Why some people can’t lose weight even when they follow the rules

By Hugo Francisco de SouzaReviewed by Lauren HardakerJan 13 2026

Even under strict supervision, some bodies resist weight loss. New research explains why biology, not effort, may determine who benefits from diet and exercise.

Study: About Unsuccessful Responders to Diet and Physical Activity Interventions: A Focus on Energy Balance and Body-Weight Loss. Image credit: Freebird7977/Shutterstock.com

In a recent review published in Nutrients, researchers reviewed evidence from controlled interventions and the broader scientific literature, including classic metabolic-ward and supervised exercise trials, to explain why some patients with obesity or metabolic conditions demonstrate “unsuccessful responder” phenotypes, the inability to lose weight or the manifestation of adverse metabolic effects despite adequate adherence to diet and exercise guidelines.

The review found that between 5 % and 20 % of individuals display the unsuccessful responder phenotype. Evaluation of biological, genetic, and environmental mechanisms that contribute to this resistance suggests that factors beyond effort or willpower, including biological responses, can significantly influence observed outcomes, even when lifestyle recommendations are followed as prescribed.

Rethinking adherence as the sole driver of weight loss

The inability of an overweight or obese individual to lose weight has traditionally been attributed to a lack of adherence, “willpower failure”. The prevailing assumption, both in clinical and fitness settings, for example, gyms, is that if a patient is not losing weight, they must be deviating from an established intervention protocol, skipping workouts, or underreporting food intake.

While several studies have established the importance of adherence in achieving positive physiological outcomes, a growing body of literature diverges from this “compliance-centric” approach, instead suggesting that human bodies do not all process energy deficits in the same manner, and that weight loss is only one of several possible health outcomes.

Researchers have now identified two subgroups of individuals that experience poor outcomes despite documented or closely monitored intervention adherence: “unsuccessful responders”, who fail to lose weight, and “adverse responders”, who experience worsening health markers, under conditions where adherence was closely supervised or, in some cases, extreme weight gain was practically impossible.

Unfortunately, a synthesis clarifying the prevalence of these phenotypes and the magnitude of individual differences when living conditions are strictly controlled remains lacking.

Evidence from tightly controlled diet and exercise interventions

The present review aims to address this knowledge gap, thereby informing future clinical and social policy by highlighting findings from several landmark clinical trials and physiological studies in which adherence was carefully monitored or enforced through supervision or metabolic ward confinement.

The review draws particular attention to evidence from well-controlled intervention models, thereby allowing for the isolation of biological resistance from behavioral non-compliance.

1. Monozygotic twin studies: Identical twins were housed in metabolic wards and subjected to precise energy deficits and supervised exercise for 100 days to measure genetic variance in weight loss.

2. The HERITAGE family study: A trial involving a 20-week exercise program in free-living participants, with all training sessions supervised and intensity and duration monitored by specialists to minimize non-adherence.

3. The PREVIEW study: A multinational trial involving over 2,000 participants who began with a supervised LED, Low-Energy Diet, designed to induce rapid weight loss, during which weight gain was practically impossible.

4. “The Biggest Loser” analysis: A study tracking competitors from a televised weight-loss competition to measure long-term metabolic adaptation, changes in resting metabolic rate, six years after the competition.

Wide biological variation persists despite identical energy deficits

The review revealed significant inter-patient variability in biologically determined weight retention or metabolic distress. For example, in the twin studies, despite all participants adhering to a daily energy deficit of approximately 1,000 kcal for 100 days, weight loss ranged dramatically from 1 kg to 8 kg.

Notably, these responses were observed to be highly similar within twin pairs, confirming that the body’s reaction to a negative energy balance is partially influenced by genetics.

Analyses of the PREVIEW study revealed that approximately 10.2 % of women and 7.9 % of men were classified as unsuccessful responders, despite comparable attendance at supervision meetings and similar levels of program engagement, although some individuals may still have experienced improvements in fitness or other health indicators despite limited weight loss. Even more concerning were the “adverse responders” in the HERITAGE study. About 8 % to 13 % of participants demonstrated a deterioration in cardiometabolic risk factors beyond expected measurement variability, blood pressure, triglycerides, insulin, and HDL cholesterol, after strictly supervised exercise.

The review further explains the mechanism of “adaptive thermogenesis”, or the slowing of metabolism beyond what is expected from weight tissue loss alone. Data from “The Biggest Loser” study revealed that competitors experienced a drop in resting metabolic rate (RMR) of 610 kcal per day following the competition. Alarmingly, six years later, despite significant weight regain, their RMRs did not recover. Instead, the gap between predicted and measured RMR, adaptive thermogenesis, increased to approximately 704 kcal per day.

Finally, the review found that biological drivers of weight retention, for example, appetitive and satiety responses, differed sharply. Successful weight losers displayed favorable adjustments in satiety-related responses, whereas unsuccessful responders did not.

Environmental factors also played a role in weight retention outcomes. The release of organic pollutants stored in body fat during weight loss was linked to reduced skeletal muscle oxidative capacity and thyroid hormone levels, potentially contributing to lower energy expenditure, although the authors emphasize that these mechanisms require further study.

Why one-size-fits-all weight loss strategies fall short

The present review highlights that conventional “one-size-fits-all” approaches to diet and exercise as weight loss interventions, while important, are not scientifically generalizable, thereby challenging traditional “willpower failure” stigmas. Between 5 % and 20 % of individuals were observed to experience biological mechanisms that make standard weight loss interventions ineffective or even counterproductive, even under conditions of adequate or closely monitored adherence.

This resistance is thought to be driven by a complex interplay of genetics, metabolic adaptation, appetite regulation, stress levels, sleep quality, and environmental exposures. While the review emphasizes that precision discrimination of responders is not yet feasible in routine practice, these findings suggest that future weight management will require a gradual shift toward more personalized and closely monitored approaches.

Clinicians should recognize that unsuccessful responders may require adjusted expectations, empathetic follow-up, and individualized intervention strategies, rather than focusing solely on body weight as the marker of success or assuming poor compliance.

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