Nature Medicine
8, 643 - 644 (2002)
doi:10.1038/nm0702-643
Elevated plasma ghrelin levels in Prader−Willi syndromeDavid E. Cummings1, Karine Clement2, Jonathan Q. Purnell3, Christian Vaisse4, Karen E. Foster1, R. Scott Frayo1, Michael W. Schwartz1, Arnaud Basdevant2
& David S. Weigle11 Department of Medicine, VA Puget Sound Health Care System and Harborview Medical Center University of Washington, Seattle, Washington, USA davidec@Uwashington.edu 2 Service de Medecine et Nutrition, Hotel-Dieu EA 3502 Paris VI University, France 3 Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA 4 Department of Medicine and Diabetes Center University of California San Francisco, California, USA To the editor
Recent advances have begun to clarify the pathogenesis of genetic obesity in humans. Mutations that affect signaling by leptin and melanocortins were hypothesized to contribute to human obesity based on their important roles in body-weight regulation in rodent models, and compelling support for this hypothesis now exists1,
2,
3. Ghrelin is a novel enteric hormone4 that increases food intake, body weight and growth-hormone (GH) secretion as potently as any known peptide4,
5,
6,
7. As the only known circulating orexigen, ghrelin is implicated in meal-time hunger8 and body-weight regulation in rodents5,
6 and humans9,
10. However, previous studies have not investigated the hypothesis that ghrelin hypersecretion might contribute to genetic obesity.
Prader−Willi syndrome (PWS) is the most common form of human syndromic obesity. It is characterized by severe hyperphagia, GH deficiency, hypogonadism, neonatal hypotonia, dysmorphic features and cognitive impairment11. Although the genetic basis of PWS involves imprinting disorders of several genes on chromosome 15, mediators of the phenotype are unknown12. Because ghrelin affects appetite as well as GH secretion, and both are abnormal in PWS, we hypothesized that this condition might involve ghrelin dysregulation. To investigate whether ghrelin might have a role in the pathogenesis of PWS or other forms of genetic obesity, we measured plasma ghrelin levels in humans with PWS, leptin receptor (LepR) mutations2, melanocortin-4 receptor (Mc4r) mutations3,
13 and appropriate controls (Table 1).
 | | |
Overnight fasting plasma ghrelin levels were 4.5-fold higher in PWS subjects (1542  271 pg/ml) than in equally obese controls (344 45 pg/ml, P < 0.001), and 2.5-fold higher than in lean controls (608 68 pg/ml, P = 0.003) (Fig. 1a). The mechanism underlying this increase is unlikely to reflect mutation of the genes encoding ghrelin or its receptor, as these are not contained within the locus responsible for PWS. However, several affected genes in that region encode factors that could indirectly affect ghrelin expression12. High ghrelin levels in PWS are unlikely to arise from deficient negative feedback by GH, as GH does not appear to regulate circulating ghrelin14.
| | Figure 1. Obesity from PWS is associated with high circulating ghrelin levels. | | |  | a, Fasting plasma ghrelin levels were measured with a radio-immunoassay that uses a polyclonal antibody raised against full-length, octanoylated human ghrelin8. Study groups are described in Table 1. Dark bars indicate subjects with known mutations; light bars indicate unaffected controls. Values are mean s.e.m. *, P < 0.001, ANOVA, PWS subjects versus all other groups. **, P < 0.01, lean controls versus all other groups except Mc4r controls. b, The normal negative correlation between BMI and plasma ghrelin levels is absent among PWS subjects. Different symbols indicate subjects with PWS ( ), a homozygous inactivating LepR mutation ( ), heterozygous Mc4r mutations ( ), and all other non-PWS subjects ( ). The regression line applies only to individuals without PWS (open symbols, n = 80, r = -0.40, P < 0.001). A negative correlation between BMI and ghrelin levels also exists among all normal subjects without known mutations (n = 54, r = -0.42, P = 0.001). In contrast, there was no correlation between BMI and ghrelin levels in the PWS group (P = 0.50). Study protocol approved by the Human Subjects Review Committee of the University of Washington.
 Full Figure and legend (27K) |
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Ghrelin secretion is reported to be inhibited by leptin15, and PWS individuals may be leptin-resistant, in view of their hyperphagia despite high leptin levels16. However, hyperghrelinemia is unlikely to arise from leptin resistance, as ghrelin levels are not elevated in obese subjects homozygous for an inactivating LepR mutation (Fig. 1a). This finding suggests that leptin signaling is not an important determinant of human ghrelin levels. Similarly, abnormalities in Mc4r, a critical central nervous system target of leptin action, are unlikely to explain increased ghrelin levels in PWS. We found low or normal ghrelin levels in subjects with each of ten different Mc4r mutations (compared with unaffected family members), including inactivating, constitutively activating and various missense substitutions (Table 1, Fig. 1a). Among all 80 non-PWS subjects, there was a negative correlation between ghrelin levels and body-mass index (BMI) (r = -0.40, P < 0.001) (Fig. 1b), indicating that ghrelin is not a major contributor to obesity in these individuals. In contrast, ghrelin levels in PWS subjects were unrelated to BMI and were uniformly above the regression line for non-PWS individuals. Thus, while obesity per se is associated with low ghrelin levels, that caused by PWS is associated with elevated ghrelin.
Ghrelin levels in PWS subjects are comparable to or higher than those reported to stimulate appetite and food intake during peripheral ghrelin administration in humans10 and rodents17. Thus, our findings are consistent with a role for hyperghrelinemia in the pathogenesis of hyperphagia in PWS. If elevated ghrelin participates in the GH deficiency of PWS, the effect might be an example of paradoxical override inhibition, which has been described with continuous GH-releasing hormone stimulation of GH18. Interventions that lower plasma ghrelin levels, such as gastric bypass surgery9, warrant consideration in the treatment of obesity from PWS.
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