In outbred Sprague-Dawley rats, about one-half develop diet-induced obesity (DIO) on a diet relatively high in fat and energy (HE diet). The rest are diet resistant (DR), gaining weight and fat at the same rate as chow-fed controls. Here we selectively bred for high (DIO) and low (DR) weight gainers after 2 wk on HE diet. By the F5 generation, both male and female inbred DIO rats gained > 90% more weight than inbred DR rats on HE diets. Even on low-fat chow diet, DIO males were 31% and females were 22% heavier than their respective DR rats. Full metabolic characterization in male rats showed that weight-matched, chow-fed DIO-prone rats had similar energy intakes and feed efficiency [body weight (kg0.75)/energy intake (kcal)] but 44% more carcass fat than comparable DR-prone rats. Their basal plasma insulin and glucose levels in the fed state were 70 and 14% higher, respectively. But, when fasted, DIO-prone oral glucose tolerance results were comparable to DR-prone rats. Chow-fed DIO-prone males also had 42% greater 24-h urine norepinephrine levels than DR-prone males. During 2 wk on HE diet, DIO rats ate 25% more, gained 115% more weight, had 36% more carcass fat, and were 42% more feed efficient than comparable DR rats. Fasted HE diet-fed DIO rats developed frank glucose intolerance during a glucose tolerance test with 55 and 158% greater insulin and glucose areas under the curve, respectively. Thus the DIO and DR traits in the outbred Sprague-Dawley population appear to be due to a polygenic pattern of inheritance.
Among outbred Sprague-Dawley rats, approximately one-half develop diet-induced obesity (DIO) and one-half are diet resistant (DR) on a diet relatively high in fat and energy content (HE diet). Here we examined the defense of body weight in these two phenotypes. After HE diet for 13 wk, followed by chow for 6 wk, DR rats gained weight comparably but their plasma leptin levels fell to 54% of chow-fed controls. When a palatable liquid diet (Ensure) was added for 13 wk, other DR rats became obese. But when switched to chow, their intakes fell by 60%, and body and retroperitoneal (RP) fat pad weights and plasma leptin and insulin levels all declined for 2 wk and then stabilized at control levels after 6 wk. In contrast, comparably obese DIO rats decreased their intake by only 20%, and their weights plateaued when they were switched to chow after 13 wk on HE diet. When a subgroup of these DIO rats was restricted to 60% of prior intake, their weights fell to chow-fed control levels over 2 wk. But their leptin and insulin levels both fell disproportionately to 30% of controls. When no longer restricted, their intake and feed efficiency rose immediately, and their body and RP pad weights and leptin and insulin levels rose to those of unrestricted DIO rats within 2 wk. Thus diet and genetic background interact to establish high (DIO) or low (DR) body weight set points, which are then defended against subsequent changes in diet composition and/or energy availability. If leptin affects energy homeostasis, it does so differentially in DIO vs. DR rats since comparably low and high levels were associated with differing patterns of weight change between the two phenotypes.
Reducing the body weight of rats prior to lesioning the lateral hypothalamus dramatically shortens the normal postlesion period of aphagia and anorexia, and can even result in an immediate postlesion hyperphagia. Further observations indicate that lesioned rats reduce their level of regulated body weight to some fixed percentage of control values. This lower level of regulation, which is chronically maintained even with adequate hydration, was found to be inversely related to the extent of lateral hypothalamic damage. The view that lateral hypothalamic aphagia and anorexia reflect a breakdown and subsequent recovery of neural control over feeding behavior is questioned. Instead, it appears that lesions of the lateral hypothalamus lower the set-point for weight regulation, and that the normal interruption of feeding following such lesions is the outcome of an active effort by the animal to bring its body weight into balance with this new level of regulation.
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.
Several years ago, we began a series of studies which we hoped would allow us to specify some of the important parameters of food reinforcers. Our first aim was the development of a method which would allow investigation of these factors in the individual organism. Hav-ing the benefit of the observations of Jenkins and Clayton (1949) and Guttman (1953), we assumed that rate of response under an interval reinforcement schedule would provide a datum sensitive to differences in reinforcing stimuli. We used pigeons, because we hoped to separate such potentially important factors as amount of food per se and number of pecks required to obtain the food. Our early efforts were uniformly disappointing: birds were run under Fl or VI conditions, with a given amount of food per reinforcement (each amount with an associated key color), until their day-to-day rates were relatively stable;3 the amount of reinforcement was then changed and the process repeated. Comparisons of the final rates achieved with each amount failed to show the expected differences, even though both amount of food and amount of consummatory responding were varied over rather wide ranges. Differences were noted, however, with four types of procedures: (1) The very first minu,tes of a daily session, prior to the delivery of the first one or two reinforcements, frequently produced rates correlated with the amount of food which, in past sessions, had been paired with the present key color. The disciminative stimulus of key color thus seemed to be controlling the response rate at the start of a session. (2) After many sessions in which one amount of food was used on odd-numbered days and a different amount on evennumbered days, rate differences were obtained during an extinction session in which the key colors formerly paired with each amount of food were presented alternately for 2-minute periods.4 (3) Although no differences between two amount-of-reinforcement conditions were observed after stable Fl 2 behavior was reached, a shift to Fl 4 BO 2 produced clearcut differences which then gradually disappeared over four daily 2-hour sessions on this new schedule. (4) A procedure similar to the "probe-stimulus" technique (Ferster & Skinner, 1957) showed response rates during probes that were correlated with the amount of reinforcement previously paired with the stimulus now used as a probe. In this procedure, two amounts of reinforcement, each with a correlated key color, were presented in alternate daily training sessions until day-to-day variability was relatively low. At this point, no differences between average rates for the two reinforcement conditions were seen. On subsequent sessions, the key light associated with one amount of food was inserted for 2-minute periods while the other amount with its key light was used for the remainder of the session. Probing with the larger-amount stimulus yielded an immediate increase in response rate; probing with the smaller-amount light gave an immediate decrease in rate. These probes were repeated three times daily...
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