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.

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.

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.

Thermogenesis after lateral hypothalamic lesions: contributions of brown adipose tissue.

The role of brown adipose tissue in the thermogenic response to lateral hypothalamic (LH) lesions was investigated. Interscapular brown adipose tissue (IBAT) temperatures were measured during the hours following bilateral electrolytic LH lesions in male rats sedated with pentobarbital sodium. Local temperature changes were also recorded from skin and colonic sites. Consistent with the view that brown adipose tissue plays a primary role in the hyperthermia produced by LH lesions, IBAT depot temperature rose before, at a faster rate, and to a higher level than the other sites. In two subsequent experiments, oxygen consumption, activity, and core temperature were monitored in freely moving male rats with LH lesions, both in warm (25 degrees C) and cold (5 degrees C) environments. The results of these experiments provide some support for the view that LH lesions produce an increase in the regulated level of body temperature. This hyperthermic and hypermetabolic state seems to be mediated, in part, by brown fat thermogenesis and may represent a general increase in sympathetic nervous activity induced by the lesion.

Relationship of thyroid hormones and norepinephrine to the lateral hypothalamic syndrome.

The role of thyroid hormones and norepinephrine in the elevated thermogenesis seen following lateral hypothalamic (LH) lesions was investigated by measuring serum thyroid hormone levels and urinary norepinephrine excretion during the 24 hours following placement of LH lesions and again one month later when body weight had stabilized at a reduced level. During the first 24 hours following LH lesions, serum thyroxine (T4) and triiodothyronine (T3) were significantly depressed. By one month postlesion, both T4 and T3 had returned to normal. In contrast, urinary excretion of norepinephrine (NE) was increased 100% during the 24 hours following LH lesions. By one month postlesion, NE had returned to normal levels. These results indicate that the elevated thermogenesis seen shortly following LH lesions does not reflect enhanced thyroid activity, but is probably a consequence of sympathetic nervous system stimulation. The return of NE to normal levels after one month is consistent with the observation that LH-lesioned rats are by one month postlesion no longer hypermetabolic, but display levels of heat production appropriate to the reduced body weight they then maintain.

Effects of beta-adrenergic blockade on lateral hypothalamic lesion-induced thermogenesis.

Oxygen consumption is markedly elevated in rats with lesions of the lateral hypothalamus (LH), a response typically associated with hyperactivity. To test for involvement of adrenergic systems in this hypermetabolic state, propranolol was administered before and immediately after LH lesions. Propranolol attenuated both the lesion-induced rise in oxygen consumption and activity in the 12 h after surgery. A second experiment evaluated the contribution of activity to this thermic response by lesioning rats immobilized by a continuous barbiturate infusion. The persistence of lesion-induced increases in oxygen consumption in the absence of activity and the attenuation of this response by propranolol demonstrated that 1) LH lesions directly alter metabolic heat production, and 2) this effect is at least partly mediated by beta-adrenergic systems. The functional significance of increased energy expenditure after LH lesions is discussed in light of the known effects of this lesion on the level of regulated body weight.

Body composition and adiposity in LH-lesioned and pair-fed obese Zucker rats.

It has been reported previously that lateral hypothalamic (LH) lesions alter body composition including reducing adipocyte cellularity in lean and obese Zucker rats. The present experiment was designed to determine whether these alterations in body composition and adipose cell number are secondary to the reduced energy consumption of LH-lesioned rats or to a direct effect of the hypothalamic lesion. Groups of lean and obese Zucker rats, sustaining lesions of the lateral hypothalamus at 10 wk of age, maintained body weight at 72% that of nonlesioned controls until killed at 32 wk. Pair-feeding nonlesioned rats to the intakes of lean and obese LH-lesioned rats produced a reduction in adipocyte number similar to that caused by lesions. However, neither the lean nor obese LH-lesioned rats displayed an increase in cell number when fed a palatable diet that markedly increased carcass lipids. This finding suggests that adipocyte number may be constrained in LH-lesioned rats. These and further observations that 1) lean control rats maintained a higher body weight than the LH-lesioned rats to which they were pair fed and 2) in obese rats, food restriction further reduced protein deposition and elevated plasma insulin relative to comparably fed LH-lesioned obese rats suggest that the LH syndrome is mimicked by simple food restriction.

