Obesity’s Known Unknowns

By Chuck Dinerstein, MD, MBA — Sep 01, 2023
Wegovy and Ozempic, both GLP-1 agonists, have taken the world by storm, providing a simple way to lose weight without changing our lifestyle. A new report in Science helps us understand what we do not know: the known unknowns of obesity. Let me summarize.
Image by hellbergstina from Pixabay

The short report is published in Science. I urge you to read the original; it is short, not too sciency, and helps you understand that the semaglutides (Wegovy and Ozempic) are only way stations to treating and understanding our increasing waistlines. Here is a summary of the salient points.

Genes versus Environment

“Confusion about the causes of obesity has arisen based on the false dichotomy of genes versus environment (rather than the combined effects of genes and environment). At any point in time, most of the variance in levels of obesity among individuals may be genetic. But, changes across time are predominantly driven by the environment. Which individuals deposit the most fat in response to environmental change is influenced by both.”

While our food environment plays a role in obesity, the driving forces remain unclear. We have a depth of understanding about rare monogenic obesity, but there are thousands of single-nucleotide variants in our genes associated with a rising BMI. It remains uncertain of the “causal mechanisms linking genetic variants to phenotypes.”

Modeling Obesity

Our weights remain stable for extended periods, especially within a stable environment. When we alter our eating or exercise patterns, our metabolism changes “to resist weight change.” This has given rise to an unproven belief that each individual has a “set point,” a “Gravitostat,” based on various ill-defined factors that keep their weight within a specific range.

Other models suggest that the relationship of consumption to exertion creates a more dynamic equilibrium. Others suggest that our bodies have upper and lower limits of weight to which we respond metabolically. While we know that Leptin plays a role in increasing hunger and suppressing energy expenditures when calories out far exceed calories in, we have no clear understanding of the metabolic mechanisms behind overfeeding.

Where does the fat go?

“The mechanisms involved in partitioning energy imbalances between lean versus adipose tissues have not yet been elucidated. … Moreover, the factors that influence the relative deposition of lipids into adipose versus non-adipose tissues are particularly important to understand because ectopic lipid deposition seems to be implicated in metabolic disease.”

Energy expenditure and nutrients

While the idea of calories in vs. calories out has a basic appeal, there is relatively little understanding of how our needs are sensed or the signals influencing appetite and behavior.

“… short-term bouts of exercise may not reliably influence food intake, [and] prolonged exercise interventions and high activity stimulate food consumption.”

Moreover, our energy expenditures, which include physical activity, resting (yes, you do burn calories sitting on the couch), and regulating our body temperature, differ. We do not understand how these three inter-relate – how “elevations of one aspect of expenditure may cause compensatory decreases in other components and/or changes in intake.”

The Brain

“Food intake and energy expenditure are controlled by the brain. Yet, it is unclear how the brain orchestrates eating behavior in response to signals from the periphery and the environment. … The recent success of glucagon-like peptide 1 receptor agonists for the treatment of obesity is because they engage these brain regions at pharmacological doses. There are probably many other brain regions involved.”

Dieting, Nutrients, and Energy Density

“How nutrients are sensed and the signals that control nutrient-specific appetites are poorly understood.”

  • The protein model suggests that we eat until our need for a specific protein level is satisfied. “However, the determinants of protein requirements, the signals of protein deficiency and surplus, and the resultant mechanisms controlling total protein intake are unclear.”
  • The carbohydrate-insulin model suggests foods with high glycemic indices, the short-acting sugars increase insulin release and drive fat accumulation. Here, too, underlying mechanisms have yet to be identified.
  • An energy density model suggests that high-fat diets result in eating less food but consuming more calories. Ultra-processed foods fit in that category. Or you can consider the alternative, the low energy density of fiber, whose consumption has declined over the last few decades – does fiber fill you up but not out?
  • “ Whether noncaloric sweeteners and the thousands of food additives common in modern foods affect satiety and energy intake is also unclear.”


There is little doubt that our gut microbiome adjusts to our food choices.

“It remains unclear whether differences in the microbiota between people with and without obesity are consistent and reproducible and whether these differences are consequences or causes of obesity.”

Social Factors

There is much evidence that obesity is a frequent traveler among family and friends. Stress is often put forward as an underlying cause. In high-income countries, “social adversity, including poverty,” are strong correlates of obesity, but in low and middle-income countries, “poverty tends to be associated with lower BMI.”

Others have suggested food insecurity fosters a “hoarding” metabolism, gaining weight for that inevitable day when the food runs out. “But what triggers the perception of food insecurity, and what the physiological reaction to it is, including increased fat storage, remain unknown.”

There is a belief that we are becoming more sedentary, but as occupational activity has declined, leisure-time activity has increased, resulting in relatively constant energy expenditures for nearly 50 years.

“Moreover, low energy expenditure from physical activity does not predispose individuals to obesity. … Although it is often asserted that increasing sedentary behavior is a major cause of the obesity pandemic, this is far from clear, and present evidence does not support this conclusion.”

Just as there may be many routes up the mountain, there are many routes to “excess adiposity.“ The latest medications treat only one of the possible underlying mechanisms, just as bariatric surgery has addressed others. But we have a lot to learn and shouldn’t believe that either medications or surgery are the answers to why our waistlines are expanding.


Source: Unanswered Questions About Obesity Science DOI: 10.1126/science.adg2718


Chuck Dinerstein, MD, MBA

Director of Medicine

Dr. Charles Dinerstein, M.D., MBA, FACS is Director of Medicine at the American Council on Science and Health. He has over 25 years of experience as a vascular surgeon.

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