Salty taste acceptance by infants and young children is related to birth weight: longitudinal analysis of infants within the normal birth weight range.

BACKGROUND: Birth weight and sodium intake are both associated with risk for hypertension. It is not known whether birth weight influences response to salty taste. OBJECTIVE: To assess the relationship between birth weight and salty taste acceptance of infants and young children. DESIGN: Acceptance of salty taste was assessed at 2 (n = 80) and 6 (n = 76) months in infants (birth weight >2.5 kg) enrolled in a prospective cohort study. Acceptance was expressed as proportional intake following 1-min ingestion tests with water and salt solutions (0.17 and 0.34 mol/l NaCl, in water). Birth weight was obtained by maternal report. Questionnaires completed by mothers and food-ranking procedures performed by children evaluated salt liking and preference in a subset (n = 38) of subjects at preschool age (36 or 48 months). SETTING: Nonprofit basic research institute in Philadelphia, PA, USA. RESULTS: Regression analysis revealed significant negative associations between birth weight and acceptance of salty taste at 2 months (0.17 mol/l, P < 0.0001; 0.34 mol/l, P < 0.01) but not at 6 months. Relationships were not affected by adjustment for potential confounders. In preschoolers, greater liking of (P < 0.05) and preference for (P < 0.01) salty foods was associated with lower birth weight in simple, but not adjusted, models. CONCLUSION: Measures related to salty taste preference were inversely related to birth weight over the first 4 years of life. Additional studies should substantiate these findings and explore whether early response to salty taste predicts future sodium intake, blood pressure, or other public health-related outcomes. SPONSORSHIP: National Institutes of Health (DC 00882).

Reduced effect of experimental peripheral hyperinsulinemia to elevate cerebrospinal fluid insulin concentrations of obese Zucker rats.

To test the effect of chronic hyperinsulinemia on cerebrospinal fluid (CSF) insulin concentrations in the obese (fafa) Zucker rat, obese and heterozygote lean (Fafa) rats were infused peripherally with insulin or vehicle for 6 days. Both basal levels and the increase of plasma immunoreactive insulin (IRI) were greater in fafa (increase = 713 microU/ml) than in Fafa (increase = 392 microU/ml) rats, P less than 0.0001. Vehicle-infused fafa rats had higher CSF IRI levels than did vehicle-infused Fafa rats (4.3 +/- 1.2 microU/ml vs. 1.5 +/- 0.4 microU/ml, P less than 0.01). CSF IRI was elevated in both insulin-infused groups (P less than 0.001). After insulin infusion Fafa rats had higher CSF IRI levels than did fafa rats (Fafa: 10.0 +/- 1.8 microU/ml vs. fafa: 7.1 +/- 0.1 microU/ml). In contrast to the effect of insulin infusion on plasma IRI, the increase of CSF IRI was greater in Fafa rats (8.5 microU/ml) than in fafa rats (4.0 microU/ml, P less than 0.001). Uptake of insulin from the periphery to the CSF therefore appears to be reduced in obese fafa Zucker rats compared to lean Fafa controls.

Immunoreactive insulin levels are elevated in the cerebrospinal fluid of genetically obese Zucker rats.

Immunoreactive insulin (IRI) concentrations were measured in plasma and cerebrospinal fluid (CSF) of four-month old genetically obese Zucker rats, their heterozygote lean littermates, and age-matched normal-weight Wistar rats. Basal plasma IRI was 201 + 35 microU/ml (means +/- SEM) in the obese animals and was significantly elevated compared to both lean Zucker rats (18 +/- 2.4 microU/ml, P less than 0.001) and Wistar rats (12 +/- 2.4 microU/ml, P less than 0.001). The mean CSF IRI concentration of fasted obese Zucker rats was 1.59 +/- 0.19 microU/ml; this was significantly higher than the CSF IRI level of either fasted Zucker lean rats (0.31 +/- 0.08 microU/ml, P less than 0.001) or Wistar rats (0.34 +/- 0.12 microU/ml, P less than 0.001). Plasma and CSF IRI concentrations were increased in free-feeding as compared with fasted animals. These data provide evidence that endogenous CSF insulin is derived from circulating plasma insulin in the rat and suggest that the hyperphagia and obesity of the Zucker fatty rat are not due to an inability of circulating insulin to gain access to the CSF.