Energy balance of rats with lateral hypothalamic lesions.

Rats with lateral hypothalamic (LH) lesions maintain body weight at a chronically reduced percentage of nonlesioned controls. An assessment of how they achieve energy balance at subnormal weight levels entailed a determination of both their energy intake and their energy expended or lost in processing ingested food, on basal heat production, on activity, and in feces or urine. It was found that the caloric intake and expenditure of LH-lesioned animals, though significantly lower than those of controls, were appropriate to the reduced metabolic body size (BW0.75) that they maintained. Likewise, energy expenditure in the LH-lesioned animals was normal in that the proportion of their ingested energy relegated to 1) basal metabolism, 2) the processing food, and 3) activity was the same as that of nonlesioned controls. Thus, unlike nonlesioned rats, which at lowered body weights both decrease their energy needs and reorder the pattern of energy expenditure, LH-lesioned animals display a normal pattern of energy utilization at reduced weight levels. These findings provide further evidence that lateral hypothalamic mechanisms play an important role in setting the level at which body weight is regulated.

Developmental study of adipose cellularity in lateral hypothalamic-lesioned Zucker obese rats.

Ten-week-old lean and obese Zucker rats were sham lesioned or received bilateral, electrolytic lesions of the lateral hypothalamus (LH). They were maintained on a wet mash diet until killing at 15 or 32 wk of age; control lean and obese rats were also killed at 6 and 10 wk. Body composition analyses were performed and adipocyte cellularity of epididymal, retroperitoneal, and subcutaneous depots were calculated. Changes in body composition of LH-lesioned rats, though similar in the two genotypes on an absolute basis, differed on a percentage basis due to the extreme adiposity of the obese rats. Retarded development of protein depots in both lesioned lean and obese rats was apparent at 15 but not 32 wk. Relative to genotypic controls, lesioned lean and obese rats had smaller adipose depots by 32 wk due to decreased adipocyte size in lean rats and reduced adipocyte number in the obese. This genotype-specific response was probably due to the chronic hyperplasia of adipocytes unique to the obese rats. This distinctive developmental pattern of the epididymal depot is discussed.

Effect of lateral hypothalamic lesions on regulation of body weight and adiposity in rats.

Obese and lean Zucker rats received bilateral electrolytic lesions of the lateral hypothalamus (LH) at 10 wk of age; control obese and lean rats were sham lesioned. After lesioning the body weights of both obese and lean animals were first reduced and then maintained until being killed (32 wk) at a stable percentage of the nonlesioned control levels (74.5 and 78.3%, respectively). Carcass analysis revealed that the adipose tissue mass was significantly lowered by LH lesions in both the obese and lean animals. Percent carcass fat of lesioned lean rats was less than that of controls (15.0 vs. 23.5%) due to the presence of slightly, but not significantly, smaller and fewer adipocytes. Though absolute levels of fat were likewise lowered in obese rats, their percent carcass fat remained at control levels (52.0 vs. 53.0%) due to equivalent decreases in other body compartments. In the lesioned rats the reduced levels of adipose tissue were associated with a significant reduction in adipocyte number; adipocyte size was unchanged. It is concluded that the lateral hypothalamus of obese Zucker rats participates in the regulation of body weight in the same manner as in lean rats. The differences noted in percent carcass fat between LH lesioned lean and obese Zucker rats are apparently related to the obese animal's known propensity to sequester energy in the form of lipid.

Digestibility in male rats with lateral hypothalamic lesions.

