Skeletal muscle mass reference curves for children and adolescents.

BACKGROUND: Skeletal muscle is key to motor development and represents a major metabolic end organ that aids glycaemic regulation. OBJECTIVES: To create gender-specific reference curves for fat-free mass (FFM) and appendicular (limb) skeletal muscle mass (SMMa) in children and adolescents. To examine the muscle-to-fat ratio in relation to body mass index (BMI) for age and gender. METHODS: Body composition was measured by segmental bioelectrical impedance (BIA, Tanita BC418) in 1985 Caucasian children aged 5-18.8 years. Skeletal muscle mass data from the four limbs were used to derive smoothed centile curves and the muscle-to-fat ratio. RESULTS: The centile curves illustrate the developmental patterns of %FFM and SMMa. While the %FFM curves differ markedly between boys and girls, the SMMa (kg), %SMMa and %SMMa/FFM show some similarities in shape and variance, together with some gender-specific characteristics. Existing BMI curves do not reveal these gender differences. Muscle-to-fat ratio showed a very wide range with means differing between boys and girls and across fifths of BMI z-score. CONCLUSIONS: BIA assessment of %FFM and SMMa represents a significant advance in nutritional assessment since these body composition components are associated with metabolic health. Muscle-to-fat ratio has the potential to provide a better index of future metabolic health.

Comparison of children's body fatness between two contrasting income groups: contribution of height difference.

OBJECTIVE: To compare measures of growth and body fatness (body mass index (BMI) and % body fat) in children from two contrasting income backgrounds and to examine the contribution of height difference to these measures. DESIGN: Cross-sectional study. SETTING: Schools in inner East London ('low income') and West London, Hertfordshire and Cambridgeshire ('high income'), UK. PARTICIPANTS: A total of 2298 children aged 5-14 years. MAIN OUTCOME MEASURES: Height, weight, BMI (weight per height(2)) and percentage body fat (%BF, by bioelectrical impedance analysis). RESULTS: Children from the 'lower income' background were significantly shorter, heavier and fatter (%BF) with a higher BMI for their age compared with those from a 'higher income' background. Prevalence of overweight/obesity was greater in the 'lower income' group children, assessed on the basis of BMI, and this income group difference was magnified when based on %BF (overfat/obese). Irrespective of the assessment tool used, overweight/overfat/obese children as a group were significantly taller for their age compared with children categorized as normal weight/normal fat. Despite the overfat/obese children being taller for their age, an 'income group' difference in height remained within this category. CONCLUSION: These findings confirm the income group influence on obesity prevalence. They also illustrate that BMI underestimates the true number of children having excess body fat, particularly in 'low income' children. Exactly why BMI seems to function differently along income group divisions in unclear, but a shorter height-for-age of the 'lower income' group children could be one explanation. These findings raise important questions about the causes and consequences of obesity in children from 'lower income' backgrounds.

Body fat reference curves for children.

OBJECTIVE: To refine the diagnosis of childhood obesity by creating new sex-specific centile curves for body fat and to base these references on a simple and affordable method that could be widely adopted in clinical practice and surveys. DESIGN: Body fat was measured by bio-impedance in 1985 Caucasian children aged 5-18 years from schools in Southern England. Smoothed centile charts were derived using the LMS method. RESULTS: The new body fat curves reflect the known differences in the development of adiposity between boys and girls. The curves are similar by sex until puberty but then diverge markedly, with males proportionately decreasing body fat and females continuing to gain. These sex differences are not revealed by existing curves based on body mass index. We present charts in which cutoffs to define regions of 'underfat', 'normal', 'overfat' and 'obese' are set at the 2nd, 85th and 95th centiles. These have been designed to yield similar proportions of overweight/overfat and obese children to the IOTF body mass index cutoffs. CONCLUSIONS: Direct assessment of adiposity, the component of overweight that leads to pathology, represents a significant advance over body mass index. Our new charts will be published by the Child Growth Foundation for clinical monitoring of body fat, along with the software to convert individual measurements to Z-scores.