Brain and liver insulin binding is decreased in Zucker rats carrying the 'fa' gene.

Insulin binding was measured in membrane particles prepared from the liver and several brain regions of 4-month-old female Zucker fa/fa (obese), Fa/fa (heterozygous), and Fa/Fa (lean) rats. High affinity insulin binding was decreased in the olfactory bulb of fatty (0.23 pmol bound/mg protein) and heterozygous (0.16 pmol/mg) rats compared with that in the lean controls (0.64 pmol/mg). Total binding was not changed in the cerebral cortex or hypothalamus. High affinity insulin binding was also decreased in the liver of both fatty (0.44 +/- 0.22 pmol/mg; P less than 0.01) and heterozygous (0.75 +/- 0.35 pmol/mg) animals compared with that in the lean rats (2.10 +/- 1.55 pmol/mg). This decreased binding is probably not due to down-regulation of receptors in the heterozygous rats, as they do not exhibit the hyperinsulinemia observed in the fatty rats. Rather, our findings suggest that there is a gene-related alteration in insulin binding in the Zucker rat, as low binding was observed in rats carrying either one (Fa/fa) or two (fa/fa) doses of the gene. We postulate that this central defect in insulin binding may contribute to inadequate perception of a central insulin feedback signal and to the hyperphagia observed in the obese rats.

Development and genetics of glutamate taste preference.

The sodium salt of glutamic acid, monosodium glutamate (MSG), and certain other amino acids and ribonucleotides impart a unique taste sensation often called 'umami.' We have been studying preference for umami substances in two systems: inbred mice and human infants. In 48-hr tests, C57BL/6J (C57) mice exhibit a lower preference threshold for MSG than do 129/J mice. Moreover, C57 mice show a greater preference across a wide range of concentrations and, at high (e.g., 300-600 mM) concentrations, consume greater amounts of MSG. To examine whether the strain difference in MSG preference might be related to a similar strain difference in preference for sucrose and other sweeteners, as might be suggested from studies with rats, preferences for MSG and sucrose in the second (F2) generation were examined. Preferences for sucrose and for MSG were not positively correlated in the F2 indicating that these strain differences depend on different genes. For human adults, unlike mice, the taste of aqueous MSG is not palatable. Our studies of human infants also indicate that MSG alone is not preferred to plain water, but, when it is added to soup, the soup plus MSG is preferred to soup alone. Ongoing studies are designed to determine whether simple mixtures of MSG with other tastants, in particular NaCl, are preferred to water alone, NaCl alone, and MSG alone.

Gastrin releasing peptide reduces meal size in rats.

The satiety-eliciting effect of gastrin-releasing peptide (GRP), a putative mammalian counterpart of bombesin (BBS), was examined in mildly food-deprived rats. Intraperitoneal injections of GRP resulted in a significant decrease of 30-minute food intake at 2, 4, 8 and 16 micrograms/kg, while 1 microgram/kg had no reliable effect. Intraperitoneal GRP at 4 and 8 micrograms/kg did not suppress 30-minute water consumption by thirsty rats. When the dose-effect curves of GRP and BBS are compared on a molar scale, GRP is approximately 30% less potent than BBS in suppressing food intake. The two dose-effect curves are similar in shape and their regression lines have parallel slopes. These data lend further support to the hypothesis that GRP is a mammalian counterpart of BBS and strengthen the argument that they may function as endogenous satiety factors.

Cholecystokinin and bombesin act independently to decrease food intake in the rat.

The satiating effects of cholecystokinin-octapeptide (CCK-8) and bombesin (BBS) when injected alone and in combination were compared in intact rats. When injected alone, both CCK-8 and BBS elicited a dose-related decrease of 30-minute food intake. Injections of BBS were less potent than the equivalent doses of CCK-8 in producing satiety. BBS reached an asymptotic level of suppression of approximately 40 percent at a dose of 2 micrograms/kg, whereas injections of 4 micrograms/kg of CCK-8 resulted in a 72 percent suppression of food intake. When the two peptides were administered in a single injection, the resulting suppression of food intake was equivalent to that which would be predicted if their effects were completely additive. These results support the hypothesis that CCK-8 and BBS act via independent mechanisms to induce satiety. A preliminary model of peptidergic satiety, based on this hypothesis, is proposed.

