Joel M. Kaplan

The neuroanatomical axis for control of energy balance.

The hypothalamic feeding-center model, articulated in the 1950s, held that the hypothalamus contains the interoceptors sensitive to blood-borne correlates of available or stored fuels as well as the integrative substrates that process metabolic and visceral afferent signals and issue commands to brainstem mechanisms for the production of ingestive behavior. A number of findings reviewed here, however, indicate that sensory and integrative functions are distributed across a central control axis that includes critical substrates in the basal forebrain as well as in the caudal brainstem. First, the interoceptors relevant to energy balance are distributed more widely than had been previously thought, with a prominent brainstem complement of leptin and insulin receptors, glucose-sensing mechanisms, and neuropeptide mediators. The physiological relevance of this multiple representation is suggested by the demonstration that similar behavioral effects can be obtained independently by stimulation of respective forebrain and brainstem subpopulations of the same receptor types (e.g., leptin, CRH, and melanocortin). The classical hypothalamic model is also challenged by the integrative achievements of the chronically maintained, supracollicular decerebrate rat. Decerebrate and neurologically intact rats show similar discriminative responses to taste stimuli and are similarly sensitive to intake-inhibitory feedback from the gut. Thus, the caudal brainstem, in neural isolation from forebrain influence, is sufficient to mediate ingestive responses to a range of visceral afferent signals. The decerebrate rat, however, does not show a hyperphagic response to food deprivation, suggesting that interactions between forebrain and brainstem are necessary for the behavioral response to systemic/ metabolic correlates of deprivation in the neurologically intact rat. At the same time, however, there is evidence suggesting that hypothalamic-neuroendocrine responses to fasting depend on pathways ascending from brainstem. Results reviewed are consistent with a distributionist (as opposed to hierarchical) model for the control of energy balance that emphasizes: (i) control mechanisms endemic to hypothalamus and brainstem that drive their unique effector systems on the basis of local interoceptive, and in the brainstem case, visceral, afferent inputs and (ii) a set of uni- and bidirectional interactions that coordinate adaptive neuroendocrine, autonomic, and behavioral responses to changes in metabolic status.

Analytical issues in the evaluation of food deprivation and sucrose concentration effects on the microstructure of licking behavior in the rat.

A microstructural analysis of licking behavior in nondeprived and 23-hr food-deprived rats (n = 15) presented with various sucrose solutions (0.03-1.0 M) in daily single-bottle, 1-hr sessions was conducted. Food deprivation and concentration interacted to increase total licks. The effects of food deprivation and concentration on burst size (BS), burst number (BN), and other parameters varied as a function of the pause criterion (PC; 0.3-100 s) used to define licking bursts. A rationale for selecting a 1-s PC for further analysis is presented. Despite the lack of correlations between temporally contiguous burst and pause combinations, mean BS decreased and pause duration increased as meals progressed. At the 1-s PC, BS increased linearly with concentration, implying that this microstructural parameter is influenced in part by taste. Food deprivation did not affect BS but rather increased BN and proportionally extended the meal duration.

Bite size, ingestion rate, and meal size in lean and obese women ☆ ☆☆

The effect of bite size on ingestion rate, satiation, and meal size was studied in nine lean and nine obese women. On separate days, subjects were given one of three bite sizes of sandwiches and one of two bite sizes of bagels with cream cheese to eat in a laboratory lunch. Decreasing bite size significantly lowered ingestion rate for the whole meal. The effect was most pronounced at the beginning of meals. As bite size decreased from 15 to 5 g, the average ingestion rate decreased from (mean +/- SEM) 19.4 +/- 2.0 to 15.9 +/- 2.0 g/min (p < 0.001). The initial ingestion rate decreased from 30.0 +/- 2.9 to 19.6 +/- 1.7 g/min (p < 0.001). The larger the bite size, the more quickly ingestion rate decelerated; by the end of meals, ingestion rate was not different across conditions. The decrease in ingestion rate with smaller bites was offset by an increase in meal duration, such that meal size did not differ across conditions. Eating behavior of lean and obese subjects was not different. There were individual differences related to ingestion rate, but these were not related to body weight nor to meal size. These results bring into question the recommendation of behavior therapists that obese people eat more slowly in order to eat less.

Long-term effects on feeding and body weight after stimulation of forebrain or hindbrain CRH receptors with urocortin.

