Growth hormone, insulin-like growth factor-1, and the insulin-like growth factor binding proteins in rats maintaining reduced body protein following lesions of the lateral hypothalamus.

Rats with lesions of the lateral hypothalamus (LH) maintain a reduced body protein mass that they effectively defend when challenged by under- or over-nutrition. The two studies reported here evaluate the potential contributions of growth hormone (GH), insulin-like growth factor-1 (IGF-1), and the insulin-like growth factor-binding (IGFBP) to this persistent maintenance of a reduced body protein mass by LH rats. At 18 weeks postlesion, it was found that the serum levels of GH, IGF-1, total IGFBP, and IGFBP-3 of LH rats maintaining reduced body protein were not different from those of age-matched controls. However, closer to the time of surgery, at which time the lesion-induced body protein adjustments are known to occur, altered hormone and binding protein levels were observed. Specifically, at 3 weeks after lesioning, the IGF-binding proteins of LH rats were significantly elevated, whereas their GH levels were lower than those of controls. Because the GH, IGF-1, and IGF-binding proteins of LH rats were comparable to those of controls at 18 weeks after lesioning, none apparently underlie the chronically reduced body protein mass that LH rats display. Closer to the time of lesioning, however, altered GH and IGF binding protein levels may contribute to the postlesion adjustments by which the body protein mass of LH rats is lowered to its reduced level.

Body weight set-points: determination and adjustment.

It is proposed that body weight, like body water and body temperature, is physiologically regulated. In the case of body weight, coordinated adjustments in both the intake and expenditure of energy serve to stabilize the weights of individuals at a specified level and to resist their displacement from this level. Obese individuals also display these behavioral and metabolic adjustments to weight perturbations and thus appear to actively resist efforts to reduce their weight from the elevated levels they ordinarily display. Experimental studies of genetically transmitted and diet-induced forms of obesity in animals similarly suggest a view of obesity as a condition of body energy regulation at an elevated set-point. An individual's set-point for regulated body weight is apparently adjustable, shifting over a lifespan in conjunction with naturally occurring but still unspecified physiologic changes. Experimentally, the set-point for body weight can be adjusted by manipulation of specific hypothalamic sites. Lesions of the lateral hypothalamus, for example, cause a chronic reduction in the level at which laboratory animals regulate body weight. It thus appears that hypothalamic mechanisms play a primary role in setting the level at which individuals regulate body weight, and it is likely that the genetic, dietary and other lifespan influences on body weight are expressed through these mechanisms.

Growth hormone or insulin-like growth factor I increases fat oxidation and decreases protein oxidation without altering energy expenditure in parenterally fed rats.

We assessed whether the increased growth in parenterally fed rats treated with growth hormone (GH) or insulin-like growth factor I (IGF-I) or both is associated with alterations in energy expenditure or macronutrient oxidation or both. Surgically stressed male rats (approximately 235 g) were given total parenteral nutrition (TPN) and treated with recombinant human GH (rhGH) (800 micrograms/d), rhIGF-I (800 micrograms/d), rhGH+rhIGF-I (800 micrograms/d of each), or TPN alone for 3 d. Treatment with GH or IGF-I or both resulted in significantly greater body weight gain, nitrogen retention, and serum total IGF-I concentrations compared with TPN alone (P < 0.0001). Assessment of respiratory gas exchange and motor activity for 23 h on day 3 indicated no significant differences between groups in either total or activity-related rates of energy expenditures (kJ/kg0.75). Estimates based on the nitrogen-free respiratory quotient (RQ) revealed fat oxidation to be significantly increased by GH (P < 0.001) and IGF-I (P < 0.03), whereas protein oxidation was significantly reduced (P < 0.0001) by these growth factors. GH and IGF-I combined further enhanced fat oxidation while reducing protein catabolism. Serum insulin concentrations were significantly increased by GH but decreased by IGF-I. GH significantly decreased serum total triiodothyronine concentrations and IGF-I significantly decreased serum corticosterone concentrations. These results suggest that treatment with GH or IGF-I can increase fat oxidation and spare protein for growth without altering energy expenditure in surgically stressed rats maintained with TPN.

The specific locus and time course of the body protein adjustments produced in rats by lesions of the lateral hypothalamus.

Lesions of the lateral hypothalamus (LH) result in a body weight reduction characterized by declines in both lean and adipose tissues. The body fat of LH-lesioned rats can be restored to or above the levels of nonlesioned rats by overfeeding. However, the protein deficit cannot be so reversed, suggesting that the lesion-induced body protein reduction is chronic. To ascertain which specific tissues surrender protein following LH lesions, the present studies measured skeletal muscle and visceral organ weights at 2 weeks and 6 months postlesion. Daily protein losses during the first 2 weeks postlesion were also assessed to determine the temporal pattern of whole-body protein adjustments. The results at 6 months postlesion suggest that LH lesions lead to reductions in the maintained mass of all protein-based tissues. The largest absolute loss was from skeletal muscle, whereas liver sustained the greatest proportional loss. Assessment of daily postlesion protein balance indicate that the majority of body protein losses occurred during the initial 6 days postlesion. Skeletal muscle mass was characterized by large losses at 2 weeks, and proportionally smaller losses at 6 months. Reductions of visceral organ mass were marginal at 2 weeks, but substantial by 6 months postlesion. Thus, whereas all protein-based tissues are reduced by LH lesions, the protein content of specific tissues appears to be altered differentially. Major reductions in total body protein occur in the first 2 weeks of the LH syndrome, with an apparent redistribution of protein later. This redistribution results in the partial restoration of skeletal muscle at the expense of existing visceral organ protein or its subsequent accretion.