Bombesin stimulates insulin secretion and reduces food intake in the baboon.

Baboons received a 5-minute intravenous infusion of either saline or bombesin (BBS; 1-4 micrograms/kg) following 3 1/2 or 16 1/2 hours of food deprivation and were then allowed to eat for 30 minutes. Plasma insulin was significantly elevated following five minutes of BBS infusion, but there was no change of plasma glucose over the same interval. Bombesin infusion resulted in a dose-dependent decrease of food intake that was independent of deprivation time. Plasma insulin levels following the 30-minute meal were significantly depressed after BBS infusions such that there was essentially no change of plasma insulin over the duration of the meal, even though the baboons did not totally suppress their food intake. Following 3 1/2 hours food deprivation, BBS suppressed the post-prandial rise of plasma glucose in a dose-dependent manner. The results provide further evidence that BBS and/or structurally-related peptides are involved in the regulation of feeding and metabolism.

Brain insulin binding is decreased in Wistar Kyoto rats carrying the 'fa' gene.

We have previously reported that insulin binding is decreased in the olfactory bulb of both heterozygous (Fa/fa) and obese (fa/fa) Zucker rats. In the present study, we measured insulin binding in membranes prepared from the olfactory bulb, cerebral cortex, and hypothalamus of control (Fa/Fa) Wistar Kyoto rats; "fatty" (fa/fa) Wistar Kyoto rats; and phenotypically lean (Fa/?) Wistar Kyoto rats. Insulin binding was decreased in all brain regions, as well as the liver of the obese Wistar Kyoto fa/fa rats. Additionally, insulin binding was decreased in the liver and brain membranes from the Fa/? Wistar Kyoto rats. As most of the Fa/? rats were probably carriers of one 'fa' gene, but the population was only slightly hyperinsulinemic, we conclude that--as in the Zucker rat--it is the presence and expression of the 'fa' gene rather than downregulation which results in the decreased insulin binding. Thus, regulation of the brain insulin receptor appears to be independent of plasma or cerebrospinal fluid insulin levels.

Genetically obese Zucker rats have abnormally low brain insulin content.

The concentration of immunoreactive insulin (IRI) extracted from the olfactory bulb, hypothalamus, hippocampus, cerebral cortex, amygdala, midbrain, and hindbrain was significantly lower in obese (fa/fa) and heterozygous (Fa/fa) Zucker rats in comparison to lean (Fa/Fa) Zucker rats. This deficit in brain IRI content was most severe in the hypothalamus and olfactory bulb and was independent of severe obesity since the marked reduction of brain IRI content was also found in heterozygous rats which possessed only one copy of the fa allele. These results demonstrate that in the 2-3 month-old female Zucker rat, the fa allele is associated with defective regulation of insulin in the brain.

Repeated weight fluctuation increases plasma insulin in the obese Wistar fatty diabetic rat.

Weight fluctuation may contribute to the expression of hyperglycemia in genetically susceptible individuals. Alternating between diets with low and high fat content also may play a contributory role. To test these hypotheses, plasma glucose and insulin levels were measured in obese prediabetic Wistar-Fatty rats after two episodes of diet switching, with and without concomitant weight loss. Following two cycles of weight loss and regain, glucose levels did not differ between weight-cycled rats and static weight controls. However, insulin concentrations of weight-cycled rats were 74% higher than those of controls, suggesting an impairment of insulin resistance. Insulin and glucose levels of animals subjected to episodes of diet switching without accompanying weight loss and regain did not differ reliably from those of controls. A single cycle of weight loss followed by regain appeared to have no effect on either glucose tolerance or insulin resistance. Together, these results suggest that insulin resistance of Wistar-Fatty rats was worsened by repeated weight fluctuation. Further, the effect of repeated weight fluctuation on insulin concentrations is not due to diet switching. Repeated weight fluctuation did not lead to the expression of hyperglycemia under the present conditions. Additional studies are needed to determine what factors modify the effects of weight fluctuation on health, behavior, and metabolism.

