Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Technical Report
  • Published:

Techniques and Methods

Challenges of considering both extremities of the weight status spectrum to better understand obesity: insights from the NUTRILEAN project in constitutionally thin individuals

International Journal of Obesity volume 47, pages 1171–1177 (2023)Cite this article

Subjects

Abstract

Background/Objectives

While the physiology of obesity has been so extensively investigated to date, only an extremely small number of studies (less than 50) have focused on the other extremity of the weight spectrum: constitutional thinness. Yet, this important state of underweight in the absence of any eating disorders provides a mirror model of obesity that might be particularly insightful in understanding obesity. Nevertheless, important methodological and recruitment-related issues appear when it comes to this complex constitutionally thin phenotype, as experienced by our research group with the realization of the ongoing NUTRILEAN clinical trial. To face this challenge, the present paper aims at identifying, analyzing, and discussing the quality of such recruitment processes in publications about constitutional thinness.

Methods

In this order, a group of experts collectively created a new grading system to assess the level of rigour and quality achieved by each study based on different criteria.

Results

The main results were that (i) metabolic-related biasing criteria were poorly observed despite being crucial, (ii) recruitment processes were not detailed enough and with sufficient explicitness, and (iii) recruiting among already identified patients would be associated with both higher sample sizes and better scores of quality.

Conclusions

The present work encourages investigators to adopt a high level of rigour despite the complexity and duration of recruitment processes for this specific population, and readers to pay close attention to the quality of recruitment when interpreting the data. To better understand obesity and its physiological adaptations, it seems essential not only to compare it to normal-weight conditions, but also to the other extremity of the weight status spectrum represented by constitutional thinness.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Heatmap of the evaluation of quality scores in the inclusion process of participants with constitutional thinness in clinical trials.
Fig. 2: A real challenge to recruit participants with constitutional thinness: insights from the NUTRILEAN study.
Fig. 3: Differentiating between two types of recruitment processes in studies on constitutional thinness: effect on the number of enrolled participants and the recruitment quality.

Similar content being viewed by others

Data availability

Data generated or analyzed during this study are available from the corresponding author upon request.

References

  1. Griffin HJ, O’Connor HT, Rooney KB, Steinbeck KS. Effectiveness of strategies for recruiting overweight and obese Generation Y women to a clinical weight management trial. Asia Pac J Clin Nutr. 2013;22:235–40.

    PubMed  Google Scholar 

  2. Bergmann S, Keitel-Korndörfer A, Herfurth-Majstorovic K, Wendt V, Klein AM, von Klitzing K, et al. Recruitment strategies in a prospective longitudinal family study on parents with obesity and their toddlers. BMC Public Health. 2017;17:145.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Riveros-McKay F, Mistry V, Bounds R, Hendricks A, Keogh JM, Thomas H, et al. Genetic architecture of human thinness compared to severe obesity. PLoS Genet. 2019;15:e1007603.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Diaz EO, Prentice AM, Goldberg GR, Murgatroyd PR, Coward WA. Metabolic response to experimental overfeeding in lean and overweight healthy volunteers. Am J Clin Nutr. 1992;56:641–55.

    Article  CAS  PubMed  Google Scholar 

  5. Schneider L, Heard I, Bréart G, Henrion R. [Maternal thinness and pregnancy]. Arch Fr Pediatr. 1979;36:1068–74.

    CAS  PubMed  Google Scholar 

  6. van Binsbergen CJ, Coelingh Bennink HJ, Odink J, Haspels AA, Koppeschaar HP. A comparative and longitudinal study on endocrine changes related to ovarian function in patients with anorexia nervosa. J Clin Endocrinol Metab. 1990;71:705–11.

    Article  PubMed  Google Scholar 

  7. Petretta M, Bonaduce D, Scalfi L, de Filippo E, Marciano F, Migaux ML, et al. Heart rate variability as a measure of autonomic nervous system function in anorexia nervosa. Clin Cardiol. 1997;20:219–24.

