevation of plasma insulin and glucose.

Studies of insulin sensitivity in vivo in weanling rats with hypothalamic obesity

Abstract Studies were performed in weanling male rats with bilateral lesions in the ventromedial hypothalamic nuclei (VMN) and sham-operated controls to evaluate (1) the endogenous insulin response to glucose, and (2) the sensitivity to exogenous insulin as manifested by both hypoglycemia and the utilization of simultaneously injected 14C-glucose. VMN rats exhibited basal hyperinsulinemia and an increased insulin secretory response to glucose. VMN and control rats exhibited similar hypoglycemic responses to exogenous insulin. Utilization of intraperitoneally injected 14C-glucose by epididymal adipose tissue and diaphragm was similarly increased by insulin in the two groups of animals. The results exclude peripheral insulin resistance as the basis for hyperinsulinemia and support the belief that it is a direct consequence of the hypothalamic lesion.

Metabolism of intravenously injected 14C-glucose in weanling rats with hypothalamic obesity

Abstract Weanling male rats with bilateral lesions in the ventromedial hypothalamic nuclei (VMN) and sham-operated controls were injected intravenously with 14 C-glucose to compare plasma glucose disappearance rates, and lipid and glycogen synthesis in liver, diaphragm, and epididymal adipose tissue. Removal of 14 C-glucose from plasma was more than twice as rapid in VMN rats as in control animals despite comparable glucose levels. Incorporation of 14 C-glucose into lipid was increased in all three tissues of VMN rats and was primarily due to an increase in fatty acid synthesis. Incorporation of label into glycogen by VMN rats was increased in adipose tissue but unchanged in liver and diaphragm. The results indicate that weanling VMN rats exhibit increase glucose utilization in vivo primarily directed toward lipogenesis. This finding is not restricted to adipose tissue but is present as well in liver and muscle.

Bronchogenic carcinoma simulating hyperparathyroidism

Four cases are reported of hypercalcemia and bronchogenic carcinoma without demonstrable bone metastases. Studies on serum calcium and phosphorous, phosphate clearance, urinary calcium, rapid calcium infusion test, and ultrafiltrable serum calcium indicated changes characteristic of primary hyperparathyroidism. Surgical extirpation of the lung carcinoma in 2 cases reverted these parameters to normal while x‐radiation of the other 2 carcinomas transiently returned serum calcium and phosphorus to normal levels. Adrenocorticoid therapy caused partial suppression of hypercalcemia in 2 instances. All 4 tumors were squamous cell carcinomas. It is concluded that the single criterion for establishing that hypercalcemia is secondary to a humorally active nonmetastatic tumor is the reduction of serum calcium in response to x‐radiation or surgical removal of the tumor.

Somatic and metabolic responses of mature female rats with dietary obesity to dorsomedial hypothalamic lesions: Effects of diet palatability☆

Abstract Caloric intake, body weight, obesity status (Lee Index) and incorporation of U-14 C-glucose into liver and retroperitoneal fat pad glycogen and lipid were studied in mature female rats that had received bilateral lesions or sham-operations in the dorsomedial hypothalamic nuclei (DMN) after dietary obesity was well established. Their diet consisted of a high-fat-sucrose chow mix, chocolate chip cookies and a drinking fluid of 32% sucrose in tap water. Comparable groups of DMN lesioned rats (DMNL rats) and sham-operated controls were maintained on lab chow pellets and tap water. Prior to the hypothalamic operation, the animals on the high-caloric regimen consumed significantly more calories than the rats on lab chow and also attained commensurately higher body weights and obesity indices. The bulk of the calories consumed during this time was derived from the cookies. Following DMNL, the animals maintained on lab chow became hypophagic and had lower body weights than the sham-operated rats, as has been previously reported. In rats on the high-caloric regimen, DMNL resulted in hyperphagia in comparison to all other groups. The greatest percentage of the calories during this time was derived from the high-fat-sucrose chow mix and sugar water. Correspondingly, DMNL rats on the high-caloric regimen had higher body weights and obesity indices than all other groups. At sacrifice, both a diet and lesion effect were noted in an elevated incorporation of U 14-C glucose in both fat pad and liver lipid and glycogen. The data are interpreted to mean that (1) when a highly palatable, high-caloric diet is available, DMNL do not exert their usual hypophagic and weight-lowering effects; (2) DMNL and control rats show excessive caloric intake when both groups are fed a highly palatable, high-caloric diet in comparison to their chow-fed counterparts. However, DMNL rats fed high-caloric diet also consume significantly more than controls fed this diet; (3) This excessive caloric intake of the DMNL rats possibly predisposes these animals to exaggerated lipogenesis in liver and adipose tissue; (4) the sham-operated controls on the high-caloric regimen also show greater lipogenesis but at a level intermediate between the chow-fed controls and the DMNL rats on the high-caloric diet.

Protein Metabolism in Weanling Rats with Hypothalamic Obesity

Summary Our findings indicate that protein synthesis is enhanced in weanling rats with hypothalamic obesity, that this enhancement is not dependent on increased amino acid transport into cells, and that muscle protein breakdown is also enhanced in these rats. The mechanisms of these changes are yet to be discovered. Finally, muscle protein has been demonstrated to be a probable source of the amino acids required to support enhanced gluconeogenesis in these rats. The authors wish to express their gratitude to Ms. Marjorie Kodis, Ms. Caroline Lorusso, and Mr. Roger Glasgow for technical assistance, and to Ms. Renee Chase who typed the manuscript.