Early-onset repeated dieting reduces food intake and body weight but not adiposity in dietary-obese female rats.

As dieting behavior and attempts at weight loss are becoming increasingly common in adolescent girls, we wished to determine whether early-onset repeated dieting influenced the development of obesity and its metabolic correlates. Female rats were fed a high-fat diet and subjected to six cycles of dieting and regain, beginning in the peripubertal period. Although dieted rats weighted less than nondieted high-fat fed controls at the completion of the sixth cycle, body composition analysis revealed that the two groups were equally obese. Cumulative caloric intake was less in dieted rats, suggesting that the pattern of consumption promoted by dieting helped to establish the obesity. Resting metabolic rate did not differ between the two groups. These data suggest that although early-onset repeated dieting may result in reduced body weight, the eventual level of adiposity may be unknowingly elevated, potentially leading to long-term health risks.

Effect of fasting interval on CCK-8 suppression of food intake in the baboon.

Baboons were infused intravenously for 5 min with the octapeptide of cholecystokinin (CCK-8) after either a 16.5- or 3.5-h fast. After a 3.5-h fast, food intake was significantly suppressed over the ensuing 30 min by 2 micrograms/kg of CCK-8 (-156 +/- 34 kcal compared with control days, P less than 0.02) and by 4 micrograms/kg of CCK-8 (-257 +/- 31 kcal, P less than 0.01). In contrast, CCK-8 had no reliable effect on food intake after the same baboons had been fasted for 16.5 h (2 micrograms/kg: -93 +/- 40 kcal, P greater than 0.05; 4 micrograms/kg: -30 +/- 82 kcal, P greater than 0.05). There was no reliable effect of 1 microgram/kg of CCK-8 on food intake at either deprivation interval. CCK-8 infusions resulted in a small increase of fasting plasma immunoreactive insulin (IRI); this effect was not related to either dose or deprivation length. Postprandial IRI and glucose concentrations were significantly suppressed by CCK-8 independently of its effect on food intake. Thus, after a 16.5-h fast, 4 micrograms/kg of CCK-8 decreased postprandial IRI from 145 +/- 65 to 29 +/- 4 microU/ml (P less than 0.01) and glucose from 101 +/- 5 to 80 +/- 3 mg/dl (P less than 0.02), despite no concomitant effect on food intake. Similar suppression of plasma IRI and glucose were observed after infusions of 1 and 2 micrograms/kg in 16.5-h-fasted animals. All doses of CCK-8 (1, 2, and 4 micrograms/kg) suppressed postprandial IRI and glucose after a 3.5-h fast.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracisternal insulin alters sensitivity to CCK-induced meal suppression in baboons.

We have previously reported that intravenous administration of the octapeptide of cholecystokinin (CCK-8) is more effective in reducing single meal size in baboons at noontime than in the morning. We have also reported that immunoreactive insulin levels in the cerebrospinal fluid (CSF) are elevated after animals have recently eaten. To test whether elevated CSF insulin levels can alter the efficacy of intravenous CCK to reduce meal size we administered subthreshold doses of CCK-8 to baboons infused with either synthetic CSF or CSF and insulin (100 microU X kg-1 X day-1) via the cisterna magna. Intravenous CCK-8 alone reduced 30-min meal size from 504 +/- 121 to 378 +/- 113 kcal (n = 7, P = NS). Chronic intracisternal insulin infusion enhanced CCK-8's suppressive effects such that 30-min meal size was reduced from 544 +/- 74 to 240 +/- 108 kcal (n = 7, P less than 0.005). Intracisternal insulin infusion had no significant effect on total food intake, basal plasma insulin and glucose levels, or postprandial plasma insulin and glucose levels. These findings suggest that central insulin may contribute to food intake regulation by modulating the ability of brain-gut peptides to alter single meal size.

Suppression of food intake by intravenous nutrients and insulin in the baboon.

