Improved bone status by the beta-blocker propranolol in an animal model of nutritional growth retardation.

The aim of the present research was to study if the beta-blocker propranolol, which is known to increase bone mass, could reverse the adverse skeletal effects of mild chronic food restriction in weanling rats. Male Wistar rats were divided into four groups: control, control+propranolol (CP), nutritional growth retardation (NGR) and nutritional growth retardation+propranolol (NGRP). Control and CP rats were fed freely with the standard diet. NGR and NGRP rats received, for 4 weeks, 80 % of the amount of food consumed by the control and CP rats, respectively. Results were expressed as mean values and sem. Food restriction induced detrimental effects on body and femur weight and length (P < 0.05) and bone structural and geometrical properties (P < 0.001), confirming results previously shown in our laboratory. However, the beta-blocker overcame the deleterious effect of nutritional stress on load-bearing capacity, yielding load, bone stiffness, cross-sectional cortical bone area and second moment of inertia of the cross-section in relation to the horizontal axis without affecting anthropometric, histomorphometric and bone morphometric parameters. The results suggest that propranolol administration to mildly chronically undernourished rats markedly attenuates the impaired bone status in this animal model of growth retardation.

Evidence from catch-up growth and hoarding behavior of rats that exposure to hypobaric air lowers the body-mass set point.

The depression of body growth rate and the reduction of body mass for chronological age and gender in growing experimental animals exposed to hypobaric air (simulated high altitude = SHA) have been associated with hypophagia because of reduced appetite. Catch-up growth during protein recovery after a short period of protein restriction only occurs if food intake becomes super-normal, which should not be possible under hypoxic conditions if the set-point for appetite is adjusted by the level of SHA. The present investigation was designed to test the hypothesis that growth retardation during exposure to SHA is due to an alteration of the neural mechanism for setting body mass size rather than a primary alteration of the central set-point for appetite. One group of female rats aged 35 d were exposed to SHA (5460m) in a SHA chamber for 27 d (HX rats). Other group was maintained under local barometric pressure conditions (NX rats). One half of both NX and HX rats were fed a protein-free diet for the initial 9 d of the experimental period. From this time on, they were fed a diet containing 20% protein, as were the remaining rats of both groups during the entire experimental period. The growth rates of both mass and length of the body were significantly depressed in well-nourished rats exposed to SHA during the entire observation period when compared to normoxic ones. At its end, body mass and body length were 24% and 21% less in HX than in NX rats. Growth rates were negatively affected by protein restriction in both NX and HX rats. During protein recovery, they reached supernormal values in response to supernormal levels of energy intake that allowed a complete catch-up of both body mass and length. The finding that energy intake during the period of protein rehabilitation in HX rats previously stunted by protein restriction was markedly higher than in HX control ones at equal levels of hypoxia demonstrates that the degree of hypoxia does not determine directly the degree of appetite and energy intake. Furthermore, the finding that catch-up growth in the stunted HX rats returns the animal only to the stunted size appropriate for the hypoxic animal supports the hypothesis that hypoxia lowers the set-point for body mass size, which is reached by inhibition of appetite. Confirmation of the hypothesis was done by assessment of the set-point of body mass by the behavioral method of the weight threshold to hoard food. It was lowered by 17.0% in HX rats.

Failure of polycythemia-induced increase in arterial oxygen content to suppress the anorexic effect of simulated high altitude in the adult rat.

The anorexic effect of exposure to high altitude may be related to the reduction in the arterial oxygen content (Ca(O2)) induced by hypoxemia and possibly the associated decreased convective oxygen transport (COT). This study was then performed to evaluate the effects of either transfusion-induced polycythemia or previous acclimation to hypobaria with endogenously induced polycythemia on the anorexic effect of simulated high altitude (SHA) in adult female rats. Food consumption, expressed in g/d/100 g body weight, was reduced by 40% in rats exposed to 506 mbar for 4 d, as compared to control rats maintained in room air. Transfusion polycythemia, which significantly increased hematocrit, hemoglobin concentration, Ca(O2), and COT, did not change the anorexic response to the exposure to hypobaric air. Depression of food intake during exposure to SHA also occurred in rats fasted during 31 h before exposure and allowed to eat ad libitum for 2 h during exposure. Body mass loss was similar in 48-h fasted rats that were either hypoxic or normoxic. Body mass loss was similar in normoxic and hypoxic rats, the former eating the amount of food freely eaten by the latter. Hypoxia-acclimated rats with endogenously induced polycythemia taken to SHA again had diminished food intake and lost body mass at rates that were very close to those found in nonacclimated ones. Exposure to SHA also led to a decrease in food consumption, body weight, and plasma leptin in adult female mice. Analysis of data suggest that body mass loss that accompanies SHA-induced hypoxia is due to hypophagia and that experimental manipulation of the blood oxygen transport capacity cannot ameliorate it. Leptin does not appear to be an inducer of the anorexic response to hypoxia, at least in mice and rats.