    Article  CAS  PubMed  Google Scholar 

  8. Hinney A, Barth N, Ziegler A, von Prittwitz S, Hamann A, Hennighausen K, et al. Serotonin transporter gene-linked polymorphic region: allele distributions in relationship to body weight and in anorexia nervosa. Life Sci. 1997;61:PL 295–303.

    Article  CAS  PubMed  Google Scholar 

  9. Scalfi L, Coltorti A, Borrelli R, Contaldo F. Postprandial thermogenesis in leanness and anorexia nervosa. Ann Nutr Metab. 1992;36:48–54.

    Article  CAS  PubMed  Google Scholar 

  10. Mazzeo SE, Slof RM, Tozzi F, Kendler KS, Bulik CM. Characteristics of men with persistent thinness. Obes Res. 2004;12:1367–9.

    Article  PubMed  Google Scholar 

  11. Bosy-Westphal A, Reinecke U, Schlörke T, Illner K, Kutzner D, Heller M, et al. Effect of organ and tissue masses on resting energy expenditure in underweight, normal weight and obese adults. Int J Obes Relat Metab Disord. 2004;28:72–79.

    Article  CAS  PubMed  Google Scholar 

  12. Slof R, Mazzeo S, Bulik CM. Characteristics of women with persistent thinness. Obes Res. 2003;11:971–7.

    Article  PubMed  Google Scholar 

  13. Miljic D, Pekic S, Djurovic M, Doknic M, Milic N, Casanueva FF, et al. Ghrelin has partial or no effect on appetite, growth hormone, prolactin, and cortisol release in patients with anorexia nervosa. J Clin Endocrinol Metab. 2006;91:1491–5.

    Article  CAS  PubMed  Google Scholar 

  14. Miljic D, Djurovic M, Pekic S, Doknic M, Stojanovic M, Milic N, et al. Glucose metabolism during ghrelin infusion in patients with anorexia nervosa. J Endocrinol Invest. 2007;30:771–5.

    Article  CAS  PubMed  Google Scholar 

  15. Fernández-García D, Rodríguez M, García Alemán J, García-Almeida JM, Picón MJ, Fernández-Aranda F, et al. Thin healthy women have a similar low bone mass to women with anorexia nervosa. Br J Nutr. 2009;102:709–14.

    Article  PubMed  Google Scholar 

  16. Tagami T, Satoh N, Usui T, Yamada K, Shimatsu A, Kuzuya H. Adiponectin in anorexia nervosa and bulimia nervosa. J Clin Endocrinol Metab. 2004;89:1833–7.

    Article  CAS  PubMed  Google Scholar 

  17. Tolle V, Kadem M, Bluet-Pajot M-T, Frere D, Foulon C, Bossu C, et al. Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women. J Clin Endocrinol Metab. 2003;88:109–16.

    Article  CAS  PubMed  Google Scholar 

  18. Marra M, Pasanisi F, Montagnese C, De Filippo E, De Caprio C, de Magistris L, et al. BMR variability in women of different weight. Clin Nutr. 2007;26:567–72.

    Article  PubMed  Google Scholar 

  19. Marra M, Caldara A, Montagnese C, De Filippo E, Pasanisi F, Contaldo F, et al. Bioelectrical impedance phase angle in constitutionally lean females, ballet dancers and patients with anorexia nervosa. Eur J Clin Nutr. 2009;63:905–8.

    Article  CAS  PubMed  Google Scholar 

  20. Germain N, Galusca B, Le Roux CW, Bossu C, Ghatei MA, Lang F, et al. Constitutional thinness and lean anorexia nervosa display opposite concentrations of peptide YY, glucagon-like peptide 1, ghrelin, and leptin. Am J Clin Nutr. 2007;85:967–71.

    Article  CAS  PubMed  Google Scholar 

  21. Germain N, Galusca B, Grouselle D, Frere D, Tolle V, Zizzari P, et al. Ghrelin/obestatin ratio in two populations with low bodyweight: constitutional thinness and anorexia nervosa. Psychoneuroendocrinology. 2009;34:413–9.

    Article  CAS  PubMed  Google Scholar 

  22. Bossu C, Galusca B, Normand S, Germain N, Collet P, Frere D, et al. Energy expenditure adjusted for body composition differentiates constitutional thinness from both normal subjects and anorexia nervosa. Am J Physiol Endocrinol Metab. 2007;292:E132–137.