Intravenous nutrients were infused at 25 and 50% of total base-line daily caloric intake to determine the role of circulating factors on spontaneous food ingestion in young adult male baboons (Papio cynocephalus). Glucose infusion suppressed food intake (15.1%) when 25% of total calories was infused (P less than 0.05) and 41.8% when 50% of total calories was infused (P less than 0.05) for 14-21 days. Both infusions produced basal hyperglycemia (82-172 mg/dl during 25% glucose and 120-239 mg/dl during 50% glucose). Both infusions also caused an increase in circulating insulin (48.1-63.1 microU/ml during 25% glucose and 68.5-77.2 microU/ml during 50% glucose). The simultaneous infusion of exogenous insulin (0.33 mU X kg-1 X min-1) prevented hyperglycemia (85.8-87.9 mg/dl during 25% glucose) but maintained raised basal peripheral insulin levels (52.4-84.4 microU/ml). The 13% suppression of food intake (P less than 0.05) was similar to glucose infusion alone. Comparable infusions of Intralipid as 25 and 50% of total daily calories also suppressed spontaneous food intake but did not produce hyperglycemia or elevated insulin levels. The magnitude of suppression was similar to that of glucose: 16% when 25% of basal calories was infused (P less than 0.05) and 31.3% when 50% of basal calories was infused (P less than 0.05). However, the pattern was different with a more rapid effect, which tended to diminish in time, rather than the slow effect found with glucose, which was maintained for 14 days. We conclude that circulating nutrients can regulate food intake independent of gastrointestinal absorption in primates.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and chronic gastrin-releasing peptide decreases food intake in baboons.

Gastrin-releasing peptide (GRP) is a peptide structurally related to bombesin that appears to be localized to the mammalian gastrointestinal tract. This study examined the ability of GRP, when administered on either an acute or chronic basis, to suppress food intake in baboons. When administered at 8 micrograms/kg iv before a morning meal, GRP significantly suppressed both food intake and the postprandial rise of plasma glucose and insulin. GRP at doses of 1, 2, 4, and 8 micrograms/kg stimulated basal insulin secretion. Chronic administration of GRP (q.o.d. for 11 days) at a low dose before the A.M. meal resulted in suppression of the A.M. meal and an initial suppression of total food intake, which recovered before the end of the treatment period. In conclusion, GRP appears to be effective in acute suppression of food intake and stimulation of basal insulin secretion in the nonhuman primate.

Increased liking for salty foods in adolescents exposed during infancy to a chloride-deficient feeding formula.

In a model selected for its similarity to the hormonal consequences of sodium deficiency, food choices of 169 adolescents exposed during infancy to a chloride-deficient feeding formula were compared to those of their closest-aged siblings. Questionnaires completed by parents were used to assess food likes and dislikes. When a salty food was mentioned by parents as one craved by either child, exposed children were more likely than siblings to crave that food (p = 0.005). Frequencies of two of four salt-related dietary behaviors [adding salt to food before tasting (p = 0.03) and to atypical foods (p = 0.05)] were higher in exposed adolescents than in siblings, while frequencies of parallel sugar-related behaviors did not differ between the groups. Foods classified as being lower in saltiness were disliked by exposed children relative to siblings (p = 0.003), although ratings of foods higher in saltiness did not differ. Finally, when asked to rank eight foods in order of preference, ranks assigned by exposed children to salty foods tended (p = 0.07) to be higher than those of siblings. The data suggest a persistent effect of early experience on human salt preference. Additional studies are needed to determine whether salt intake is increased in this and other populations that suffer electrolyte depletion during early development.

Peptides and the control of meal size.

There are now a large number of experiments demonstrating that peripheral administration of exogenous cholecystokinin or its synthetic analogue, CCK-8, reduces meal size in a number of species. The peptide interacts with other factors which influence satiety, and treatments thought to be effective in eliciting secretion of cholecystokinin have predictable effects on meal size. Cholecystokinin is effective in the genetically obese Zucker rat, obese rats with lesions of the ventromedial hypothalamus, and subdiaphragmatically vagotomized rats. Somatostatin and bombesin are also reasonable candidates for satiety factors. Intraperitoneal naloxone reduces meal size in rats, and beta-endorphin injected intraventricularly causes an increase in meal size of 50% over 30 minutes. We conclude that cholecystokinin and bombesin may interact in weight regulation and control of meal time food intake.