The weight loss resistance phenomenon
Groundbreaking international study finds that even those who don’t lose weight can gain significant metabolic health benefits, offering a new, more inclusive definition of success in lifestyle interventions
An innovative study conducted by researchers from Ben-Gurion University of the Negev (BGU), Harvard T.H. Chan School of Public Health, and Leipzig University Medical Center is challenging decades of conventional wisdom around what defines success in dieting and lifestyle interventions. For too long, weight loss has been viewed as the ultimate goal—but what happens when individuals stick to the plan, adopt healthier habits, and still don’t lose weight?
These so-called “weight loss resistant” individuals—often sidelined or labeled as failures—are finally getting scientific attention. And the message is clear: their bodies may still be transforming in crucial and measurable ways.
Published in The European Journal of Preventive Cardiology in June 2025, the study presents a pooled analysis of 761 participants from three landmark long-term randomized controlled trials: DIRECT, CENTRAL, and DIRECT PLUS. Participants were followed over 18 to 24 months to assess how different bodies respond to structured lifestyle interventions. While one-third of participants achieved clinically significant weight loss (defined as losing more than 5% of their initial body weight), another third lost between 0–5%. Strikingly, 28% of participants—despite high adherence—did not lose weight at all or even gained some. Yet, these so-called “resistant” individuals experienced notable improvements in key health markers.
Compared to their peers, these weight loss resistant individuals were slightly older and more often women. Despite no visible weight change, they showed significant internal improvements: higher HDL (“good”) cholesterol, lower leptin levels, and reduced visceral and liver fat—as assessed through magnetic resonance imaging (MRI). These are deep metabolic shifts with real cardiometabolic consequences.
“This reframes how we define clinical success,” says Dr. Anat Yaskolka Meir, the study’s first author, a registered dietitian and postdoctoral researcher at Harvard T.H. Chan School of Public Health. “We have been conditioned to equate weight loss with health, but our findings prove that’s not the whole picture. Even people who do not lose weight can improve their metabolism and reduce their long-term risk for disease. That’s a message of hope, not failure.”
The research team categorized participants into three groups: successful weight loss responders (>5% loss), moderate responders (0–5%), and weight loss resistant (≤0%). Even moderate responders showed marked improvements across health indicators such as waist circumference, triglycerides, insulin resistance, blood pressure, and liver enzymes.
To explain the variability in outcomes, the team also integrated innovative omics tools, including DNA methylation, proteomics, and metabolomics. Twelve specific DNA methylation sites emerged as strong predictors of successful long-term weight loss, yielding a predictive AUC of 0.73. This novel finding opens the door to personalized nutrition and more tailored lifestyle interventions in the future.
“This population is often ignored, misunderstood, or dismissed,” said Dr. Gal Tsaban, co-first author, cardiologist, and clinical researcher at BGU’s Faculty of Health Sciences and the Mayo Clinic. “But our study shows that lifestyle change works, even when the weight doesn’t shift. The body responds in deeper, subtler, and profoundly meaningful ways.”
What makes this study particularly powerful is its unique pooled design, bringing together three rigorously conducted, workplace-based clinical trials in Israel with high adherence rates and comprehensive metabolic profiling. Participants were randomized to dietary interventions including low-fat, low-carbohydrate, Mediterranean, and green-Mediterranean diets—yet across all approaches, the pattern of weight loss resistance and metabolic gain remained consistent.
“Some people are biologically wired to respond differently to the same diet,” said Prof. Iris Shai, principal investigator of the DIRECT, CENTRAL, and DIRECT PLUS trials, and professor of nutrition at Ben-Gurion University and adjunct professor at Harvard Chan School. “This isn’t just about willpower or discipline—it’s about biology. And now we’re getting close to understanding it.” Shai adds: “This is more than a scientific insight—it’s a public health message. We must stop equating the scale with success. Everyone who embraces healthier habits deserves to know that their body is likely improving—even if the mirror doesn’t reflect it.”
As the field of cardiometabolic prevention evolves, this research offers a more inclusive and empowering perspective on what it means to live healthfully. Not every journey shows up on the scale. But every healthy change counts.
Funding:
The study was supported by the German Research Foundation (DFG)—Project number 209933838—through the Collaborative Research Center SFB1052 “Obesity Mechanisms,” with specific support for Prof. Iris Shai (B11) and Prof. Matthias Blüher (B1).
Authorship and Institutional Collaboration:
This collaborative study brought together a diverse team of international researchers across medicine, epidemiology, nutrition, and systems biology.
From Ben-Gurion University of the Negev (BGU), Israel, the lead institution, contributors included Iris Shai (Principal Investigator), Anat Yaskolka Meir, Gal Tsaban, Ehud Rinott, Hila Zelicha, Dan Schwarzfuchs, and Yftach Gepner. Additional contributors from BGU included Assaf Rudich and Ilan Shelef.
From Harvard T.H. Chan School of Public Health and Harvard Medical School, USA, the team included Frank Hu, Meir Stampfer, Dong D. Wang, and Liming Liang. From Leipzig University Medical Center and Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG), Germany, key contributors were Matthias Blüher, Nora Klöting, Maria Keller, Peter Kovacs, and Michael Stumvoll. Supporting molecular and laboratory analyses were conducted by Uta Ceglarek and Berend Isermann from the Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics at Leipzig. Additionally, the international team was joined by Lu Qi from Tulane University, School of Public Health and Tropical Medicine, USA, further enhancing the study’s expertise in nutritional epidemiology.