A study of central fatness using waist-to-height ratios in UK children and adolescents over two decades supports the simple message--'keep your waist circumference to less than half your height'.

OBJECTIVE: To examine the influence of age and gender on the waist:height ratio (WHTR) in children and to compare changes over time in WHTR, a measure of central fatness in British children. DESIGN: Representative cross-sectional surveys in 1977, 1987 and 1997. SETTING: Great Britain and Northern Ireland. PARTICIPANTS: Survey 1: children aged 5-16 years measured in 1977 (boys) and 1987 (girls) (BSI, n=8135) and Survey 2: children aged 11-16 measured in 1997 (NDNS, n=773). OUTCOME MEASURES: From Survey 1, waist: height ratio related to age and sex and the proportion of children with a WHTR greater than 0.500 (a boundary value suggested for adults). From Survey 2, comparison of WHTR in children with that from Survey 1 and the actual proportion of children with a WHTR greater than 0.500 compared with the expected proportion using the survey 1 as reference. RESULTS: WHTR decreased with age (P<0.01 for trend), with the mean WHTR being significantly lower in girls (P<0.01). WHTR was significantly greater in children in Survey 2 compared with those measured 10 and 20 years earlier in Survey 1 (P<0.0001). The proportion of children where WHTR exceeded the 0.500 boundary value in Survey 2 was 17% of boys and 11.7% of girls (against 5.0 and 1.5%, respectively, in Survey 1, P<0.0001). The increase in WHTR in boys exceeded that in girls. CONCLUSIONS: Values of WHTR during the past 10-20 years have increased greatly showing that central fatness in children has risen dramatically. WHTR is more closely linked to childhood morbidity than body mass index (BMI) and we suggest it should be used as an additional or alternative measure to BMI in children as well as adults. A simple public health message that is the same for adults and children of both sexes and all ages could be stated as 'keep your waist circumference to less than half your height'.

Trends in waist circumferences in young British children: a comparative study.

OBJECTIVE: To compare waist circumference (a measure of central fatness) and body mass index (BMI, a measure of general fatness) between a contemporary cohort and similar aged British children measured in 1987. DESIGN: : Comparative study of two cohorts. The first was a cross-sectional survey and the second an ongoing longitudinal survey. SETTING: : The cross-sectional study was conducted throughout Great Britain during 1987. The ongoing longitudinal study was conducted in the Avon region between 1995 and 1998. PARTICIPANTS: A total of 1821 children were measured in the cross-sectional study, and around 1000 children were measured in the longitudinal study. Ages ranged between 2 and 5 y. MAIN OUTCOME MEASURES: Waist circumference, height, weight and BMI. Values were expressed as mean+/-s.d. Age-related measures were compared. RESULTS: At equivalent ages, mean waist circumference values were greater in the contemporary children, compared with children measured in the earlier cross-sectional study in 1987 (P<0.05). Although boys from the contemporary cohort had the larger absolute waist circumference measurements, the absolute and percentage differences in waist circumference between the cohorts were greater for the girls. Mean BMI values were slightly but significantly higher in the contemporary children compared with children measured in the earlier cross-sectional study (P<0.05). The proportional increase in waist circumference for each age-sex group generally exceeded the proportional increase in BMI. CONCLUSION: These results suggest that central fatness in young British children has increased over the period of 1987-97 to a greater extent than general fatness. This should be of concern since evidence associates greater central adiposity with adverse levels of cardiovascular risk factors in children. Furthermore, the study highlights important shortcomings of the BMI measurement, in that it provides no information on body fat distribution and can mask true obesity-related risk in children.

Within- and between-laboratory precision in the measurement of body volume using air displacement plethysmography and its effect on body composition assessment.

