Barbara J. Mullen

Recombinant Tumor Necrosis Factor-α Chronically Administered in Rats: Lack of Cachectic Effect

Abstract Recombinant human tumor necrosis factor-α (rHuTNF) was injected into rats to test its reported cachectic effects. Rats were subcutaneously injected daily at 1730 hr with either saline or rHuTNF (0.25 mg/kg body wt) for either 5 or 14 days. Daily food intakes were significantly depressed only for the first day and first two days of rHuTNF injection in animals treated for 5 days and 14 days, respectively. There were no significant differences in daily body weights among the groups. Analysis of carcass composition revealed no significant differences in percentage of lipid or protein. Liver and inguinal pad weights were not significantly different. In vitro determination of lipogenesis showed it was enhanced in the inguinal pad and depressed in the liver only after 14 days of treatment. These results demonstrate that although in vivo rHuTNF may specifically alter tissue metabolism, it does not, by itself, result in a sustained cachectic effect.

Effect of starvation or restriction on self-selection of macronutrients in rats

Two models of food deprivation were used to study feeding behavior: starvation and dietary restriction. Rats starved for 3 days had decreased protein intake during the first 2 days of refeeding followed by increased carbohydrate consumption compared to controls. During refeeding, total intake was initially low compared to controls. In a second starvation study of similar design, brain tissues [raphe, ventromedial hypothalamus (VMH)] and sera were collected for analysis before refeeding and on day 2 of refeeding. Starved and starved-refed rats had increased serum beta-hydroxybutyrate versus controls. In rats restricted for 5 days (5 g/day), total food intake was increased immediately and was characterized primarily by carbohydrate intake. Serotonin levels in the raphe were decreased in restricted rats and 5-hydroxyindole acetic acid (5-HIAA) increased in restricted-refed rats. Restriction caused an increase in blood levels of beta-hydroxybutyrate and a decrease in insulin and glucose compared to controls. Fat selection remained low throughout all studies. The data suggest that starvation and food restriction elicit different patterns of macronutrient selection upon refeeding.

Novel approach to diet design for determining macronutrient preference

Previous studies indicate that rats fed a saturated vs. unsaturated fat consume more of a high-protein/low-carbohydrate and less of a low-protein/high-carbohydrate diet. Present studies were conducted to determine whether saturated-fat-fed rats are preferring protein or avoiding carbohydrate. Three combinations of diets were prepared in which one macronutrient was held constant and two covaried: 1) high protein/low carbohydrate and low protein/high carbohydrate, 2) high fat/low carbohydrate and low fat/high carbohydrate, and 3) high fat/low protein and low fat/high protein. Male Sprague-Dawley rats (75-99 g) were fed either 34% tallow (n = 30) or corn oil (n = 30) diets for 4 days. These diets were removed and one third of each group was given one of the diet combinations. Rats previously fed tallow consumed more high-protein/low-carbohydrate and low-carbohydrate/high-fat diets and less high-carbohydrate/low-fat diet than controls previously fed corn oil. These data suggest that tallow-fed animals are avoiding carbohydrate rather than preferring protein.

Somatostatin and growth hormone-releasing factor release from zucker rat hypothalamic tissue

Plasma somatotropin (ST) levels are depressed in the genetically obese Zucker rat compared to those of their littermates. It is believed that this defect is associated with one or both of the hypothalamic neuropeptides that control ST release: growth hormone releasing factor (GRF) and somatostatin (SS). The mechanism by which SS and GRF neuropeptides are regulated remains uncertain. The objective of this study was to examine the effect of 2 deoxy-glucose (2DG), isoproterenol (ISO), tryptophan (TRP), and 5HT on SS and GRF release in hypothalamic tissue from lean and obese Zucker rats. An in vitro perifusion system was established to examine the release of SS and GRF from perifused hypothalami taken from 8- and 12-week-old Zucker rats under basal conditions and in response to 2DG, ISO, TRP, 5HT, and KCl administration. Hypothalami were perifused with Dulbeccos modified eagles medium continuously at 37 degrees C for 5 h at a flow rate of 100 ml/min. ISO and 2DG significantly (p < 0.05) increased SS levels from the obese rat, but no effect was observed from the lean littermate. GRF was not affected by 2DG or ISO in either genotypes. TRP and 5HT failed to affect SS or GRF release in lean or obese Zucker rats. It is proposed that the obese Zucker rat is more sensitive to glucose deprivation and to beta-adrenergic stimulation of SS release than the lean littermate.

Control of Food Intake: Mechanisms and Consequences

The major nutritional problem facing the U.S. population is obesity. Obesity has recently been described as a disease state that precipitates at least 26 other disease states. A National Institutes of Health consensus panel has concluded that obesity is a potential killer. For example, people between ages 20 to 44 who are obese are FIVE TIMES more likely to have high blood pressure and THREE TIMES more likely to have diabetes. If obesity is defined as being 20% or more above desirable weight, then about 40% of American women between the ages of 40 and 49 are obese as are about 32% of men in the same age category. The eating disorders, anorexia and bulimia, are additional problems facing an increasing number of young women. In college women the incidence of anorexia is as high as 1 in 200. In order to understand this major nutritional problem it is necessary to understand the normal mechanisms of energy balance regulation and where these mechanisms fail. This discussion focuses on energy balance regulation and the factors influencing abnormal regulation that lead to either obesity or anorexia.