    Article  CAS  PubMed  Google Scholar 

  23. Galusca B, Zouch M, Germain N, Bossu C, Frere D, Lang F, et al. Constitutional thinness: unusual human phenotype of low bone quality. J Clin Endocrinol Metab. 2008;93:110–7.

    Article  CAS  PubMed  Google Scholar 

  24. Estour B, Marouani N, Sigaud T, Lang F, Fakra E, Ling Y, et al. Differentiating constitutional thinness from anorexia nervosa in DSM 5 era. Psychoneuroendocrinology. 2017;84:94–100.

    Article  PubMed  Google Scholar 

  25. Orthofer M, Valsesia A, Mägi R, Wang Q-P, Kaczanowska J, Kozieradzki I, et al. Identification of ALK in Thinness. Cell. 2020;181:1246–1262.e22.

    Article  CAS  PubMed  Google Scholar 

  26. Bang EB, Ko JK, Kwag KH, Lee GY, Kim Y-R. A comparison of patients with anorexia nervosa and women who are constitutionally thin. Eur Eat Disord Rev. 2020;28:633–42.

    Article  PubMed  Google Scholar 

  27. Florent V, Baroncini M, Jissendi-Tchofo P, Lopes R, Vanhoutte M, Rasika S, et al. Hypothalamic structural and functional imbalances in anorexia nervosa. Neuroendocrinology. 2019;110:552–62.

    Article  PubMed  Google Scholar 

  28. Margaritelis NV, Theodorou AA, Kyparos A, Nikolaidis MG, Paschalis V. Effect of body composition on redox homeostasis at rest and in response to exercise: the case of underfat women. J Sports Sci. 2019;37:1–8.

    Article  Google Scholar 

  29. Marra M, Sammarco R, De Filippo E, De Caprio C, Speranza E, Contaldo F, et al. Resting energy expenditure, body composition and phase angle in anorectic, ballet dancers and constitutionally lean males. Nutrients. 2019;11:502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hasegawa A, Usui C, Kawano H, Sakamoto S, Higuchi M. Characteristics of body composition and resting energy expenditure in lean young women. J Nutr Sci Vitaminol. 2011;57:74–79.

    Article  CAS  PubMed  Google Scholar 

  31. Paschalis V, Nikolaidis MG, Theodorou AA, Deli CK, Raso V, Jamurtas AZ, et al. The effects of eccentric exercise on muscle function and proprioception of individuals being overweight and underweight. J Strength Cond Res. 2013;27:2542–51.

    Article  PubMed  Google Scholar 

  32. Pasanisi F, Pace L, Fonti R, Marra M, Sgambati D, De Caprio C, et al. Evidence of brown fat activity in constitutional leanness. J Clin Endocrinol Metabol. 2013;98:1214–8.

    Article  CAS  Google Scholar 

  33. Santonicola A, Siniscalchi M, Capone P, Gallotta S, Ciacci C, Iovino P. Prevalence of functional dyspepsia and its subgroups in patients with eating disorders. World J Gastroenterol. 2012;18:4379–85.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Galusca B, Verney J, Meugnier E, Ling Y, Edouard P, Feasson L, et al. Reduced fibre size, capillary supply and mitochondrial activity in constitutional thinness’ skeletal muscle. Acta Physiol. 2018;224:e13097.

    Article  CAS  Google Scholar 

  35. Germain N, Viltart O, Loyens A, Bruchet C, Nadin K, Wolowczuk I, et al. Interleukin-7 plasma levels in human differentiate anorexia nervosa, constitutional thinness and healthy obesity. PLoS ONE. 2016;11:e0161890.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Galusca B, Jeandel L, Germain N, Alexandre D, Leprince J, Anouar Y, et al. Orexigenic neuropeptide 26RFa: new evidence for an adaptive profile of appetite regulation in anorexia nervosa. J Clin Endocrinol Metab. 2012;97:2012–8.