Research on the contribution of CRH receptor stimulation to energy homeostasis has focused on forebrain substrates. In this study, we explored the effects of caudal brainstem administration of the CRH receptor agonist, urocortin, on food intake and body weight, and on plasma glucose and corticosterone (CORT) in non-deprived rats. Urocortin (0, 0.3, 1, 3 microg) delivered, respectively, to the fourth and lateral ventricles yielded substantial suppression of food intake measured 2, 4 and 24 h later. A significant but more modest anorexia was observed between 24 and 48 h after injection. Intake responses did not differ between the injection sites, but body weight loss measured 24 h after lateral-i.c.v. injection was substantially greater than that after fourth-i.c.v. injection. Fourth-i.c.v. urocortin administration (3 microg) produced substantial elevations in plasma glucose and CORT that were not distinguishable in magnitude and duration from responses to lateral-i.c.v. delivery. Unilateral microinjection of urocortin into the dorsal vagal complex significantly reduced 24-h food intake at a dose (0.1 microg) that was subthreshold for the response to ventricular administration, suggesting that fourth-i.c.v. effects are mediated in part by stimulation of CRH receptors in this region of the caudal brainstem. The results indicate that similar effects can be obtained from stimulation of anatomically disparate populations of CRH receptors, and that interactions between forebrain and hindbrain structures should be considered in the evaluation of CRH contributions to food intake and body weight control.

Neurological dissociation of gastrointestinal and metabolic contributions to meal size control.

A method was developed to separate gastrointestinal (GI) and metabolic contributions to meal size and applied to intact and chronic decerebrate (CD) rats. The effect of a 10-ml milk diet preload or 24 hr of food deprivation on the consumption of a 0.1-M sucrose solution was compared with intake in a no-deprivation/no-preload condition. In the no-deprivation/no-preload condition, rats were given their normal complement of feedings but had the contents of their stomachs removed via a gastric cannula before the intake test. Compared with the no-deprivation/no-preload condition, intact and CD rats consumed significantly less after the preload, but only intact rats ate more after deprivation. Thus intact rats were sensitive to both GI and metabolic influences on intake, whereas CD rats responded to only the GI manipulation. The experiments showed that GI and metabolic contributions to the deprivation response are mediated by neural structures that are at least partly nonoverlapping. The GI component is likely to be contained within the caudal brainstem. The neural systems required for the response to the metabolic changes accompanying deprivation appear to be more widely distributed.

Sucking behavior of preterm neonates as a predictor of developmental outcomes.

Objectives: The relationship between the pattern of sucking behavior of preterm infants during the early weeks of life and neurodevelopmental outcomes during the first year of life was evaluated. Methods: The study sample consisted of 105 preterm infants (postmenstrual age [PMA] at birth = 30.5 ± 2.8 weeks [mean ± SD]; birth weight = 1476 ± 460 g; mean length of hospital stay = 41.6 ± 31.4 days). All infants received a 5-minute sucking test at 34 and at 40 weeks PMA, with outcomes evaluated at 6 and/or 12 months corrected gestational age via the Bayley Scales of Infant Development. Results: As expected, 6- and 12-month values for the Psychomotor Developmental Index (PDI) and Mental Developmental Index (MDI) of the Bayley Scales of Infant Development were significantly below the normative levels established for infants delivered at term. A significant association between neonatal sucking pattern at 40 weeks PMA and developmental outcome at 12 months corrected gestational age was obtained. Each of the 3 simple sucking parameters evaluated (number of sucks, mean number of sucks per bursts and mean sucking pressure peaks), as well as a composite parameter (average of the respective parameter z-scores), was significantly related to both PDI and MDI at 12 months. Conclusions: Multivariable models, adjusting for PMA at birth, length of hospital stay, and other predictors, affirmed that sucking performance at 40 weeks PMA was a significant, independent predictor of developmental status 1 year later. Standardization of an instrument for neonatal sucking assessment may offer a cost-effective early screening strategy for preterm infants at greatest risk for developmental delay.