mRNA of cytokines in bone marrow and bone biomarkers in response to propranolol in a nutritional growth retardation model.

BACKGROUND: The aim of this study was to assess mRNA of IL-6, TNFα and IL-10 cytokines in bone marrow, possible mediators involved in altered bone remodeling with detrimental consequences on bone quality in NGR (Nutritional growth retardation) rats. METHODS: Weanling male Wistar rats were assigned either to control (C) or experimental group (NGR) (n=20 each). C and NGR groups were assigned to 2 groups according to receiving saline solution (SS) or propranolol hydrochloride (P): C, C+P (CP), NGR or NGR+P (NGRP). For 4 weeks, NGR and NGRP rats received 80% of the amount of food consumed by C and CP, respectively, the previous day, corrected by body weight. P (7 mg/kg/day) was injected ip 5 days/week, for 4 weeks in CP and NGRP rats. Body weight and length were recorded. After 4 weeks, blood was drawn. Femurs were dissected for RNA isolation from bone marrow and mRNA of cytokines assays. RESULTS: Food restriction induced a significant negative effect on body growth in NGR and NGRP rats (p<0.001). P had no effects on zoometric parameters (p>0.05). CTX-I increased in NGR rats vs. C (p<0.001), but diminished in NGRP (p<0.01). Serum osteocalcin, PTH, calcium and phosphate levels remained unchanged between groups (p>0.05). In NGR, bone marrow IL-6 mRNA and IL-10 mRNA levels were low as compared to other groups (p<0.05). In contrast, bone marrow TNF-α mRNA levels were significantly high (p<0.05). CONCLUSIONS: This study provides evidences that NGR outcomes in a bone marrow proinflammatory microenvironment leading to unbalanced bone remodeling by enhancement of bone resorption reverted by propranolol.

Dyslipidemia is not associated with cardiovascular disease risk in an animal model of mild chronic suboptimal nutrition.

Previous studies performed in an experimental model of nutritional growth retardation (NGR) have observed metabolic adaptation. We hypothesized that changes in lipid-lipoprotein profile, glucose, and insulin levels occur, whereas overall body growth is reduced.The aim of this study was to assess serum lipid-lipoprotein profile, hepatogram, insulinemia and glycemia, and CVD risk markers in rats fed a suboptimal diet. Weanling male rats were assigned either to control (C) or NGR group. In this 4-week study, C rats were fed ad libitum a standard diet, and NGR rats received 80% of the amount of food consumed by C. Zoometric parameters, body fat content, serum lipid-lipoprotein profile, hepatogram, insulinemia, and glycemia were determined, and the cardiovascular disease (CVD) risk markers homeostasis model assessment-insulin resistance and homeostasis model assessment and ß-cell function were calculated. Suboptimal food intake induced a significant decrease in body weight and length, which were accompanied by a reduction of 50% in body fat mass. Serum lipoproteins were significantly higher in NGR rats, with the exception of high-density lipoprotein cholesterol, which remained unchanged. Nutritional growth retardation rats had decreased triglycerides compared with C rats. No significant differences were detected in liver function parameters. The CVD risk markers homeostasis model assessment (HOMA)-insulin resistance and homeostasis model assessment and ß-cell function were significantly lower in NGR rats. Mild chronic suboptimal nutrition in weanling male rats led to growth retardation and changes in the lipid-lipoprotein profile, glucose, and insulin levels while preserving the integrity of liver function. These data suggest a metabolic adaptation during suboptimal food intake, which ensures substrates flux to tissues that require constant energy-in detriment to body growth. The CVD risk markers suggested that mild chronic food restriction of approximately 20% could provide protection against this degenerative disease.