This is an excerpt from “On the causes of obesity and its treatment: The end of the beginning” by Jeffrey M. Friedman from Cell Metabolism (vol 37, issue 3, pp 570-577,  March 04, 2025. It’s worth reading because it reinforces the fact (yes, fact) that overeating is not due to poor self-control or self-discipline. It’s not a lifestyle choice but is highly influenced by genetics and heredity. It’s worth reading because it will change your view of your eating and weight and your understanding of what often drives it. 

Conclusions and the future

Thirty years ago, obesity was considered by many to be a lifestyle disorder, the management of which was limited to a recommendation, first made by Hippocrates, that patients eat less and exercise more. Adipose tissue was viewed as a passive vessel storing energy in times of surfeit and discharging during privation. Also, the role of intestinal hormones to control metabolism was largely unexplored.

Current research has established that obesity is a biologic disorder caused by alterations in the function of CNS pathways that control energy balance. This and the availability of new treatments suggest that we should consider obesity in the same way as we do other chronic conditions such as heart disease, hypercholesterolemia, diabetes, or hypertension. These diseases also have a biologic basis, and while modifying one’s lifestyle such as by reducing salt or sugar intake or increasing one’s physical activity is of benefit, in most patients these behavioral measures are not sufficient to adequately treat them. The data thus suggest that, similar to these conditions, we should now consider obesity a disease.

This conclusion is wholly consistent with our views on the causes and treatment of arterial hypertension. Both obesity and hypertension are quantitative traits with a greatly increased risk of comorbid conditions when levels are high and an intermediate risk when blood pressure or BMI are borderline. Similar to obesity, several single gene mutations have been shown to cause hypertension, while in the majority of patients there is polygenic inheritance. Hypertension, like obesity, requires continuous treatment, and it recurs when treatment is stopped. Similar to obesity, hypertension increases the risk of cardiovascular events and other comorbid conditions, and when blood pressure is extremely high, it constitutes a major health risk. Finally, at its extremes in leptin-deficient patients and stage 3 (morbidly) obese patients, the health risk is clear, and it is a disease. But what about the overweight or patients with mild, stage 1 obesity? Until recently, the threshold for hypertension was a systolic blood pressure of >140 mmHg, but now patients with a systolic blood pressure of 130–139 are considered to have stage 1 hypertension, for which lifestyle modifications are often recommended. Medical treatment of blood pressure, however, is clearly indicated in patients with higher blood pressure and clearly indicated in patients with cardiovascular disease and heart failure. The available evidence suggests that we should regard overweight and mild, stage 1 obese patients in a similar manner and consider lifestyle modifications, reserving the use of medical treatment for patients with a BMI over 30, particularly those with a comorbid condition. The similarities among these conditions further suggest that the stigmatization of obese patients is no more warranted than would be the stigmatization of patients with heart disease or hypertension. This stigmatization should end. 

The discovery of the causes of obesity and means for treating it also reveal that obesity is a brain disorder. Each of the single gene mutations that are known to cause obesity in humans alters the function of appetitive pathways in the brain, as do the new treatments. This has led to an explosion of information about the neural circuits that regulate appetite, and feeding is (arguably) the best delineated complex behavior. In aggregate, mapping of the neural targets of leptin and incretins has provided a deeper understanding of the specific pathways that control appetite over distinct time scales, with incretins modulating appetite by inducing satiety over the short term and leptin regulating energy balance over the long term. The homeostatic and satiety systems, as well as reward pathways, clearly communicate with one another, and the nature of these interactions is ripe for further study. However, little is known about the nature of this communication, nor is it known where and how the decision to initiate feeding is made, referred to by Sherrington as the “final common path.” The future holds the promise that we will understand how different signals from gut, adipose tissue, and elsewhere are integrated to regulate the initiation of this behavior.

Other opportunities and questions are raised by these advances, many of which have important therapeutic implications. Can we develop tailored therapies for distinct subgroups of patients, including those for whom the new agents are not effective? Will it be possible to extricate the efficacy of these drugs from the nausea and other gastrointestinal side effects that many patients experience? Are there means for maintaining weight loss (in addition to behavioral measures) to obviate the need for lifelong treatment with the new peptide-based therapeutics? Is the loss of muscle mass in patients on the peptide therapeutics (or in patients who successfully maintain weight loss by dieting) clinically significant, and can it be remediated? Why do GIPR agonists and antagonists both augment the efficacy of GLPRAs? What is the mechanism by which the new peptide therapeutics synergize with leptin to ameliorate leptin resistance? What causes leptin resistance and will reversing or bypassing it lead to new treatments in humans? Why do GLPRAs show clinical benefits in an array of conditions ranging from metabolic disease to renal function to cardiovascular disease to addiction to neurodegeneration? How and where is the decision to eat made? With a new understanding of the causes of obesity and means for treating it, will it continue to be stigmatized? It will be exciting to learn the answers to these and many other questions that arise in the coming years.

The future of this field is bright and growing brighter. The transformative developments summarized here mark the end of a period replete with important discoveries and the beginning of a new age where the causes of obesity will be more fully understood, and a battery of highly effective precision medicines are likely to be available to improve the health of overweight and obese patients.

Best,

Karen