Chronically altered body protein levels following lateral hypothalamic lesions in rats.

Rats maintaining reduced body weights after lesions of the lateral hypothalamus (LH; LH rats) are characterized by smaller body protein masses. Two experiments were conducted to determine whether this reduced protein mass is actively defended. In the first, it was found that LH rats induced to overeat and restore body weight to the level of nonlesioned controls markedly increased their body fat without significantly increasing body protein. That is, LH rats at normal body weights were notably obese. In the second experiment, body protein losses produced by food restriction in LH rats were both relatively small and proportionally the same as those seen in similarly restricted nonlesioned controls. These observations demonstrate that LH rats retain the capacity for preserving body protein when challenged by either under- or overnutrition. The apparently irreversible reduction in the body protein mass thus appears to be the result of a specific lean tissue downregulation induced by LH damage.

Fever and the acute elevation in whole-body thermogenesis induced by lateral hypothalamic lesions.

Three studies investigated the role of fever in the acute elevation of heat production induced by lateral hypothalamic (LH) lesions and the mechanisms by which this thermogenic response can be attenuated by reductions in body weight. In Study 1, reducing the weights of rats prior to lesioning the LH attenuated both the usual postlesion fever and elevation in thermogenesis. In Study 2, blocking prostaglandin synthesis with indomethacin likewise blunted both the lesion-induced fever and thermogenesis. In Study 3, treating already weight-reduced rats with indomethacin attenuated, but still failed to eliminate, the lesion-induced fever. Together, these results suggest that both the fever and increased thermogenesis induced by LH lesions are mediated, at least in part, by prostaglandin mechanisms which themselves are influenced by body energy status.

Energy expenditure in rats maintained with intravenous or intragastric infusion of total parenteral nutrition solutions containing medium- or long-chain triglyceride emulsions.

Energy expenditure was determined in male Fischer 344 rats (235-246 g) fed by intravenous (IV) or intragastric (IG) infusion with total parenteral nutrition solutions providing 65% of nonprotein energy as fat from long-chain triglyceride (LCT) or a 3:1 admixture of medium-chain triglyceride (MCT) and LCT emulsions. Respiratory gas exchange and somatomotor activity were assessed continuously for 24 h during d 5 and 11 of infusion feeding. The MCT infusion resulted in one-third the weight gain noted with LCT infusion (MCT, 10 +/- 2 g/14 d; LCT, 32 +/- 4 g/14 d; P less than 0.0001). Insulin concentration was 60% higher with IV than with IG infusion and approximately 100% higher with IV-MCT than with IG-MCT or LCT infusion (P less than 0.05). Rats receiving IV infusion of MCT displayed similar levels of motor activity but 8-13% greater daily energy expenditure (kJ.kg-0.75.kJ intake-1) than rats receiving IG-MCT or LCT infusion (P less than 0.05). The MCT infusion also resulted in an elevation in respiratory quotient after cessation of nutrient infusion (MCT, 0.87-0.92; LCT, 0.83-0.85; P less than 0.05). Total and resting energy expenditure decreased approximately 13% from 5 to 11 d of infusion feeding. The lower weight gain and greater energy expenditure seen with MCT- compared with LCT-supplemented total parenteral nutrition may be mediated by higher insulin concentrations.

Nicotine effects on body weight: a regulatory perspective.

Rats infused with nicotine were initially hypophagic and lost weight. Although food intake recovered, body weight remained 8-12% below normal. Elevating (or reducing) body weight before treatment prolonged (or shortened) initial hypophagia; weight reliably stabilized at the reduced level. At this reduced weight, the treated rats' daily resting energy expenditure was comparable with that of normal-weight controls (262.3 vs 261.9 kJ.d-1.kg body wt-0.75). Reducing the weight of controls to that of treated rats caused their expenditure to drop to 250.6 kJ.d-1.kg body wt-0.75, an energy-conserving adjustment that treated rats also displayed when their weight was lowered from its already-reduced level. Terminating nicotine treatment led initially to hyperphagia, which abated upon body weight being restored to normal. Normal daily energy expenditures at reduced weights suggest that nicotine lowers regulated body energy. Acute intake adjustments associated with initiation (or cessation) of nicotine treatment can be viewed as responses appropriate to bringing body energy into balance with the altered regulation level.

Heat production and body weight changes following lateral hypothalamic lesions.

Factors causing rats with lateral hypothalamic (LH) aphagia to lose weight at a faster rate than food deprived controls were investigated in two experiments. In Experiment 1, the heat production of LH-lesioned and control rats was measured by indirect calorimetry for four days following surgery. A higher rate of energy expenditure was shown to account for the greater weight loss of the LH-lesioned rats. In Experiment 2, the heat production of rats receiving LH lesions either at normal or reduced body weights was measured continuously for 24 hours following surgery. Reducing body weight prior to lesioning attenuated postlesion heat production. It was also found that, though the heat production of LH-lesioned rats was consistently higher than that of nonlesioned rats of similar body weight, the fundamental relationship between body weight and heat production was unchanged by the lesion. These findings of higher rates of energy expenditure when at the same weight as nonlesioned animals, accompanied by normal adjustments in expenditure in response to weight change, are consistent with the view that LH-lesioned rats, both behaviorally and metabolically, regulate body weight at a reduced level. Their elevated rate of heat production following lesioning can be seen as an adaptive metabolic adjustment which, coupled with LH aphagia, leads to the rapid decline in body weight to a lower maintenance level.