OBJECTIVE: To determine and compare the extent of within- and between-laboratory precision in body volume (BV) measurements using air displacement plethysmography (ADP), the BOD POD body composition system, and to interpret any such variability in terms of body composition estimates. DESIGN: Repeated test procedures of BV assessment using the BOD POD ADP were reproduced at two laboratories for the estimation of precision, both within and between laboratories. SUBJECTS: In total, 30 healthy adult volunteers, 14 men (age, 19-48 y; body mass index (BMI), 19.7-30.3 kg/m2) and 16 women (age, 19-40 y; BMI, 16.3-35.7 kg/m2), were each subjected to two test procedures at both laboratories. Two additional volunteers were independently subjected to 10 repeated test procedures at both laboratories. MEASUREMENTS: Repeated measurements of BV, uncorrected for the effects of isothermal air in the lungs and the surface area artifact, were obtained using the BOD POD ADP, with the identical protocol being faithfully applied at both laboratories. Uncorrected BV measurements were adjusted to give estimates of actual BV that were used to calculate body density (body weight (BWt)/actual BV) from which estimates of body composition were derived. The differences between repeated BV measurements or body composition estimates were used to assess within-laboratory precision (repeatability), as standard deviation (SD) and coefficient of variation; the differences between measurements reproduced at each laboratory were used to determine between-laboratory precision (reproducibility), as bias and 95% limits of agreement (from SD of the differences between laboratories). RESULTS: The extent of within-laboratory methodological precision for BV (uncorrected and actual) was variable according to subject, sample group and laboratory conditions (range of SD, 0.04-0.13 l), and was mostly due to within-individual biological variability (typically 78-99%) rather than to technical imprecision. There was a significant (P<0.05) bias between laboratories for the 10 repeats on the two independent subjects (up to 0.29 l). Although no significant bias (P=0.077) was evident for the sample group of 30 volunteers (-0.05 l), the 95% limits of agreement were considerable (-0.68 to 0.58 l). The effects of this variability in BV on body composition were relatively greater: for example, within-laboratory precision (SD) for body fat as % BWt was between 0.56 and 1.34% depending on the subject and laboratory; the bias (-0.59%) was not significant between laboratories, but there were large 95% limits of agreement (-3.67 to 2.50%). CONCLUSION: Within-laboratory precision for each BOD POD instrument was reasonably good, but was variable according to the prevailing conditions. Although the bias between the two instruments was not significant for the BV measurements, implying that they can be used interchangeably for groups of similar subjects, the relatively large 95% limits of agreement indicate that greater consideration may be needed for assessing individuals with different ADP instruments. Therefore, use of a single ADP instrument is apparently preferable when assessing individuals on a longitudinal basis.

Evaluation of factors determining the precision of body composition measurements by air displacement plethysmography.

OBJECTIVES: To investigate methodological precision of air displacement plethysmography for assessment of body composition in a heterogenous sample of adults. DESIGN: Accuracy of volume measurements by air displacement plethysmography (ADP) for a range of known volumes was ascertained. Repeated measurements of body volume, lung volume, and derived body composition using the BODPOD measurement system were performed. Influence of surface area estimation on ADP measurement was investigated as a possible source of variation. SETTING: Clinical Nutrition Laboratory, School of Health & Sports Science, University of North London, London, UK. SUBJECTS: One hundred and two healthy subjects (57 women, 45 men) who ranged in age between 16 and 55 y and in BMI (kg/m(2)) between 17.8 and 41.9. STUDY DESIGN: Cross-sectional study of healthy adults for comparison with previous studies. Repeat measurements of raw body volume, lung volume and % body fat (BF) by ADP were all performed on the same day. RESULTS: From the range of known volumes a marked increase in the CV and a significantly greater measurement error were found at volumes below 40 l (P=0.04). Repeat measurements of raw body volume in human subjects resulted in a technical error equivalent to 0.8% BF. There was no significant difference found between measured and predicted lung volume and the 95% confidence interval for difference was only 0.3% BF. Repeat measurements of lung volume in our subset resulted in a technical error equivalent to 0.5% BF. Although body surface area estimation only accounted for variation in % BF of 0.1%, the extent of variation appeared to be governed by leanness (P<0.001). CONCLUSIONS: Although ADP retains excellent precision, in practice, repeat measurements of ADP should be performed whenever possible to allow for erroneous volume measurement within one procedure. Protocols for ADP measurement should be created with an awareness of those factors, which may affect measurements. SPONSORSHIPS: This study was supported by the University of North London Diversity & Development Fund.