    Article  CAS  PubMed  Google Scholar 

  37. Gunes A, Yıldırım Bas F, Arslan B, Tok L, Tok Ö, Salman Z. Assessment of corneal parameters in patients with constitutional thinness using scheimpflug imaging. Semin Ophthalmol. 2016;33:175–8.

    PubMed  Google Scholar 

  38. Galusca B, Prévost G, Germain N, Dubuc I, Ling Y, Anouar Y, et al. Neuropeptide Y and α-MSH circadian levels in two populations with low body weight: anorexia nervosa and constitutional thinness. PLoS ONE. 2015;10:e0122040.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Ling Y, Carayol J, Galusca B, Canto C, Montaurier C, Matone A, et al. Persistent low body weight in humans is associated with higher mitochondrial activity in white adipose tissue. Am J Clin Nutr. 2019;110:605–16.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Ling Y, Galusca B, Martin F-P, Bartova S, Carayol J, Moco S, et al. Resistance to lean mass gain in constitutional thinness in free-living conditions is not overpassed by overfeeding. J Cachexia Sarcopenia Muscle. 2020;11:1187–99.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Bailly M, Germain N, Féasson L, Costes F, Estour B, Hourdé C, et al. Skeletal muscle of females and males with constitutional thinness: a low intramuscular lipid content and oxidative profile. Appl Physiol Nutr Metab. 2020;45:1287–98.

    Article  CAS  PubMed  Google Scholar 

  42. Bailly M, Boscaro A, Thomas T, Féasson L, Costes F, Pereira B, et al. New insights on bone tissue and structural muscle-bone unit in constitutional thinness. Front Physiol. 2022;13:921351.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Gabriel T, Massoubre C, Hanachi M, Doré J, Lambert C, Germain N, et al. Association of gut-specific non-inflammatory T lymphocytes with chronic anorexia nervosa and constitutional thinness. Eur Eat Disord Rev. 2022. https://doi.org/10.1002/erv.2934.

  44. Cominetti O, Núñez Galindo A, Corthésy J, Carayol J, Germain N, Galusca B, et al. Proteomics reveals unique plasma signatures in constitutional thinness. Proteomics Clin Appl. 2022;16:e2100114.

    Article  PubMed  Google Scholar 

  45. Germain N, Galusca B, Caron-Dorval D, Martin J-F, Pujos-Guillot E, Boirie Y, et al. Specific appetite, energetic and metabolomics responses to fat overfeeding in resistant-to-bodyweight-gain constitutional thinness. Nutr Diabetes. 2014;4:e126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. World Health Organization. Prevalence of underweight among adults. 2020. https://www.who.int/data/gho/data/indicators/indicator-details/GHO/prevalence-of-underweight-among-adults-bmi-18-(crude-estimate)-(-). Accessed 20 Mar 2020.

  47. Estour B, Galusca B, Germain N. Constitutional thinness and anorexia nervosa: a possible misdiagnosis? Front Endocrinol. 2014;5:175.

    Article  Google Scholar 

  48. Bailly M, Germain N, Galusca B, Courteix D, Thivel D, Verney J. Definition and diagnosis of constitutional thinness: a systematic review. Br J Nutr. 2020;124:531–47.

    Article  CAS  PubMed  Google Scholar 

  49. Bailly M, Boscaro A, Pereira B, Féasson L, Boirie Y, Germain N, et al. Is constitutional thinness really different from anorexia nervosa? A systematic review and meta-analysis. Rev Endocr Metab Disord. 2021. https://doi.org/10.1007/s11154-021-09650-4.

  50. Bailly M, Boscaro A, Pereira B, Courteix D, Germain N, Galusca B, et al. Underweight but not underfat: is fat-free mass a key factor in constitutionally thin women? Eur J Clin Nutr. 2021;75:1764–70.

