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Changes in levels of peripheral hormones controlling appetite are inconsistent with hyperphagia in leptin-deficient subjects

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Abstract

Congenital leptin deficiency, a rare genetic disorder due to a homozygous mutation in the leptin gene (LEP), is accompanied by extreme obesity and hyperphagia. A number of gastrointestinal hormones have been shown to critically regulate food intake but their physiological role in hyperphagic response in congenital leptin deficiency has not been elucidated. This study is the first to evaluate the fasting and postprandial profiles of gut-derived hormones in homozygous and heterozygous carriers of LEP mutation. The study subjects from two consanguineous families consisted of five homozygous and eight heterozygous carriers of LEP mutation, c.398delG. Ten wild-type normal-weight subjects served as controls. Fasting and 1-h postprandial plasma ghrelin, glucagon-like peptide (GLP) 1, peptide YY (PYY), leptin and insulin levels were measured by immunoassays. Fasting plasma ghrelin levels in homozygotes remained remarkably unchanged following food consumption (P = 0.33) in contrast to a significant decline in heterozygous (P < 0.03) and normal (P < 0.02) subjects. A significant postprandial increase in PYY was observed in heterozygous (P < 0.02) and control subjects (P < 0.01), but not in the homozygous group (P = 0.22). A postprandial rise in GLP-1 levels was significant (P < 0.02) in all groups. Interestingly, fasting leptin levels in heterozygotes were not significantly different from controls and did not change significantly following meal. Our results demonstrate that gut hormones play little or no physiological role in driving the hyperphagic response of leptin-deficient subjects. In contrast, fasting and postprandial levels of gut hormones in heterozygous mutation carriers were comparable to those of normal-weight controls.

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References

  1. C. Bjorbaek, B.B. Kahn, Leptin signaling in the central nervous system and the periphery. Recent Prog. Horm. Res. 59, 305–331 (2004)

    Article  CAS  PubMed  Google Scholar 

  2. A. Oswal, G. Yeo, Leptin and the control of body weight: a review of its diverse central targets, signaling mechanisms, and role in the pathogenesis of obesity. Obesity (Silver Spring) 18, 221–229 (2010)

    Article  Google Scholar 

  3. K.G. Murphy, S.R. Bloom, Gut hormones and the regulation of energy homeostasis. Nature 444, 854–859 (2006)

    Article  CAS  PubMed  Google Scholar 

  4. H. Ariyasu, K. Takaya, T. Tagami et al., Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J. Clin. Endocrinol. Metab. 86, 4753–4758 (2001)

    Article  CAS  PubMed  Google Scholar 

  5. T.R. Castaneda, J. Tong, R. Datta, M. Culler, M.H. Tschop, Ghrelin in the regulation of body weight and metabolism. Front. Neuroendocrinol. 31, 44–60 (2010)

    Article  CAS  PubMed  Google Scholar 

  6. P.J. English, M.A. Ghatei, I.A. Malik, S.R. Bloom, J.P. Wilding, Food fails to suppress ghrelin levels in obese humans. J. Clin. Endocrinol. Metab. 87, 2984–2987 (2002)

    Article  CAS  PubMed  Google Scholar 

  7. B. Otto, U. Cuntz, E. Fruehauf, R. Wawarta et al., Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur. J. Endocrinol. 145, 669–673 (2001)

    Article  CAS  PubMed  Google Scholar 

  8. A.A. van der Klaauw, J.M. Keogh, E. Henning, A. Blackwood, A.M. Haqq, J.Q. Purnell, I.S. Farooqi, Postprandial total ghrelin suppression is modulated by melanocortin signaling in humans. J. Clin. Endocrinol. Metab. 98, E288–E292 (2013)

    Article  PubMed Central  PubMed  Google Scholar 

  9. A.M. Haqq, I.S. Farooqi, S. O’Rahilly et al., Serum ghrelin levels are inversely correlated with body mass index, age, and insulin concentrations in normal children and are markedly increased in Prader–Willi syndrome. J. Clin. Endocrinol. Metab. 88, 174–178 (2003)

    Article  CAS  PubMed  Google Scholar 

  10. A.P. Goldstone, M. Patterson, N. Kalingag et al., Fasting and postprandial hyperghrelinemia in Prader–Willi syndrome is partially explained by hypoinsulinemia, and is not due to peptide YY3-36 deficiency or seen in hypothalamic obesity due to craniopharyngioma. J. Clin. Endocrinol. Metab. 90, 2681–2690 (2005)

    Article  CAS  PubMed  Google Scholar 

  11. E. Ekblad, F. Sundler, Distribution of pancreatic polypeptide and peptide YY. Peptides 23, 251–261 (2002)

    Article  CAS  PubMed  Google Scholar 

  12. R.L. Batterham, H. Heffron, S. Kapoor et al., Critical role for peptide YY in protein-mediated satiation and body-weight regulation. Cell Metab. 4, 223–233 (2006)