The development of waist circumference percentiles in British children aged 5.0-16.9 y.

OBJECTIVE: To develop waist circumference percentile curves for British children and to compare these curves with those from other countries. DESIGN: Cross-sectional study. SETTING: School-aged population. SUBJECTS: A representative sample of school children from the geographical regions of Great Britain, approximately in proportion to their age distribution. The sample population consisted of 8355 children (3585 males, 4770 females) with ages ranging between 5.0 and 16.9 y. INTERVENTIONS: Waist circumferences were measured with a flexible non-elastic tape and waist circumference percentiles were constructed and smoothed using the LMS method. MAIN OUTCOME MEASURES: Smoothed waist circumference percentile curves. RESULTS: Mean waist circumference increased with age in both boys and girls. For girls, curves began to plateau after the age of 13 y whereas, for boys, waist percentile curves continued to increase more sharply after this age. However, these curves mainly reflect the patterns of waist circumference in Caucasian children. CONCLUSIONS: These curves represent the first waist circumference percentiles for British children and could be used provisionally for both clinical and possibly epidemiological use, although they should be validated against equivalent longitudinal data. SPONSORSHIP: This project has been sponsored by UNL Diversity and Development Fund.

Nutritional influences in early life upon obesity and body proportions.

Close relationships exist between patterns of intra-uterine growth and the risk of ischaemic heart disease, hypertension, diabetes, insulin-resistance syndrome, obesity and some cancers later in life. Earlier studies placed emphasis on low birth weight and reduced growth, but it is now clear that disproportions in early growth are of great importance. Disproportion may be identified as disproportions of fetal and placental growth (and the risk of high blood pressure), or in head circumference, length and weight. It is hypothesized that the availability of nutrients at different times during gestation, by interacting with the maternal and fetal hormonal profile, predisposes to different patterns of growth. The same interaction programmes critical metabolic functions and determines the metabolic capacity at all later ages. People who were exposed to severe undernutrition during the Dutch hunger winter showed increased adiposity if the exposure was during early pregnancy, but decreased adiposity if the exposure was during late pregnancy. In men born in the UK, those with evidence of retarded fetal growth had significantly greater waist/hip circumference ratios for any given body mass index (the ratio fell with increasing weight at one year of age). In Mexican-Americans and non-Hispanic Caucasian Americans, people in the lowest third of birth weight had more truncal fat than those in the highest third. Offspring of rats exposed to marginally reduced protein intakes during pregnancy manifest a similar pattern of growth and metabolic change to that seen in humans, with perturbations of appetite and body fat patterning. Studies in rats suggest that programming of the hypothalamus, especially the hypothalamic-pituitary-adrenal axis might be the mechanism through which these changes are brought about.

Interleukin-1 beta-induced anorexia and pyrexia in rat: relationship to hypothalamic neuropeptide Y.

We investigated the effect of recombinant human interleukin-1 beta (rhIL-1 beta)-induced anorexia and pyrexia on the hypothalamic neuropeptide Y (NPY)-ergic system, which stimulates feeding and reduces thermogenesis. In meal-fed rats, food intake decreased by 83%, 90 min after IL-1 beta treatment (1.3 micrograms/100 g ip; n - 8) vs. controls. NPY concentrations were significantly higher in the medial preoptic area (MPO), paraventricular (PVN), ventromedial (VMN), and dorsomedial (DMN) nuclei but unchanged in the arcuate nucleus (ARC) in both IL-1 beta-treated and pair-fed groups. Indomethacin (0.25 mg/100 g ip) reduced IL-1 beta-induced anorexia and tended to normalize NPY concentrations. In study 2, IL-1 beta increased core temperature by 1.1 degrees C above preinjection values (P < 0.001) and significantly raised NPY concentrations in the MPO, PVN, VMN, and DMN compared with controls, 60 min postinjection. Indomethacin prevented the pyrexia and normalized hypothalamic NPY levels. As NPY concentrations were not increased in the ARC (the hypothalamic site of synthesis), we suggest that the increased NPY levels may result from blocked release, which would be in accord with the known experimental effects of NPY.

