Treating Obesity as a Disease
A review and assessment of recent literature for the clinical applications of new research in treating obesity as a disease. Plus: Extra commentary with our new podcast, After Hours.
March 2021
Volume 10, Issue 1

Chapter 2: Long-Term Hormonal and Metabolic Adaptations to Weight Loss



Maintaining long-term weight loss through diet and exercise can be nearly impossible, especially for people with severe obesity. Studies have shown that even with intensive behavioral treatment, most patients regain 30% to 35% of their lost weight in the year following weight loss. By 5 years, 50% of patients return to their baseline weight. Most patients regain weight after losing it even when they are working hard to keep it off. Weight regain, also known as weight recidivism, can occur after weight loss from any modality, even in patients who have undergone bariatric surgery. This process is primarily a physiological process, and not the result of loss of will power.

Why Does Weight Regain Happen?

Weight recidivism occurs because reducing body weight triggers adaptive mechanisms that drive weight regain. Body weight is tightly regulated by hormones from the GI tract, pancreas, and adipose tissue that act primarily in the hypothalamus to regulate food intake and energy expenditure. With weight loss, hormonal adaptations result in increased appetite and an increased preference for high calorie foods. Compounding this, adaptive thermogenesis is a slowing of metabolic rate as a response to weight loss.

This is not simply a resumption of old habits. Weight regain is physiological. The body, specifically the adipose tissue, has a "set point" so that after weight loss and fat loss, physiological changes re-establish the higher body weight and level of body fat. There are several factors responsible for weight regain after weight loss.


A genetic basis for obesity and the response to weight loss has been clearly established. Large-scale genome-wide studies have identified nearly 150 genetic variants associated with obesity. Even when someone loses weight, their genetics may be driving them back to the higher set point. It is estimated that the effect is approximately 50% genetics and 50% environment.

Neural Factors

Obesity is associated with an increased preference for foods high in fat and sugar that taste delicious. People trying to reduce their intake of these foods report unpleasant physical and psychological sensations, including insatiable cravings, fatigue, and poor mood. Losing weight is associated with effects in pleasure and reward centers, driven by dopamine. With weight loss, a decrease in reward from food intake occurs, resulting in dopamine signaling that drives an increased consumption to make up for the deficit. Human beings need pleasure, and food is a source of pleasure. When the source of pleasure is removed people feel deprived, driving hedonic hunger.

Hormonal Adaptations to Weight Loss

Body weight is tightly regulated by hormones that act primarily in the hypothalamus. Hormones from the GI tract, pancreas, and adipose tissue regulate food intake and energy expenditure. Reducing body weight triggers adaptive mechanisms to prevent starvation. Even when someone is overweight, the body perceives weight loss as starvation and vigorously defends against weight loss as a survival mechanism.

This landmark study by Sumithran, et al., evaluated changes in levels of appetite-regulating hormones that occur during weight loss and prolonged weight maintenance. Subjects were enrolled in a 10-week weight-loss program with a low-calorie diet. Circulating levels of leptin, ghrelin, peptide YY, glucagon-like peptide 1, amylin, cholecystokinin, and insulin. Subjective ratings of appetite were assessed at baseline, at 10 weeks, and at 62 weeks. Subjects lost about 30 pounds on average over the 10-week weight loss phase. At 10 weeks, there were significant reductions in levels of satiety hormones leptin, peptide YY, cholecystokinin, insulin, and amylin. The hunger hormone ghrelin was increased. There was also a significant increase in subjective ratings of appetite. One year later, significant decreases in satiety hormones as well as increases in ghrelin and hunger ratings persisted.

Adaptive Thermogenesis

Adaptive thermogenesis is a slowing of metabolic rate as a response to weight loss. This metabolic adaptation is a biological survival mechanism that conserves energy in the face of starvation and dangerously low energy supplies.

The Biggest Loser Study evaluated 16 contestants of the popular TV weight loss competition. Weight, body composition and metabolic rate were measured at the end of competition and 6 years later. Participants rapidly lost massive amounts of weight regaining most with time. The winner of the competition, Danny Cahill, lost 239 pounds. By the end of the 6 year follow up, he had regained 100 pounds. 13 of the 14 contestants regained all or most of their weight in 6 years. 4 contestants were heavier than before the competition. There was only one contestant who weighed less than she did at the end of the competition. Another contestant regained 80% of his weight, then had bariatric surgery and lost some weight, but did not lose all of the weight he had regained after the show.

Resting metabolic rate was substantially reduced at the end of the competition, indicating a large degree of metabolic adaptation. Biggest Loser participants continued to experience this metabolic adaptation years after the competition despite regaining most of the weight. Their resting metabolic rates were decreased by about 600 calories per day at the end of the competition and were even lower at 700 calories below baseline 6 years later. Weight loss is accompanied by a slowing of resting metabolic rate that is often greater than would be expected based on measured changes. This phenomenon is called “metabolic adaptation” or “adaptive thermogenesis.”

Maintaining weight lost will always be a challenge for our patients. Numerous factors including genetics, hormones, nutrients, and the microbiome are involved in the homeostatic regulation of body weight known as the set point. Many of these are altered by weight loss. This is a compensatory response to an energy deficit which persists for at least 12 months after weight loss. The long-term persistence of hormonal and metabolic adaptions to weight loss suggest that the high rate of weight recidivism among people with obesity who have lost weight has a physiological basis and is not simply the result of the voluntary resumption of poor food choices. Human biology is a powerful driver of weight regain.


Next Article:
After Hours Podcast Episode 2: J. Michael Gonzalez-Campoy MD, PhD, FACE
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