expert roundtables

Confronting Biological Adaptations to Weight Loss

by Caroline M. Apovian, MD, FACP, FTOS, DABOM, Louis J. Aronne, MD, Judith Korner, MD, PhD

Overview

Numerous biological mechanisms, along with hormonal and neural interactions, undermine a patient’s efforts to maintain weight loss. Our featured experts discuss the importance of confronting the biological adaptations that favor weight regain.

Q: How should clinicians and patients confront the biological adaptations to weight loss? 

Caroline Apovian, MD, FACP, FTOS, DABOM

Director, Nutrition and Weight Management
Section of Endocrinology, Diabetes, and Nutrition
Boston Medical Center
Professor of Medicine, Boston University School of Medicine
Boston, MA

“Because of these physiological adaptations, we now understand that obesity is a disease and not simply a matter of one’s lack of willpower.”

Caroline M. Apovian, MD, FACP, FTOS, DABOM

Since the discovery of leptin in 1994 by Friedman and colleagues, a growing body of research has shown that hormones released from the gastrointestinal tract, the pancreas, and even fat tissue itself create signals that are integrated to regulate food intake and energy expenditure. Obesity medicine specialists and primary care physicians should be aware that these biological adaptations are going to work toward restoring the patient’s body weight set point through increased hunger and other mechanisms. Because of these physiological adaptations, we now understand that obesity is a disease and not simply a matter of one’s lack of willpower. It is the responsibility of clinicians to inform their patients of these adaptations so that patients do not feel a sense of failure if they regain the weight that they had previously lost. These are biological adaptations that—without intensive lifestyle and behavioral modification, medication, and/or bariatric surgery—almost force the patient to regain the weight.

Louis J. Aronne, MD

Sanford I. Weill Professor of Metabolic Research
Director, Comprehensive Weight Control Center
Weill Cornell Medicine
New York, NY

“We do not give up on patients who have trouble losing weight—that would be like not treating hypertension in a patient who was advised to reduce his or her salt intake but 
failed to do so.”

Louis J. Aronne, MD

I am continually being asked, “What is the disease? People are just eating too much and not exercising enough.” The disease appears to be injury to the hypothalamic neurons that carry all of these hormonal signals. With weight gain, the most likely explanation is that there appears to be fewer critical proopiomelanocortin (POMC) neurons in the hypothalamus, and that the ones that remain are damaged and/or surrounded by inflammatory cells. It is not just a matter of consuming too many calories; the signaling neurons are being damaged by obesogenic diets and calorie overload, ratcheting up the body weight set point.

This is critical to the use of medication. Because many physicians believe that a patient’s inability to lose weight is a behavioral problem rather than a biological problem, they often question the use of medication and, rather, expect the patient to change his or her behavior. I think that the failure of most behavioral programs over the long-term is attributed to a failure to recognize that something physical is occurring. While, certainly, there are people who can achieve weight-loss success with diet and physical activity, we should not give up on those who cannot. We do not give up on patients who have trouble losing weight—that would be like not treating hypertension in a patient who was advised to reduce his or her salt intake but failed to do so. The medical treatment paradigm makes more sense than ever. With weight loss, there is a shift in the levels of a variety of hormones such as leptin and ghrelin, making it increasingly difficult for individuals to lose weight. So, my advice to clinicians and to patients when confronting these biological adaptations is, first and foremost, to set modest expectations. Do not expect the patient to achieve an ideal body weight. If patients lose just 5% of their body weight, their risk of developing diabetes will decrease by approximately 50%. If patients lose 10% of their body weight, this risk will decrease by 80%. That is significant. Physicians and patients should focus on those health benefits because they are achievable.

Judith Korner, MD, PhD

Professor of Medicine
Department of Medicine and Division of Endocrinology and Metabolism
Director, Weight Control Center
New York Presbyterian/ Columbia University Medical Center
New York, NY

“It is almost soothing for patients to hear that this is a biological issue and not a personal failing.” 

Judith Korner, MD, PhD

It is vitally important for clinicians to talk to their patients about these biological adaptations. Oftentimes, patients have never heard of them, and they do feel like a failure because they cannot lose weight or their weight keeps cycling up and down. A patient of mine once said that, over the course of her lifetime, she has lost the weight of a Volkswagen. It is almost soothing for patients to hear that this is a biological issue and not a personal failing. With some types of bariatric surgery, the change in hormones is different than the changes that occur just with diet, which may be 1 of the reasons why surgery works: there are fewer counterregulatory pathways to kick in. There is also evidence that with surgery there are increases in gut hormones that actually suppress appetite.

Ideally, we would like to see the development of an antagonist to ghrelin or an agonist that stimulates POMC production, the hormone that Dr Aronne mentioned. Another hormone in the brain, the agouti-related protein (AgRP), is an extremely strong signal to induce hunger and to accumulate fat. The body has a choice to make every time it takes on a calorie: Store that calorie as muscle, store it as fat, or burn it. With high levels of hormones such as ghrelin or AgRP, the body makes the decision to store it as fat. That also creates a vicious cycle (ie, the more fat that is present, the less energy that is expended, because fat is less metabolically active than muscle). And this results in a patient trying to lose weight while fighting against hormones that do not only induce hunger and lower metabolism, but also may encourage more fat accumulation.

References

Greenway FL. Physiological adaptations to weight loss and factors favouring weight regain. Int J Obes (Lond). 2015;39(8):1188-1196.

Jais A, Brüning JC. Hypothalamic inflammation in obesity and metabolic disease. J Clin Invest. 2017;127(1):24-32.

MacLean PS, Wing RR, Davidson T, et al. NIH Working Group report: innovative research to improve maintenance of weight loss. Obesity (Silver Spring). 2015;23(1):7-15.

Melby CL, Paris HL, Foright RM, Peth J. Attenuating the biologic drive for weight regain following weight loss: must what goes down always go back up? Nutrients. 2017;9(5):pii: E468.

Schwartz MW, Baskin DG. Leptin and the brain: then and now. J Clin Invest. 2013;123(6):2344-2345.

Shibata M, Banno R, Sugiyama M, et al. AgRP neuron-specific deletion of glucocorticoid receptor leads to increased energy expenditure and decreased body weight in female mice on a high-fat diet. Endocrinology. 2016;157(4):1457-1466.

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