Megestrol acetate stimulates food and water intake in the rat: effects on regional hypothalamic neuropeptide Y concentrations.

Megestrol acetate, a synthetic progestogen, stimulates appetite through an unknown mechanism. We tested the hypothesis that it might act, at least in part, by stimulating the activity of hypothalamic pathways containing neuropeptide Y, a potent central appetite stimulant in rats. Administration of megestrol acetate (50 mg/kg/day, n = 8) for 9 days significantly increased food and water intake compared with untreated controls (n = 8). Treated rats showed significant (90-140%) increases in neuropeptide Y concentrations in the arcuate nucleus (where neuropeptide Y is synthesized), in the lateral hypothalamic area (through which arcuate neurones project) and in the medial preoptic area, ventromedial nucleus and dorsomedial nucleus. The latter are sites of neuropeptide Y release and sensitive to neuropeptide Y-induced hyperphagia. Megestrol acetate may therefore stimulate neuropeptide Y synthesis, transport and release, and this could contribute to its appetite-stimulating effects.

Effects of chronic vanadate administration in the STZ-induced diabetic rat. The antihyperglycemic action of vanadate is attributable entirely to its suppression of feeding.

Vanadate treatment can lower glycemia in diabetic rats. This action is generally attributed to vanadate's insulinomimetic properties, but vanadate also inhibits feeding, which could lower blood glucose. We therefore assessed the contribution of hypophagia to vanadate's antihyperglycemic action in a 3-week study of streptozocin-induced (STZ) diabetic rats. Untreated diabetic rats (n = 8) ate 54% more food than nondiabetic control rats (P < 0.001). Diabetic rats given sodium metavanadate (0.5 mg in 0.5 ml of water by gavage twice daily; n = 8) had significantly lower food intakes (P < 0.001) than untreated diabetic rats. In vanadate-treated diabetic rats, blood glucose levels were significantly lower than in untreated diabetic rats (P < 0.001). Untreated diabetic rats pair-fed to the food intake of the vanadate-treated diabetic rats (n = 8) showed virtually identical blood glucose falls (P > 0.05 vs. vanadate-treated diabetic rats). Vanadate treatment did not affect plasma insulin concentrations in diabetic rats. In nondiabetic rats (n = 8), vanadate treatment significantly reduced food intake (P < 0.05) and also lowered plasma insulin concentrations (P < 0.05) without significantly affecting glycemia. To investigate the mechanism of vanadate's hypophagic effect, we also measured regional hypothalamic levels of neuropeptide Y (NPY), a potent central appetite stimulant that is thought to drive hyperphagia in STZ-induced diabetes. Hypothalamic NPY concentrations rise markedly in diabetes and are normalized by insulin replacement. Unlike insulin, vanadate treatment did not normalize regional hypothalamic NPY concentrations in diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuropeptide Y receptor numbers are reduced in the hypothalamus of streptozotocin-diabetic and food-deprived rats: further evidence of increased activity of hypothalamic NPY-containing pathways.