    Article  CAS  PubMed  Google Scholar 

  13. T.E. Adrian, G.L. Ferri, A.J. Bacarese-Hamilton, H.S. Fuessl, J.M. Polak, S.R. Bloom, Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 89, 1070–1077 (1985)

    CAS  PubMed  Google Scholar 

  14. A.A. van der Klaauw, J.M. Keogh, E. Henning, V.M. Trowse, W.S. Dhillo, M.A. Ghatei, I.S. Farooqi, High protein intake stimulates postprandial GLP1 and PYY release. Obesity (Silver Spring) (2012). doi:10.1002/oby.20154

    Google Scholar 

  15. R.A. Pittner, C.X. Moore, S.P. Bhavsar et al., Effects of PYY[3–36] in rodent models of diabetes and obesity. Int. J. Obes. Relat. Metab. Disord. 28, 963–971 (2004)

    Article  CAS  PubMed  Google Scholar 

  16. K. Zwirska-Korczala, S.J. Konturek, M. Sodowski et al., Basal and postprandial plasma levels of PYY, ghrelin, cholecystokinin, gastrin and insulin in women with moderate and morbid obesity and metabolic syndrome. J. Physiol. Pharmacol. 58(Suppl 1), 13–35 (2007)

    PubMed  Google Scholar 

  17. M.D. Turton, D. O’Shea, I. Gunn, S.A. Beak et al., A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379, 69–72 (1996)

    Article  CAS  PubMed  Google Scholar 

  18. R.S. Ahima, S.Y. Osei, Leptin signaling. Physiol. Behav. 81, 223–241 (2004)

    Article  CAS  PubMed  Google Scholar 

  19. K.D. Niswender, M.W. Schwartz, Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities. Front. Neuroendocrinol. 24, 1–10 (2003)

    Article  CAS  PubMed  Google Scholar 

  20. M.W. Schwartz, S.C. Woods, D. Porte Jr, R.J. Seeley, D.G. Baskin, Central nervous system control of food intake. Nature 404, 661–671 (2000)

    CAS  PubMed  Google Scholar 

  21. A.J. van der Lely, M. Tschop, M.L. Heiman, E. Ghigo, Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr. Rev. 25, 426–457 (2004)

    Article  PubMed  Google Scholar 

  22. C.T. Montague, I.S. Farooqi, J.P. Whitehead et al., Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903–908 (1997)

    Article  CAS  PubMed  Google Scholar 

  23. I.S. Farooqi, S. O’Rahilly, Monogenic human obesity syndromes. Recent Prog. Horm. Res. 59, 409–424 (2004)

    Article  CAS  PubMed  Google Scholar 

  24. S. Saeed, T.A. Butt, M. Anwer, M. Arslan, P. Froguel, High prevalence of leptin and melanocortin-4 receptor gene mutations in children with severe obesity from Pakistani consanguineous families. Mol. Genet. Metab. 106, 121–126 (2012)

    Article  CAS  PubMed  Google Scholar 

  25. A.I. Blakemore, P. Froguel, Investigation of Mendelian forms of obesity holds out the prospect of personalized medicine. Ann. N. Y. Acad. Sci. 1214, 180–189 (2010)

    Article  CAS  PubMed  Google Scholar 

  26. I.S. Farooqi, J.M. Keogh, S. Kamath et al., Partial leptin deficiency and human adiposity. Nature 414, 34–35 (2001)

    Article  CAS  PubMed  Google Scholar 

  27. A.M. Wren, L.J. Seal, M.A. Cohen et al., Ghrelin enhances appetite and increases food intake in humans. J. Clin. Endocrinol. Metab. 86, 5992–5995 (2001)

    Article  CAS  PubMed  Google Scholar 

  28. M. Tschop, C. Weyer, P.A. Tataranni, V. Devanarayan, E. Ravussin, M.L. Heiman, Circulating ghrelin levels are decreased in human obesity. Diabetes 50, 707–709 (2001)

    Article  CAS  PubMed  Google Scholar 

  29. Y. Sun, S. Ahmed, R.G. Smith, Deletion of ghrelin impairs neither growth nor appetite. Mol. Cell. Biol. 23, 7973–7981 (2003)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. H. Kirchner, K.M. Heppner, J. Holland, D. Kabra, M.H. Tschöp, P.T. Pfluger, Ablation of ghrelin O-acyltransferase does not improve glucose intolerance or body adiposity in mice on a leptin-deficient ob/ob background. PLoS One 8, e61822 (2013)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. B.O. Yildiz, M.A. Suchard, M.L. Wong, S.M. McCann, J. Licinio, Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity. Proc. Natl. Acad. Sci. USA. 101, 10434–10439 (2004)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. C. Bizzarri, A.E. Rigamonti, A. Luce et al., Children with Prader–Willi syndrome exhibit more evident meal-induced responses in plasma ghrelin and peptide YY levels than obese and lean children. Eur. J. Endocrinol. 162, 499–505 (2010)