Effects of Central Oxytocin Administration on Intraoral Intake of Glucose in Deprived and Nondeprived Rats

We evaluated the effects of lateral intracerebroventricular administration of oxytocin (OT) and/or a selective oxytocin-receptor antagonist (OTX), 1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-OT, on ingestion of intraorally delivered 12.5% glucose in rats that were either nondeprived or deprived of food for 20 h. In deprived rats, OT delivered 30 min before an initial intake test yielded a dose-related reduction of intraoral glucose intake. The highest dose tested, 20 nmol, reduced intraoral glucose intake by 45%. The effect was short-lived, however. Intraoral intake for a second test, initiated 60 min after the termination of the first, increased as a function of OT dose so that total session intake was unaffected by OT treatment. The suppression of intraoral intake by 20 nmol OT was reversed by pretreatment (45 min before testing) with OTX. In nondeprived rats, by contrast, OT yielded no effect on first-test, second-test, or total session intakes. Significant increases in first-test and total session intakes were obtained when OTX (20 nmol) was administered alone both in deprived (32% increase in first-test intake) and nondeprived (31% increase) rats. In general, the results obtained are consistent with the suggestion that OT contributes to the control of meal size and, in particular, to the process of satiation, which is the aspect of ingestive control highlighted by the specialized intake test used in the present study.

Overfeeding-induced weight gain suppresses plasma ghrelin levels in rats

The elevation of plasma ghrelin associated with weight loss has been taken as evidence of a role for ghrelin in the adaptive response to body weight change. However, there has been no clear experimental evidence that circulating ghrelin is suppressed by weight gain. We investigate this issue using a model of involuntary (intra-gastric gavage) overfeeding-induced obesity. Rats were first maintained at normal body weight with 4 daily tube-feedings of liquid diet (2.11 kcal/ml), each delivered at a volume of 9 ml. Gavage volume was then increased to 13 ml/feeding for 2 weeks, during which rats gained 25% of their initial body weight. Fasting plasma ghrelin levels and the response to 9- and 13-ml intra-gastric load sizes were measured during the weight-stable and overfed conditions. We found that: 1) weight gain decreased circulating ghrelin levels; 2) this response could not be attributed to additional food in the gastrointestinal tract; 3) the ghrelin response to nutrient loads was diminished in the obese vs normal-weight conditions. Having discounted diet composition and differences in gastric contents at the time of blood sampling, the decrease in ghrelin levels with overfeeding can be unambiguously attributed to physiological correlates of weight gain.

Daily caloric intake in intact and chronic decerebrate rats

Daily caloric intake regulation was studied in chronic supracollicular decerebrate rats with a complete transection of the neural axis at the meso-diencephalic juncture and in intact controls. For 1 week, each rat received 3 intraorally delivered meals per day. They were challenged to maintain their 3-meal daily intake over 1 week in which only 2 meals per day were delivered. Intact rats increased meal size to compensate for the lost opportunity to feed, whereas chronic decerebrate rats did not. Results suggest that, although the caudal brainstem, as previously shown (Grill & Kaplan, 1990), is sufficient to modulate ingestive behavior in taste reactivity and single-meal tests, it is not sufficient to regulate daily caloric intake. Although it is possible that chronic decerebrate rats retain a long-term regulatory competence that is somehow masked under the meal omission paradigm, forebrain-hindbrain interactions appear necessary for the coordination of short- and long-term intake control processes.

Suckling behavior as a function of gestational age: A cross-sectional study

Abstract In the present study, we provide a cross-sectional analysis of sucking organization as a function of gestational age (GA). One hundred and eighty six infants (GA 33–40 weeks) were observed during 5-min test sessions with the Kron Nutritive Sucking Apparatus either on the second day (GA 35–40), or as soon as was practicable during the first week (GA 33 and 34) of life. The within-burst suck frequency did not vary with GA suggesting that this basic aspect of patterned sucking behavior was already in place in the most premature infants. For four sucking parameters (number of sucks per session, duration of sucking bursts, burst time as percentage of sucking bout, and mean maximum sucking pressure) that varied with GA, the transitions were not seen across the earliest GAs, but rather occurred between 36/37 and full term (38–42 weeks GA). An earlier transition (GA33/34) was suggested for the coefficient of variation (CV) for the distribution of within-burst intersuck intervals and for the CV of the maximum sucking pressure distribution. Significant changes were described over bout quintiles for several parameters, but there were no meaningful interactions between GA and the manner by which sucking changes as meals progress. Our results suggest that different aspects of the sucking pattern mature at different GAs, and are of relevance to discussions of neurobehavioral development.