    Article  CAS  PubMed  Google Scholar 

  51. Estour B, Galusca B, Germain N. [Constitutional thinness]. Corresp Métab Horm Diabètes Nutr. 2012;XVI:109–14.

    Google Scholar 

  52. Estour B, Galusca B, Germain N. [Constitutional thinness]. Cah Nutr Diét. 2013;48:26–32.

    Article  Google Scholar 

  53. Estour B, Galusca B, Germain N. Thinness, weight loss and constitutional thinness. Med Mal Metab. 2016;10:10–15.

    Google Scholar 

  54. Galusca B, Germain N, Estour B. Thinness, bone and fracture risk. Med Mal Metab. 2016;10:16–21.

    Google Scholar 

  55. Germain N, Galusca B, Estour B. Thinness and resistance to weight gain: a proof of concept. Med Mal Metab. 2016;10:28–33.

    Google Scholar 

  56. Galusca B, Germain N, Estour B. Maigreur et hormones de régulation de l’appétit. Méd Mal Métab. 2016;10:22–27.

    Google Scholar 

  57. Decker ST, Matias AA, Bannon ST, Madden JP, Alexandrou-Majaj N, Layec G. Effects of cigarette smoke on in situ mitochondrial substrate oxidation of slow- and fast-twitch skeletal muscles. Life Sci. 2023;315:121376.

    Article  CAS  PubMed  Google Scholar 

  58. Blauw LL, Boon MR, Rosendaal FR, de Mutsert R, Gast KB, Willems van Dijk K, et al. Smoking is associated with increased resting energy expenditure in the general population: the NEO study. Metabolism. 2015;64:1548–55.

    Article  CAS  PubMed  Google Scholar 

  59. Hellerstein MK, Benowitz NL, Neese RA, Schwartz JM, Hoh R, Jacob P, et al. Effects of cigarette smoking and its cessation on lipid metabolism and energy expenditure in heavy smokers. J Clin Invest. 1994;93:265–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Seoane-Collazo P, Romero-Picó A, Rial-Pensado E, Liñares-Pose L, Estévez-Salguero Á, Fernø J, et al. κ-Opioid signaling in the lateral hypothalamic area modulates nicotine-induced negative energy balance. Int J Mol Sci. 2021;22:1515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of the Metabolic Adaptations to Exercise under Physiological and Pathological Conditions (AME2P), UPR 3533, CRNH Auvergne, University of Clermont Auvergne, Clermont-Ferrand, France

    Audrey Boscaro, Julien Verney, David Thivel & Mélina Bailly

  2. Department of Kinesiology, Faculty of Medicine, Laval University, Quebec, QC, Canada

    Angelo Tremblay

  3. National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK

    James A. King

  4. NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and the University of Leicester, Leicester, UK

    James A. King

  5. Biostatistics Unit, Délégation à la Recherche Clinique et à l’Innovation (DRCI), Clermont-Ferrand, France

    Bruno Pereira

  6. Department of Sport Medicine and Functional Explorations, University Teaching Hospital of Clermont-Ferrand, Diet and Musculoskeletal Health Team, CRNH, INRA, University of Clermont Auvergne, Clermont-Ferrand, France

    Frédéric Costes, Valérie Julian & Martine Duclos

  7. Department of Clinical Nutrition, University Teaching Hospital of Clermont-Ferrand, Diet and Musculoskeletal Health Team, CRNH, INRA, University of Clermont Auvergne, Clermont-Ferrand, France

    Yves Boirie

Authors
  1. Audrey Boscaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julien Verney
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angelo Tremblay
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James A. King
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bruno Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Frédéric Costes
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Valérie Julian
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Martine Duclos
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yves Boirie
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David Thivel
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mélina Bailly
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AB and MB contributed to writing the original draft and the review & editing. AB performed data curation. JAK and DT provided feedback in the writing review and editing process. MB, DT, JV, and AT conducted the conceptualization, investigation, and project administration. DT, JV and MB were responsible of the funding acquisition. BP was implied in formal analysis and methodological aspects. AT, FC, BJ, MD, and YB contributed to supervision, validation, resources and visualization.

Corresponding author

Correspondence to Audrey Boscaro.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Boscaro, A., Verney, J., Tremblay, A. et al. Challenges of considering both extremities of the weight status spectrum to better understand obesity: insights from the NUTRILEAN project in constitutionally thin individuals. Int J Obes 47, 1171–1177 (2023). https://doi.org/10.1038/s41366-023-01360-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-023-01360-y

Search

Advanced search

Quick links