This web page was created programmatically, to learn the article in its unique location you'll be able to go to the hyperlink bellow: https://www.medrxiv.org/content/10.64898/2026.08.25.26361367v1and if you wish to take away this text from our website please contact us [ad_1] AbstractBackground Lifestyle interventions are central to weight problems prevention and administration, but interindividual variability in response stays incompletely understood. Here, we leveraged genetically outlined, distinct weight problems endotypes to look at lifestyle-body mass index (BMI) associations throughout organic pathways. Methods In the UK Biobank, we analyzed 305,713 contributors with partitioned polygenic scores (pPSs) representing 10 weight problems endotypes. We evaluated interactions between endotype-specific genetic susceptibility and bodily exercise, weight-reduction plan, sedentary conduct, and sleep on BMI utilizing multivariable linear regression. Primary findings have been externally evaluated within the All of Us Research Program utilizing Fitbit-derived life-style measures. Results Favorable life-style behaviors have been related to decrease BMI for all weight problems endotypes, however the magnitude of those associations diversified considerably throughout endotypes. Higher endotype-specific pPSs strengthened the advantages of bodily exercise (7 endotypes), nutritious diet (3 endotypes), nonsedentary conduct (5 endotypes), and enough sleep (7 endotypes) on BMI. Distinct endotypes demonstrated the best responsiveness to completely different life-style domains, with the metabolically unhealthy endotype displaying the strongest interplay with bodily exercise, metabolically wholesome endotype with sedentary conduct, hypothalamic dysregulation endotype with weight-reduction plan, and hypoinsulin 2 endotype with sleep, akin to variations in BMI of 0.22-0.49 kg/m2 between the very best and lowest pPS deciles. These interplay patterns have been constant within the All of Us cohort. Conclusions Obesity endotypes modify the affiliation between life-style behaviors and BMI, demonstrating that responsiveness to life-style behaviors is heterogeneous and pathway dependent. These findings present a framework for precision weight problems prevention by figuring out people who could derive higher profit from particular life-style interventions.Competing Interest StatementDr. Sui stories serving as a marketing consultant from Arboretum Lifesciences. Dr. Abou-Karam stories serving as a marketing consultant for Goodpath. Dr. Natarajan stories investigator-initiated grants from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis; private charges from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Novartis, Roche / Genentech, is a co-founder of TenSixteen Bio, is a scientific advisory board member of Esperion Therapeutics, geneXwell, and TenSixteen Bio; and spousal employment at Vertex. Dr. Ellinor has obtained sponsored analysis help from Bayer AG and IBM Health, and he has served on advisory boards or consulted for Bayer AG, MyoKardia and Novartis. Dr. Fahed stories being co-founder of Goodpath and Avigena, serving as scientific advisor to MyOme, Arboretum Health, Novartis, and Aditum Bio and receiving sponsored analysis awards from Foresite, Sarepta Therapeutics, and Allelica. All different authors report no disclosures.Author DeclarationsI affirm all related moral pointers have been adopted, and any crucial IRB and/or ethics committee approvals have been obtained.YesThe particulars of the IRB/oversight physique that supplied approval or exemption for the analysis described are given under:The North West Multi-Centre Research Ethics Committee of the UK Biobank gave moral approval for this work. IRB of Massachusetts General Hospital gave moral approval for this work.I affirm that every one crucial affected person/participant consent has been obtained and the suitable institutional varieties have been archived, and that any affected person/participant/pattern identifiers included weren't identified to anybody (e.g., hospital employees, sufferers or contributors themselves) outdoors the analysis group so can't be used to establish people.YesI perceive that every one scientific trials and some other potential interventional research have to be registered with an ICMJE-approved registry, akin to ClinicalTrials.gov. I affirm that any such research reported within the manuscript has been registered and the trial registration ID is supplied (observe: if posting a potential research registered retrospectively, please present an announcement within the trial ID area explaining why the research was not registered prematurely).Yes I've adopted all applicable analysis reporting pointers, akin to any related EQUATOR Network analysis reporting guidelines(s) and different pertinent materials, if relevant.YesData AvailabilityAll knowledge produced within the current research can be found upon affordable request to the authors.Funder Information DeclaredSarnoff Cardiovascular Research Foundation, https://ror.org/04csczr47National Heart Lung and Blood Institute, https://ror.org/012pb6c26, R01HL142711, R01HL127564, R01HL148050, R01HL151283, R01HL148565, R01HL135242, R01HL151152, R01HL164629, K08HL161448National Research Foundation of Korea, https://ror.org/013aysd81, RS2023-00262527National Institute of Diabetes and Digestive and Kidney Diseases, https://ror.org/00adh9b73, R01DK125782National Human Genome Research Institute, https://ror.org/00baak391, U01HG011719Fondation Leducq, https://ror.org/01czwga19, TNE-18CVD04National Institutes of Health, https://ror.org/01cwqze88, 1RO1HL092577, 1R01HL157635, 5R01HL139731American Heart Association, https://ror.org/013kjyp64, 18SFRN34110082European Union, https://ror.org/019w4f821, MAESTRIA 965 286Massachusetts General Hospital, [ad_2] This web page was created programmatically, to learn the article in its unique location you'll be able to go to the hyperlink bellow: https://www.medrxiv.org/content/10.64898/2026.08.25.26361367v1and if you wish to take away this text from our website please contact us