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Systemic treatment with dexfenfluramine (dF), fluoxetine, or serotonin (5-hydroxytryptamine, 5-HT) recently was shown to suppress fat and occasionally protein but not carbohydrate intake in rats when a macronutrient selection paradigm was employed. These reports contrast with the prevailing literature, which for the past decade has described a role for serotonin neurotransmission in the modification of dietary carbohydrate consumption. To test the hypothesis that the suppression of fat selection and/or consumption by systemic serotonin agonists involves stimulation of central 5-HT receptors, a series of experiments was performed in nondeprived rats. In experiment 1, third cerebroventricular (3V) infusion of the nonselective 5-HT antagonist metergoline prevented the reduction in fat but not carbohydrate feeding caused by systemic dF. Furthermore, 3V metergoline alone increased fat intake. In experiments 2 and 3, 3V infusion of 5-HT(1B/2C) receptor agonists D-norfenfluramine (DNF) or quipazine inhibited fat intake exclusively. Next, the infusion of DNF or 5-HT into the region of the paraventricular nucleus (PVN) reduced both fat and protein intake (experiments 4 and 5). Finally, in experiment 6, when rats were grouped by baseline diet preference, 5-HT infused into the PVN led to a dose-related decrease in fat intake in both carbohydrate- and fat-preferring rats. In contrast, there were no dose effects of 5-HT on carbohydrate or protein intake in either preference group. However, in fat-preferring rats, the highest dose of 5-HT reduced intake of all three macronutrient diets. These results demonstrate a selective effect of exogenous serotonergic drugs in the hypothalamus to reduce fat rather than carbohydrate intake and suggest that higher baseline fat intake enhances responsivity to serotonergic drugs.

These experiments were designed to test the hypothesis that the contrasting patterns of macronutrient selection described previously in AKR/J (fat preference) and SWR/J (carbohydrate preference) mice are not dependent on a single diet paradigm. The effect of mouse strain on proportional fat intake was tested in naive mice by presenting two-choice diets possessing a variety of physical, sensory, and nutritive properties. In three separate experiments, AKR/J mice preferentially selected and consumed a higher proportion of energy from the high-fat diet than SWR/J mice. Specifically, this phenotypic difference was observed with 1) fat-protein vs. carbohydrate-protein diets, independent of fat type (vegetable shortening or lard), 2) isocaloric, high- vs. low-fat liquid diet preparations, and 3) high- vs. low-fat powdered-granular diets. These results confirm our previous observation of a higher proportional fat intake by AKR/J compared with SWR/J mice using the three-choice macronutrient selection diet and show that this strain difference generalizes across several diet paradigms. This strain difference is due largely to the robust and reliable fat preference of the AKR/J mice. In contrast, macronutrient preference in SWR/J mice varied across paradigms, suggesting a differential response by this strain to some orosensory or postingestive factor(s).

As a first step toward developing a mouse model to characterize genetic factors linked to the preferential intake of dietary carbohydrate or fat, we have identified two mouse strains that exhibit distinctly different patterns of macronutrient selection. Macronutrient selection was evaluated in AKR/J and SWR/J mice, two strains that have been characterized previously for their sensitivity to high-fat dietary obesity. Mice were adapted to a self-selection protocol in which separate carbohydrate, fat, and protein sources were simultaneously available. AKR/J mice ate 30% more calories than the SWR/J mice. Furthermore, strain comparisons revealed a significantly higher proportion of fat intake by the AKR/J mice (69 vs. 28%), and in the SWR/J mice a significantly higher intake of carbohydrate (62 vs. 24%). The mice were then returned to a standard chow diet for 10 wk. These mice subsequently were allowed to self-select from two composite energy diets (carbohydrate and protein, or fat and protein). Once again, AKR/J mice selected a greater proportion of energy from the fat/protein diet (85%) than did the SWR/J strain (32%). These findings suggest a possible relationship between sensitivity to dietary obesity and fat selection.

Anorectic weight-losing Fischer 344 rats bearing a methylcholanthrene-induced sarcoma received intraperitoneal injections of rabbit antiserum raised against murine tumor necrosis factor (TNF)-alpha at 14, 18, and 24 days after tumor induction. Treatment of tumor-bearing rats with TNF antiserum partially reversed the tumor-induced reduction in food intake compared with tumor-bearing rats that received control serum. In the same tumor-bearing animals, treatment with TNF antiserum delayed the onset and significantly reduced the decline in mean 12-h daytime and nighttime intra-abdominal temperatures on days 18-25. However, anti-TNF antibody treatment did not alter the declines in carcass weight or motor activity measured from day of tumor induction until death or reduce the tumor burden at death. We conclude that an endogenous TNF response may be one of the factors involved in the development of cancer anorexia and that this cytokine has temperature-lowering properties.

Temporal patterns of the cachectic effects of tumor growth and their relation to systemic levels of tumor necrosis factor (TNF) and IL-6 (interleukin-6) were examined in a rat model of experimental cancer cachexia employing the methylcholanthrene (MCA) sarcoma. Fischer 344 rats, implanted with biotelemeters for measuring temperature and activity, were implanted subdermally with tumor tissue fragments. Ad libitum-fed and pair-fed controls were sham incised. Bioassays for TNF and IL-6 were performed on serial plasma samples, obtained via jugular vein at 3- to 6-day intervals throughout the experimental period. Tumor growth induced significant anorexia, weight loss, and a decline in motor activity corresponding to an increase in mean plasma IL-6 levels, independent of reduced food intake or weight loss alone as shown in pair-fed controls. A significant lowering of body temperature then developed, followed by a two- to threefold increase in water consumption. The patterns of weight loss and temperature reduction differed in rate and degree from those seen with pair feeding.

A human recombinant interleukin-1 receptor antagonist (IL-1ra) recognizes the two known IL-1 receptors and blocks the binding and many biological effects of both IL-1 alpha and IL-1 beta. The effectiveness of IL-1ra in modifying the fever and plasma IL-6 responses elicited by lipopolysaccharide (LPS) in vivo was tested in Fischer 344 rats. Animals that received IL-1ra 0.5 mg/kg intraperitoneally followed 10 min later by 10 micrograms/kg of LPS displayed significantly lower mean fever responses 2-4 h after injection than rats that received vehicle and LPS (0.48 +/- 0.13 vs. 0.95 +/- 0.16 degrees C, P = 0.016). Plasma levels of IL-6 at 4 h after injection were not different in IL-1ra-treated rats compared with controls (407,725 vs. 729,169 U/ml). Based on our previous finding that preadministration of antiserum to IL-1 beta markedly suppressed plasma IL-6 after LPS, and recent evidence that molar excesses of IL-1ra blocked IL-1-induced circulating IL-6 levels, the possibility that IL-1 is responsible for the induction of bioactive IL-6 during inflammation cannot be ruled out. Similarly, the inability of the IL-1ra to completely suppress the febrile responses of rats to LPS in the present study may be dose related. Alternatively, the induction of bioactive IL-6 by IL-1 in the rat may be mediated primarily through some receptor other than the type I (e.g., the type II receptor).