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Editorial |
Endocrinology and Diabetes Unit British Columbia’s Children’s Hospital University of British Columbia Vancouver, Canada V6H 3V4
Address all correspondence and requests for reprints to: Jean-Pierre Chanoine, Endocrinology and Diabetes Unit, Room K4-212, British Columbia’s Children’s Hospital, 4480 Oak Street, Vancouver, British Columbia, Canada V6H 3V4. E-mail: jchanoine{at}cw.bc.ca.
Eat less, move more, change your behavior! These three pillars form the cornerstone of today’s therapy of overweight and are offered to most pediatric patients suffering from weight excess. Perhaps unsurprisingly, these recommendations are seldom successfully implemented, and few overweight children and adolescents achieve meaningful weight reduction at 1 yr after intervention. Childhood and adolescent overweight remains a rapidly growing problem in need of effective solutions (1).
At a population level, most studies have demonstrated a strong association between weight gain and decreased activity (or increased inactivity), poor eating habits, and unhealthy lifestyle. For instance, in the field of nutrition, the negative effects of overconsumption of high-density foods, increased caloric intake from sugar-sweetened beverages, and increased portion sizes are well known. Skipping breakfast, a decreasing number of meals taken as a family, and visiting fast-food outlets have also been associated with an increase in the prevalence of overweight in youth. Similar studies have focused on physical activity and behavior and identified numerous potentially modifiable risk factors (2).
At the individual level, however, the unique characteristics that make a given child exquisitely sensitive to one or more of the above-described risk factors remain largely unknown. Are all children and adolescents equally sensitive to high-density foods, increased portion size, and excess sugar-sweetened beverages? Does reduced physical activity increase the risk of being overweight similarly in all subjects? A better understanding of the individual characteristics underlying the greater sensitivity of a given subject to a specific risk factor for overweight is arguably a key step toward proposing individualized, more effective therapeutic approaches.
Do Ghrelin and Peptide YY (PYY) Regulate Appetite?
In this issue, Bacha and Arslanian (3) identify differences in plasma ghrelin and PYY concentrations between two groups of prepubertal, African-American (AA) and American white (AW) children with a large range of body weights. They demonstrate that the absolute decrease in the concentrations of ghrelin, an orexigenic peptide, following an oral glucose tolerance test is 32% smaller in AA compared with AW children. They also show that fasting and postprandial concentrations of PYY, an anorexigenic peptide, are 17–19% lower in AA compared with AW children.
Ghrelin is secreted primarily by the fundus of the stomach and circulates as both acylated and deacylated forms. Exogenous administration of acylated ghrelin (but not of the deacylated form) stimulates appetite. This effect is mediated mainly through the GH secretagogue receptor 1a in the hypothalamus and depends upon acylation of ghrelin. These early data raised the hypothesis that ghrelin could play a direct role in the pathophysiology of obesity by stimulating food intake. However, as in adults, ghrelin concentrations are decreased in obese compared with lean children (4) and adolescents (5), making such a simple role of ghrelin in the etiology of obesity unlikely. Ghrelin concentrations increase with fasting and rapidly decrease following caloric intake in lean and obese children (4) and adolescents (5), but the magnitude of this decrease is blunted in obese subjects (4, 5), possibly suggesting decreased fullness for a similar caloric intake. Evidence is now accumulating that ghrelin, or rather changes in ghrelin concentrations, may play an important physiological role in both short-term and long-term energy balance (6).
PYY 1–36 is a 36-amino-acid peptide hormone that is released postprandially by the intestine in proportion to the calories ingested. It circulates as two main endogenous forms, PYY 1–36 and PYY 3–36, resulting from the enzymatic cleavage of PYY 1–36. The effects of PYY on appetite are mediated though several orexigenic and anorexigenic Y receptors located in the hypothalamus. Although administration of PYY in the central nervous system consistently stimulates food intake in rodents, Batterham et al. demonstrated that peripheral administration of PYY 3–36 markedly decreased food intake in rodents (7) and humans (8), possibly through preferential access to the anorexigenic Y2 receptor in the hypothalamus. However, the extent to which peripheral injection of PYY 3–36 inhibits food intake remains disputed (9). Similar to data in adults, lower PYY concentrations (10) or a blunted PYY response to caloric intake (5) have been reported in adolescents, supporting the concept that inappropriately low PYY concentrations could play a role in the pathophysiology of overweight in youth.
Taken together, Bacha and Arslanian’s data (3) raise the intriguing hypothesis that the smaller postprandial ghrelin decrease and the lower PYY concentrations observed in AA compared with AW children could reflect lower satiety in AA compared with AW children and could explain, at least partly, the higher incidence of overweight in AA children (11). A smaller postprandial decrease in ghrelin concentrations may result in decreased fullness and greater caloric intake during the subsequent meal (12). Similarly, lower PYY concentrations could lessen the negative feedback of PYY on the hypothalamic Y2 receptor and decrease the anorexigenic signal (13).
However, several key questions need to be answered before this hypothesis can be proven or disproven:
1. Do AA children eat more than AW children? Energy intake was found to be 9% higher in AA compared with AW girls participating in the National Heart, Lung, and Blood Institute Growth and Health Study (14), contrasting with a similar intake measured in AA and AW children participating in the Bogalusa study (15). This point remains to be clarified.
2. Do the above-described results apply to the concentrations of acylated ghrelin and of 3–36 PYY? In the present study, total (acylated + deacylated) ghrelin and total [(1–36) + (3–36)] PYY concentrations were measured. However, deacylated ghrelin, which is devoid of orexigenic properties, represents more than 90% of total circulating ghrelin in adolescents (16), and the ratio of circulating PYY [PYY (3–36) to PYY (1–36)] is markedly higher in lean compared with obese adults (13). In addition, although the concentrations of total PYY increase 4-fold after a meal, this increase is only 55% for the 3–36 PYY isoform (17). Such studies would require the use of specific assays as well as of inhibitors protecting acylated ghrelin from desacylation and PYY 1–36 from enzymatic cleavage into PYY 3–36.