The body weight of male rats with lateral hypothalamic lesions remained approximately 20% below that maintained by nonlesioned controls. One month following surgery, both food intake and energy losses in feces and urine were measured in all animals for five days. The percentage of ingested food absorbed by the gut ("digestibility") was determined from calorimetric analysis of the feces to be slightly, though significantly, higher for the lesioned animals (79.7% vs 77.4%). Resorptive capacity, as indicated by the percentage of absorbed energy lost in the urine, was determined to be the same for the lesioned and control animals (4.8% vs 4.5%). These results indicate that the digestive, absorptive, and resorptive processes of LH-lesioned animals are at least as efficient as those of nonlesioned animals maintaining normal body weights. Thus, though LH-lesioned animals are reported to display various gastrointestinal dysfunctions, alterations in digestive or resorptive efficiency are apparently not responsible for their chronically-reduced body weights.

Body weight and body composition of male rats following hypothalamic lesions.

Carcass analyses were performed on 160 male rats maintaining reduced, normal, or elevated levels of body weight following lateral hypothalamic (LH), sham (control), or ventromedial hypothalamic (VMH) lesions, respectively. Extracted body lipid (ranging from 26 to 738% of the control mean) correlated highly (r = +0.95) with the level of maintained body weight (which ranged from 67 to 191% of control). Neither the nonfat solids (which ranged from 60 to 123% of control) contributed significantly to the variance in body weight (r = +0.01 and +0.06, respectively). Fat thus accounted for approximately 90% of the overall variance in body weight among LH, control, and VMH animals. Consideration of only the LH data, however, revealed a breakdown of this close covariance of body fat and weight. Fat mass correlated significantly with body weight in LH rats maintaining weight 0-12% below normal; but, at maintained body weights below 88%, the correlation between weight and fat in LH rats was only +0.07. Variation in lean body mass then better accounted for differences in body weight. The implications of these observations for existing lipostatic theories of weight regulation are discussed.

Hypothalamic map of stimulation current thresholds for inhibition of feeding in rats.

The rat hypothalamus was mapped for the purpose of identifying regions at which electrical stimulation caused the feeding behavior of a hungry animal to be inhibited. At each inhibitory site a determination was also made of the minimal stimulation current necessary for the inhibition of feeding. The results indicated that the inhibitory sites with the lowest current thresholds tended to form a discrete cluster in the lateral part of the ventromedial nucleus and the adjacent neuropil bordering it ventrolaterally. A few low thresholds were also found in the anterior hypothalamic area. The higher thresholds formed an orderly ascending gradient radiating away from the ventromedial nucleus and its ventrolaterally situated anatomical projections. In areas related to ascending monoamine pathways, including the lateral hypothalamus, preoptic region, and arcuate nucleus, as well as in the mammillary bodies, stimulation usually failed to suppress feeding behavior. Implications bearing on neuroregulatory models of feeding behavior are discussed.

Effect of a quinine-adulterated diet upon body weight maintenance in male rats with ventromedial hypothalamic lesions.

Male rats offered a quinine-adulterated diet after receiving either ventromedial hypothalamic or sham lesions displayed nearly identical periods of anorexia before maintaining their body weight at a stable but reduced level. When starved prior to surgery to a body weight below this reduced maintenance level, both ventromedial hypothalamic and control animals displayed an intial period of rapid weight gain on the quinine-adulterated diet. When subsequently offered only this diet for an 8-wk period, both groups, after castration, maintained the same reduced level of body weight. Thus, ventromedial hypothalamic animals overeat and become obese on palatable diets, but defend the same lower weight level as controls when challenged with unpalatable diets. Impairment of a mechanism setting the upper, but not the lower, weight limits is responsible for the greatly expanded range of body weights generated in the ventromedial hypothalamic animal by manipulation of diet palatability.

Lateral hypothalamic demyelination and cachexia in a case of "malignant" multiple sclerosis.

A 41-year old woman had profound weight loss and cachexia as a manifestation of rapidly fatal multiple sclerosis. Demyelinating lesions were present in the lateral hypothalamus. Data from animal experiments have indicated that lateral hypothalamic lesions cause a weight loss associated with a lowering of the regulation level or "set-point" for body weight. This case suggests, therefore, that a rapid decline in the level of maintained body weight in a patient without pituitary disease or general organic disorder, or distinct emotional disorder, may represent a clinical manifestation of tissue injury of the lateral hypothalamus.