Neuropeptide Y (NPY) injected into the hypothalamus stimulates feeding and affects pituitary secretion. Insulin-deficient diabetes and food deprivation markedly increase hypothalamic NPY and NPY mRNA levels, suggesting increased activity of NPYergic pathways in the hypothalamus, which could account for hyperphagia and neuroendocrine changes in these conditions. To clarify these changes, NPY receptor characteristics were compared amongst rats with 3-weeks' untreated streptozotocin diabetes, insulin-treated normoglycemic diabetics, and non-diabetics, and also in food-deprived (72 h), food-deprived then refed, and in freely fed rats. Hypothalamic tissue homogenates (pooled from 3 rats; n = 9 per group) in Tris/HCl buffer were incubated with 30 pM [125I]porcine NPY and unlabeled NPY (range, 1 pM to 1 microM) for 1 h. Bound and free fractions were separated by vacuum filtration. Scatchard analysis revealed both high-affinity (Kd 0.3-0.8 nM) and low-affinity (Kd 14-40 nM) NPY receptor populations. Compared with nondiabetics, diabetic rats showed significantly reduced numbers (Bmax) of both high-affinity receptors (10 +/- 2 vs. 57 +/- 2 pmol/mg protein; p < 0.001) and low-affinity receptors (113 +/- 25 vs. 544 +/- 48 pmol/mg protein; p < 0.001). Insulin treatment partially restored Bmax of both high- and low-affinity receptors (24 +/- 1 and 334 +/- 60 pmol/mg protein, respectively; p < 0.01 vs. both other groups). Food deprivation also reduced Bmax of high-affinity (36 +/- 2 vs. 56 +/- 7 pmol/mg protein in freely fed; p < 0.05) and low-affinity receptors (288 +/- 6 vs. 457 +/- 17 pmol/mg protein; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Increased neuropeptide Y concentrations in specific hypothalamic nuclei of the rat following treatment with methysergide: evidence that NPY may mediate serotonin's effects on food intake.

Neuropeptide Y (NPY) is a potent central appetite stimulant found in hypothalamic neurons that have close anatomical associations with neurons containing serotonin, a powerful anorectic agent. To determine whether the two neurotransmitters interact functionally, we have studied the effects on regional hypothalamic NPY concentrations of acute and chronic administration of methysergide, a 5-HT1BC/serotonin receptor antagonist. Chronic methysergide treatment (10 mg/kg/day) was given by subcutaneously implanted osmotic minipumps (n = 8). Acute effects of methysergide were determined 4 h after a single injection (10 mg/kg) in a separate group (n = 8). Controls (n = 8) had implanted minipumps delivering saline, and also received a saline injection 4 h before sacrifice. Food intake was significantly increased (p < 0.01) by both acute and chronic methysergide treatment. In the chronically treated rats, NPY levels were significantly increased over controls in the arcuate nucleus (ARC; by 41%, p = 0.02) and paraventricular nucleus (PVN; by 40%, p < 0.01). Acute methysergide treatment also increased NPY concentrations in the ARC (by 81%, p < 0.01) and PVN (by 30%, p < 0.01). Methysergide administration, which stimulated feeding, therefore raised NPY concentrations in the ARC, where NPY is synthesized, and in the PVN, a major site of NPY release where NPY injection induces hyperphagia. These findings suggest that NPYergic and serotoninergic innervations in the hypothalamus interact to regulate food intake, and raise the possibility that increased NPY release may mediate the hyperphagic effect of serotoninergic 5-HT1BC/receptor blockade.

Widespread increases in regional hypothalamic neuropeptide Y levels in acute cold-exposed rats.

Neuropeptide Y injected into the hypothalamus or third ventricle stimulates feeding and inhibits the sympathetic activation of brown adipose tissue. To clarify the involvement of hypothalamic neuropeptide Y in cold-induced thermogenesis, groups of rats exposed to 4 degrees for 2.5 or 18 h were compared with warm-adapted rats (22 degrees C). Neuropeptide Y was measured in eight selected hypothalamic regions, including those known to be involved in the regulation of energy expenditure. Activation of brown adipose tissue was confirmed by significant six- to nine-fold increases in brown adipose tissue uncoupling protein messenger RNA. Compared with warm-adapted controls, neuropeptide Y levels were significantly raised by 80-170% in several hypothalamic regions of rats exposed to cold for 2.5 h, namely the medial preoptic area, paraventricular nucleus, ventromedial nucleus, dorsomedial nucleus and lateral hypothalamic area. Neuropeptide Y levels in 18-h cold-exposed rats were similarly elevated in these regions and were also significantly increased in the anterior hypothalamic area (75%). By contrast, neuropeptide Y levels in the arcuate nucleus, the main hypothalamic site of synthesis, were not increased by cold exposure, being significantly reduced by 21% after 2.5 h exposure and comparable with controls after 18 h. As neuropeptide Y injection inhibits brown adipose tissue activation, we suggest that the rapid and dramatic increases in neuropeptide Y levels in specific hypothalamic regions occur because cold exposure might inhibit the release of neuropeptide Y and so cause accumulation of neuropeptide Y in these sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in hypothalamic NPY and CRF in anorexic tumor-bearing rats.

Regional hypothalamic concentrations of neuropeptide Y (NPY) and corticotropin-releasing factor (CRF), respectively a stimulant and an inhibitor of feeding behavior, were investigated in hypothalamic nuclei in rats carrying the Yoshida sarcoma. Tumor-bearing rats (n = 10), non-tumor-bearing controls (n = 10), and food-restricted rats (n = 10), which did not carry tumors but were pair-fed to match the reduced food intake of the tumor-bearing group, were studied after 10 days. NPY concentrations in the arcuate nucleus (ARC, the main site of NPY synthesis) were significantly increased above controls (P < 0.01) in both tumor-bearing and food-restricted groups. However, NPY concentrations in the paraventricular nucleus (PVN, an NPY-sensitive site of NPY release) showed opposing changes, with a 25% decrease (P = 0.052) in the tumor-bearing but a 48% increase (P < 0.01) in the food-restricted group. CRF concentrations in both the PVN and the ARC were significantly reduced (P < 0.01) in the food-restricted group, but remained close to control values in the tumor-bearing group (P not significant). Changes in hypothalamic appetite-regulating neuropeptides in cancer anorexia, which may result from the action of cytokines produced by a host defense response or the tumor itself, may account for reduced feeding. Such changes may include impaired activity of NPY or failure of CRF activity to be suppressed after underfeeding and weight loss.

Intense exercise and food restriction cause similar hypothalamic neuropeptide Y increases in rats.

Neuropeptide Y (NPY) is a potent central appetite stimulant whose concentrations rise markedly in hypothalamic appetite-regulating regions in food-deprived rats. To determine whether increased energy expenditure also affects hypothalamic NPY, we studied the effects of intense physical exercise in rats (n = 10) running voluntarily on a large-diameter exercise wheel. Running was initiated by restricting food intake but stabilized at an average of 8 km/day when food intake was matched to that in 11 nonexercised, freely fed controls [23.9 +/- 1.9 (SE) g/day vs. 24.7 +/- 1.3 g/day; P > 0.5]. Running expended approximately 40% of daily energy intake, and weight gain was significantly inhibited. A separate group (n = 10) of nonexercised rats was food restricted (approximately 15 g/day) to match the weights of the exercised rats. The rats were killed after 40 days, when both experimental groups weighed 30% less than controls (P < 0.01). Hypothalamic NPY concentrations showed significant (P < 0.01) increases of 30-70% in specific regions (arcuate and dorsomedial nuclei and medial preoptic and lateral hypothalamic areas) in both the running and food-restricted groups, compared with controls. There were no significant differences between the two experimental groups in NPY concentrations in any hypothalamic region. These findings suggest that negative energy balance, whether caused by reduced energy intake or increased expenditure, increases hypothalamic NPYergic activity. As NPY acts on the hypothalamus to increase body weight, these data support the postulated homeostatic role of NPY in maintaining nutritional state.

Peripheral insulin administration attenuates the increase in neuropeptide Y concentrations in the hypothalamic arcuate nucleus of fasted rats.