3. Are differences in the endogenous concentrations of ghrelin and PYY associated with differences in hunger or fullness? Recent circumstantial data suggesting that this may actually be the case need to be confirmed. In adults initiating meals on a voluntary basis, in the absence of external clues, changes in ghrelin concentrations parallel changes in hunger, suggesting that ghrelin may play a role in meal initiation (18). A greater caloric content in a test meal is associated with higher peak PYY concentrations and greater fullness (13), and this relationship is statistically significant in both obese and lean adult subjects (19).
4. Do the hormonal differences reported by Bacha and Arslanian translate into differences in short- and long-term caloric intake? There is, to my knowledge, no study that has directly addressed this issue. This last point will likely be difficult to prove—or disprove—as the small daily change in caloric intake necessary to cause a 1-kilo (2.2 pounds) change in weight gain over a 1-yr period (20–30 kcal/d) is difficult to detect. In support of this hypothesis, Roth et al. (10) recently observed in a cohort of prepubertal obese children that the magnitude of the weight loss over a 1-yr period paralleled the increase in fasting PYY over this time period. A possible interpretation of these data are that the increase in endogenous PYY may mediate the weight loss.
Differences in Ghrelin and PYY between AA and AW Children: Is Race an Issue?
Bacha and Arslanian (3) characterized the two groups of children on the basis of racial identity, defined as being from AA or AW descent for three generations (3). A similar definition is used in many studies reporting a greater prevalence of overweight in AA compared with AW children and adolescents (11). The definition of race has evolved with time, and there is presently little consensus on what it exactly means (20). A more restrictive definition would define people of the same race on the basis of homogeneity with respect to biological inheritance. A less restrictive definition would also include cultural, socioeconomic, and religious qualities in the characterization of the differences between groups rather than just their genetic ancestry.
For instance, for a similar body mass index, AA children show greater insulin resistance compared with AW children, likely reflecting a greater genetic susceptibility to insulin resistance (21). As insulin potentially acts as a physiological inhibitor of ghrelin secretion (reviewed in Ref. 6), the smaller ghrelin decrease following caloric intake observed by Bacha and Arslanian (3) could reflect some degree of resistance to the action of insulin on ghrelin secretion. However, being from AA descent may also be a confounding factor for several environmental and cultural nutritional factors playing a physiopathological role in the increased prevalence of childhood obesity. For instance, AA girls are more likely to skip breakfast, a habit associated with a greater risk of overweight (22). Low-income AA mothers are more likely to choose a higher cut-point for the perception of overweight in their children compared with low-income AW mothers, an attitude that could affect overall feeding practice in a family (23). The prevalence of breastfeeding is lower in AA compared with AW infants (24), whereas the concentrations of ghrelin are reported to be lower in breastfed compared with formula-fed infants (25). How these early nutritional experiences affect the development of the hormonal machinery controlling appetite is unknown. It is suggested that the differences observed by Bacha and Arslanian likely reflect a mix of genetic and environmental determinants. Future studies looking at individual differences that may favor the development of obesity in children and adolescents should also focus on the role of socioenvironmental factors known to be associated with a higher risk of excessive weight gain.
In conclusion, in the search for more effective treatments of childhood and adolescent overweight, unraveling the individual differences that play a pathophysiological role in the development of weight excess is an important step. This may ultimately lead to the recognition that children and adolescents have a different sensitivity to the determinants of overweight and to the development of more individualized and effective interventions. As for appetite regulation, pharmacotherapeutic agents such as PYY 3–36 and antagonists of the ghrelin/GH secretagogue receptor 1a axis are being developed (26). Whether individual ghrelin and PYY profiles will help selecting the overweight subjects who are most likely to be good responders to these new agents remains to be determined.
Acknowledgments
Critical review of the manuscript by Drs. Guy Van Vliet and Ariane Alimenti is gratefully acknowledged.
Footnotes
This work was supported by Grant 1637 from the Canadian Diabetes Association. Dr. Jean-Pierre Chanoine is a recipient of Grant SAB2005-0016 (Ministerio de Educación y Ciencia, España).
Abbreviations: AA, African-American; AW, American white; PYY, peptide YY.
Received June 7, 2006.
Accepted June 19, 2006.
References
This article has been cited by other articles:
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  C. Maier, M. Riedl, G. Vila, P. Nowotny, M. Wolzt, M. Clodi, B. Ludvik, and A. Luger Cholinergic Regulation of Ghrelin and Peptide YY Release May Be Impaired in Obesity Diabetes, September 1, 2008; 57(9): 2332 - 2340. [Abstract] [Full Text] [PDF]
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 J. Z. Kasa-Vubu, A. Rosenthal, E. G. Murdock, and K. B. Welch Impact of Fatness, Fitness, and Ethnicity on the Relationship of Nocturnal Ghrelin to 24-Hour Luteinizing Hormone Concentrations in Adolescent Girls J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 3246 - 3252. [Abstract] [Full Text] [PDF]
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 N. Germain, B. Galusca, C. W Le Roux, C. Bossu, M. A Ghatei, F. Lang, S. R Bloom, and B. Estour Constitutional thinness and lean anorexia nervosa display opposite concentrations of peptide YY, glucagon-like peptide 1, ghrelin, and leptin Am. J. Clinical Nutrition, April 1, 2007; 85(4): 967 - 971. [Abstract] [Full Text] [PDF]
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