Skip to main content

Thank you for visiting 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.

An integrated model of obesity pathogenesis that revisits causal direction

Weight gain indicates a positive energy balance, with calorie intake exceeding expenditure. However, this fact of physics cannot inform causality. Potential pathways to obesity include a positive energy balance that drives weight gain or weight gain that drives the positive energy balance. Here, we propose an integrated model of obesity pathogenesis that incorporates both pathways.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: An integrated model of obesity pathogenesis.


  1. Sørensen, T. I. A. Challenges in the study of causation of obesity. Proc. Nutr. Soc. 68, 43–54 (2009).

    Article  Google Scholar 

  2. Schwartz, M. W. et al. Obesity pathogenesis: an endocrine society scientific statement. Endocr. Rev. 38, 267–296 (2017).

    Article  Google Scholar 

  3. Hill, J. O. Understanding and addressing the epidemic of obesity: an energy balance perspective. Endocr. Rev. 27, 750–761 (2006).

    Article  Google Scholar 

  4. Roberts, S. B. et al. Energy expenditure and subsequent nutrient intakes in overfed young men. Am. J. Physiol. 259, R461–R469 (1990).

    CAS  PubMed  Google Scholar 

  5. Friedman, M. I. Fuel partitioning and food intake. Am. J. Clin. Nutr. 67, 513S–518S (1998).

    CAS  Article  Google Scholar 

  6. Lustig, R. H. Childhood obesity: behavioral aberration or biochemical drive? Reinterpreting the First Law of Thermodynamics. Nat. Clin. Pract. Endocrinol. Metab. 2, 447–458 (2006).

    CAS  Article  Google Scholar 

  7. Ludwig, D. S. et al. The carbohydrate–insulin model: a physiological perspective on the obesity pandemic. Am. J. Clin. Nutr. 114, 1873–1885 (2021).

    Article  Google Scholar 

  8. Pawlak, D. B., Kushner, J. A. & Ludwig, D. S. Effects of dietary glycaemic index on adiposity, glucose homoeostasis, and plasma lipids in animals. Lancet 364, 778–785 (2004).

    CAS  Article  Google Scholar 

  9. Hjorth, M. F., Zohar, Y., Hill, J. O. & Astrup, A. Personalized dietary management of overweight and obesity based on measures of insulin and glucose. Annu. Rev. Nutr. 38, 245–272 (2018).

    CAS  Article  Google Scholar 

  10. Malik, V. S., Schulze, M. B. & Hu, F. B. Intake of sugar-sweetened beverages and weight gain: a systematic review. Am. J. Clin. Nutr. 84, 274–288 (2006).

    CAS  Article  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding authors

Correspondence to David S. Ludwig or Thorkild I. A. Sørensen.

Ethics declarations

Competing interests

D.S.L. received royalties for books that recommend a carbohydrate-modified diet; his spouse owns a nutrition education and consulting business. T.I.A.S. declares no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ludwig, D.S., Sørensen, T.I.A. An integrated model of obesity pathogenesis that revisits causal direction. Nat Rev Endocrinol 18, 261–262 (2022).

Download citation

  • Published:

  • Issue Date:

  • DOI:


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing