Obesity Endotypes Unmask Heterogeneous Responses to Healthy Lifestyle Behaviors
- 1Broad Institute of MIT and Harvard
Abstract
BackgroundLifestyle interventions are central to obesity prevention and management, yet interindividual variability in response remains incompletely understood. Here, we leveraged genetically defined, distinct obesity endotypes to examine lifestyle-body mass index (BMI) associations across biological pathways.
MethodsIn the UK Biobank, we analyzed 305,713 participants with partitioned polygenic scores (pPSs) representing 10 obesity endotypes. We evaluated interactions between endotype-specific genetic susceptibility and physical activity, diet, sedentary behavior, and sleep on BMI using multivariable linear regression. Primary findings were externally evaluated in the All of Us Research Program using Fitbit-derived lifestyle measures.
ResultsFavorable lifestyle behaviors were associated with lower BMI for all obesity endotypes, but the magnitude of these associations varied significantly across endotypes. Higher endotype-specific pPSs strengthened the benefits of physical activity (7 endotypes), healthy diet (3 endotypes), nonsedentary behavior (5 endotypes), and adequate sleep (7 endotypes) on BMI. Distinct endotypes demonstrated the greatest responsiveness to different lifestyle domains, with the metabolically unhealthy endotype showing the strongest interaction with physical activity, metabolically healthy endotype with sedentary behavior, hypothalamic dysregulation endotype with diet, and hypoinsulin 2 endotype with sleep, corresponding to differences in BMI of 0.22-0.49 kg/m{superscript 2} between the highest and lowest pPS deciles. These interaction patterns were consistent in the All of Us cohort.
ConclusionsObesity endotypes modify the association between lifestyle behaviors and BMI, demonstrating that responsiveness to lifestyle behaviors is heterogeneous and pathway dependent. These findings provide a framework for precision obesity prevention by identifying individuals who may derive greater benefit from specific lifestyle interventions.
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BibTeX
@misc{malik2026obesity,
title = {{Obesity Endotypes Unmask Heterogeneous Responses to Healthy Lifestyle Behaviors}},
author = {D. Malik and M. S. Kim and I. Shim and Y. Sui and R. Abou-Karam and M. Song and H.-H. Won and P. Natarajan and P. T. Ellinor and A. C. Fahed},
howpublished = {medRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.25.26361367},
url = {https://www.medrxiv.org/content/10.64898/2026.08.25.26361367v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Obesity Endotypes Unmask Heterogeneous Responses to Healthy Lifestyle Behaviors
AU - D. Malik
AU - M. S. Kim
AU - I. Shim
AU - Y. Sui
AU - R. Abou-Karam
AU - M. Song
AU - H.-H. Won
AU - P. Natarajan
AU - P. T. Ellinor
AU - A. C. Fahed
PY - 2026
DA - 2026/08/25
PB - medRxiv
DO - 10.64898/2026.08.25.26361367
UR - https://www.medrxiv.org/content/10.64898/2026.08.25.26361367v1
AB - BackgroundLifestyle interventions are central to obesity prevention and management, yet interindividual variability in response remains incompletely understood. Here, we leveraged genetically defined, distinct obesity endotypes to examine lifestyle-body mass index (BMI) associations across biological pathways. MethodsIn the UK Biobank, we analyzed 305,713 participants with partitioned polygenic scores (pPSs) representing 10 obesity endotypes. We evaluated interactions between endotype-specific genetic susceptibility and physical activity, diet, sedentary behavior, and sleep on BMI using multivariable linear regression. Primary findings were externally evaluated in the All of Us Research Program using Fitbit-derived lifestyle measures. ResultsFavorable lifestyle behaviors were associated with lower BMI for all obesity endotypes, but the magnitude of these associations varied significantly across endotypes. Higher endotype-specific pPSs strengthened the benefits of physical activity (7 endotypes), healthy diet (3 endotypes), nonsedentary behavior (5 endotypes), and adequate sleep (7 endotypes) on BMI. Distinct endotypes demonstrated the greatest responsiveness to different lifestyle domains, with the metabolically unhealthy endotype showing the strongest interaction with physical activity, metabolically healthy endotype with sedentary behavior, hypothalamic dysregulation endotype with diet, and hypoinsulin 2 endotype with sleep, corresponding to differences in BMI of 0.22-0.49 kg/m{superscript 2} between the highest and lowest pPS deciles. These interaction patterns were consistent in the All of Us cohort. ConclusionsObesity endotypes modify the association between lifestyle behaviors and BMI, demonstrating that responsiveness to lifestyle behaviors is heterogeneous and pathway dependent. These findings provide a framework for precision obesity prevention by identifying individuals who may derive greater benefit from specific lifestyle interventions.
ER -