    Article  CAS  PubMed  Google Scholar 

  33. A.P. Goldstone, E.L. Thomas, A.E. Brynes et al., Visceral adipose tissue and metabolic complications of obesity are reduced in Prader–Willi syndrome female adults: evidence for novel influences on body fat distribution. J. Clin. Endocrinol. Metab. 86, 4330–4338 (2001)

    Article  CAS  PubMed  Google Scholar 

  34. L. Purtell, L. Sze, G. Loughnan et al., In adults with Prader–Willi syndrome, elevated ghrelin levels are more consistent with hyperphagia than high PYY and GLP-1 levels. Neuropeptides 4, 301–307 (2011)

    Article  Google Scholar 

  35. A. De Silva, S.R. Bloom, Gut hormones and appetite control: a focus on PYY and GLP-1 as therapeutic targets in obesity. Gut Liver 6, 10–20 (2012)

    Article  PubMed Central  PubMed  Google Scholar 

  36. J.L. Chan, V. Stoyneva, T. Kelesidis, P. Raciti, C.S. Mantzoros, Peptide YY levels are decreased by fasting and elevated following caloric intake but are not regulated by leptin. Diabetologia 49, 169–173 (2006)

    Article  CAS  PubMed  Google Scholar 

  37. M. Korbonits, P.J. Trainer, J.A. Little et al., Leptin levels do not change acutely with food administration in normal or obese subjects, but are negatively correlated with pituitary-adrenal activity. Clin. Endocrinol. (Oxf.) 46, 751–757 (1997)

    Article  CAS  Google Scholar 

  38. M. Romon, P. Lebel, J.C. Fruchart, J. Dallongeville, Postprandial leptin response to carbohydrate and fat meals in obese women. J. Am. Coll. Nutr. 22, 247–251 (2003)

    Article  PubMed  Google Scholar 

  39. J. Dallongeville, B. Hecquet, P. Lebel et al., Short term response of circulating leptin to feeding and fasting in man: influence of circadian cycle. Int. J. Obes. Relat. Metab. Disord. 22, 728–733 (1998)

    Article  CAS  PubMed  Google Scholar 

  40. I.S. Farooqi, G. Matarese, G.M. Lord et al., Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J. Clin. Invest. 110, 1093–1103 (2002)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. J. Levi, S.L. Gray, M. Speck et al., Acute disruption of leptin signaling in vivo leads to increased insulin levels and insulin resistance. Endocrinology 152, 3385–3395 (2011)

    Article  CAS  PubMed  Google Scholar 

  42. P.R. Flatt, C.J. Bailey, A.M. Cameron, B.J. Gould, Age effects on glycosylated blood proteins in lean and obese hyperglycaemic (ob/ob) mice. Diabetes Res. 3, 241–243 (1986)

    CAS  PubMed  Google Scholar 

  43. J. Seufert, T.J. Kieffer, J.F. Habener, Leptin inhibits insulin gene transcription and reverses hyperinsulinemia in leptin-deficient ob/ob mice. Proc. Natl. Acad. Sci. USA. 96, 674–679 (1999)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Y. Sun, M. Asnicar, P.K. Saha, L. Chan, R.G. Smith, Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice. Cell Metab. 3, 379–386 (2006)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by Imperial NIHR Biomedical Research Centre Grant (WPGA_P33399; P. F). Support of Dr Alex Blakemore during initial stages of this study and expert technical help of Mohsin Arshad is gratefully acknowledged. We thank the participating family members for their cooperation.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Genomics of Common Disease, Hammersmith Hospital, Imperial College London, Burlington-Danes Building, Du Cane Road, London, W12 0NN, UK

    Sadia Saeed, Mario Falchi & Philippe Froguel

  2. Department of Medicine, Hammersmith Hospital, Imperial College London, London, W12 0NN, UK

    Paul R. Bech, Mohammad A. Ghatei & Stephen R. Bloom

  3. Medical Special Unit, Division of Medicine, Services Hospital, Lahore, 54000, Pakistan

    Tayyaba Hafeez

  4. Centre for Research in Molecular Medicine, University of Lahore, Lahore, 5400, Pakistan

    Rabail Alam & Muhammad Arslan

  5. Department of Biological Sciences, Forman Christian College (A Chartered University), Armacost Building, Lahore, 54600, Pakistan

    Muhammad Arslan

  6. Centre National de la Recherche Scientifique, University Lille North of France, Pasteur Institute, 59000, Lille, France

    Philippe Froguel

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  1. Sadia Saeed
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Correspondence to Muhammad Arslan or Philippe Froguel.

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Saeed, S., Bech, P.R., Hafeez, T. et al. Changes in levels of peripheral hormones controlling appetite are inconsistent with hyperphagia in leptin-deficient subjects. Endocrine 45, 401–408 (2014). https://doi.org/10.1007/s12020-013-0009-9

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  • DOI: https://doi.org/10.1007/s12020-013-0009-9

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