Fasting increases neuropeptide Y (NPY) concentrations in the arcuate nucleus (ARC), its site of synthesis, and in other regions of the rat hypothalamus. Neuropeptide Y is a potent central orexigenic agent and may therefore stimulate appetite during fasting. We tested the hypothesis that low plasma insulin levels stimulate ARC levels of NPY in fasted rats. Compared with freely fed controls (n = 8), rats fasted for 72 h (n = 8) showed significantly lower plasma insulin levels (28.9 +/- 1.6 vs. 52.6 +/- 5.7 pmol/l; p < 0.001) and higher ARC NPY concentrations (14.2 +/- 1.8 vs. 8.4 +/- 2.2 fmol/micrograms protein; p < 0.001). Fasted rats treated with subcutaneous insulin (5 U/kg/day; n = 10), which nearly normalized plasma insulin (46.6 +/- 2.8 pmol/l), showed intermediate ARC NPY levels (11.2 +/- 1.4 fmol/micrograms protein; p < 0.01 vs. controls and untreated fasted rats). Insulin administered peripherally, therefore, attenuates fasting-induced NPY increases in the ARC, supporting the hypothesis that hypoinsulinemia stimulates hypothalamic NPY.

Insulin deficiency is a specific stimulus to hypothalamic neuropeptide Y: a comparison of the effects of insulin replacement and food restriction in streptozocin-diabetic rats.

Untreated insulin-deficient diabetes causes hyperphagia and neuroendocrine disturbances that may be partly mediated by increased hypothalamic activity of neuropeptide Y (NPY), a potent central appetite stimulant. The metabolic signal that stimulates hypothalamic NPY is unknown. This study aimed to determine whether insulin deficiency or hyperglycemia was responsible. Regional hypothalamic NPY concentrations were compared in streptozocin-diabetic (STZ-D) rats rendered nearly normoglycemic by either insulin replacement or food restriction. Untreated STZ-D rats were hyperphagic and showed significantly increased (p less than 0.01) hypothalamic NPY concentrations in the arcuate nucleus and lateral hypothalamic area. Once-daily ultralente insulin injections corrected hypoinsulinemia and hyperglycemia, abolished hyperphagia, and normalized NPY concentrations in all hypothalamic regions. By contrast, food restriction effectively lowered glycemia without raising insulin levels. In these underfed diabetic rats, NPY concentrations rose further and were significantly higher than nondiabetic and untreated diabetic levels in most hypothalamic regions. We conclude that insulin deficiency is a major stimulus to hypothalamic NPY in STZ-D, whereas hyperglycemia may exert an inhibitory influence. These findings support the hypothesis that hypothalamic NPY responds to specific metabolic cues and is involved in regulating energy balance and conserving body weight.

Hypothalamic neuropeptide Y disturbances in the obese (cp/cp) JCR:LA corpulent rat.

Regional hypothalamic neuropeptide Y (NPY) concentrations were compared between cp/cp JCR:LA corpulent rats, which were grossly obese, hyperphagic, and hyperinsulinemic, and lean (+/+) controls. In freely fed cp/cp rats, NPY levels in the arcuate nucleus (ARC) were 31% higher than in lean rats (p less than 0.001). In lean rats, chronic food restriction significantly raised NPY levels by 22% in the ARC (p less than 0.05) and by 44% in the dorsomedial nucleus (DMH; p less than 0.05). By contrast, food-restricted cp/cp rats showed no change in the ARC, but NPY levels rose in the DMH (by 36%; p less than 0.05) and ventromedial nucleus (31%; p less than 0.05). Increased NPY levels in the ARC, the major site of hypothalamic NPY synthesis, suggests increased NPYergic activity in cp/cp rats; given the central actions of NPY, this could contribute to hyperphagia, obesity, and hyperinsulinemia in this syndrome. Abnormal NPY responses to food deprivation further suggest dysregulation of NPY in cp/cp rats.