Textbooks, public health guidelines, and patient education materials characteristically conceptualize obesity as a disorder of energy balance. According to the conventional view reflected in the energy balance model (EBM), overeating generates excess adiposity. Dietary treatment focuses on decreasing energy intake to reduce stored body fat.
An alternative view, the carbohydrate-insulin model (ICM), posits an opposite path: that increased adiposity drives overeating.
Instead, dietary treatment aims to reduce body fat storage primarily through hormonal mechanisms that directly impact adipose tissue, thus producing a negative energy balance.
The objective of this review is to compare the characteristics of both models, evaluate the strengths of the scientific evidence and specify improvements in the formulation of the EBM to promote a constructive clash of paradigms.
| The new energy balance model: a focus on food intake |
Both models of obesity share a common characteristic: the presumed homeostatic regulation of a critical physiological parameter to promote optimal functioning. In MBE, body weight ( or body fat ) is the regulated variable, a possibility with some evolutionary support: while adequate body fat is necessary to survive in times of food scarcity, excess fat could increase risk of predation.
The new MBE proposes that the brain controls food intake to regulate body weight through endocrine, metabolic, and nervous system signals that act in response to the body’s dynamic energy needs as well as environmental influences. This control system focuses on reward, appetite, and sensory processing involving salience, desire, and motivation that operate primarily below our awareness.
Obesity is the result of the increased availability and marketing of a wide variety of ultra-processed, inexpensive, convenient, energy-rich foods that are high in portions, fat and sugar, and low in protein and fiber. These exposures cause overeating, and excess energy is deposited in body fat.
| The carbohydrate-insulin model: a special case of the metabolic paradigm |
The MCI represents an opposing paradigm, with origins in the early 20th century. Consider the supply of metabolic fuels in the blood as the regulated parameter. While adequate body fat may aid survival during famine, access to metabolic fuels is necessary for immediate survival, given the dependence of all tissues, and especially the brain, on a continuous supply of fuel.
This model proposes that a high glycemic load diet with large amounts of rapidly digesting carbohydrates (i.e., free sugar, processed grains, most starchy vegetables) elicits hormonal responses that inhibit fat mobilization (lipolysis) and promote the deposition of fat in adipose tissue
Consumption of a meal high in glycemic load produces a high ratio of insulin to glucagon and GIP to GLP-1 secretion. This highly anabolic hormonal profile shifts substrate partitioning toward the depot, leaving less energy available for metabolically active tissue, including the brain, especially in the late postprandial period. The brain responds to this metabolic state by activating pathways that control hunger and other appetitive responses to promote energy intake.
If an individual resists the urge to eat by restricting food, metabolic fuels are conserved through reduced energy expenditure manifesting as fatigue (leading to sedentary behavior), decreased thermogenesis from non-exercise activity , increased muscle efficiency and other mechanisms.
| Evidence regarding the two models |
The natural course of obesity, which generally develops over years or decades, involves excessive storage of 1 to 2 grams. of fat/day on average too small to measure in short-term (i.e., ≤2 weeks) metabolic feeding studies. While this effect could be observed in longer-term observational studies and trials, causal inference from these data may be limited by poor compliance with test diets and confounding.
Furthermore, few studies have focused on childhood, a dynamic stage of obesity development. Although animal studies can elucidate the mechanisms, their translation to humans remains problematic. For these reasons, the vast literature on the pathogenesis of obesity can be selectively cited to make opposing points, as each side of this debate has challenged the other.
> Animal research
Although rodents and humans have not evolved to eat the same diets, experimental animal research has been considered in this debate.
Methodological problems can be avoided by a direct examination of the causal direction. While hormonal responses to macronutrients may differ between species due to evolutionary divergence, the biological mechanisms affecting fat storage are highly conserved, enhancing the potential translation of rodent studies to humans.
In MBE, diet drives fat deposition by increasing food consumption. Therefore, when animals on an obesogenic diet are paired fed with their littermates on an isocaloric control diet, ensuring equal energy intake, the effects on body composition should be identical.
Glycemic index (GI) studies offer another way to circumvent species-specific differences in macronutrient metabolism. In a line of research involving several strains and species of rodents, the effects of GI were examined by substituting starch type, controlling for macronutrients, saturated fat, sugar, and micronutrients.
Despite consuming fewer calories, these animals had more body fat at the expense of lean body tissues. Although multiple mechanisms (e.g., gut microbiome) may mediate these effects, they contradict a fundamental premise of MBE, that dietary composition does not have calorie-independent effects on fat deposition.
Studies of insulin action are another reference. In MCI, increased insulin secretion promotes fat storage through direct peripheral mechanisms. MBE, with its focus on the central actions of hormones, appears to predict the opposite, given the anorexic actions of insulin in the brain. These adiposity studies, involving chronic insulin administration and genetic models of reduced insulin secretion, support MCI.
> Brain and genetics
While nervous systems have evolved to control energy intake, the brain also controls virtually all aspects of metabolism, including glucose metabolism. Clearly, genetic factors influence human obesity risk, with BMI heritability estimated at 30% based on whole genome sequencing.
Thus, genetic studies indicate pathways involving obesity that operate inside and outside the brain; in many cases, these appear consistent with the MCI. Taken together, the gene expression data do not definitively differentiate between the two models, in view of the brain’s role in controlling food intake and energy metabolism and communicating through neural, metabolic and hormonal signals.
> Epidemiology
Based on observational studies, the MBE states that there is no evidence to suggest that carbohydrate intake explains differences between countries in body weight, but these ecological comparisons are of little value for this variable. Countries with high carbohydrate consumption, for example, tend to be poor, with a substantial proportion of the population undernourished, malnourished, and engaged in subsistence agriculture.
Furthermore, the authors of this model ignore a long and rich history of observations linking the emergence of common chronic disorders, including obesity, to population-wide nutritional transitions that typically include increased consumption of highly refined grains, sugar, and beverages. sugary
Prospective cohort studies provide greater ability to control for confounders, particularly socioeconomic status, although residual confounders may remain. Furthermore, body weight and other measures of adiposity are especially susceptible to reverse causation (the tendency of people to change their diets as a result, rather than a cause, of weight gain or obesity).
While both the MBE and the MCI agree that epidemiological data suggest a variety of possible dietary drivers of excess caloric intake, other authors raise new questions about this concept, at least as it relates to the current stage of the epidemic. obesity in the US
Based on nationally representative surveys, energy intake has stagnated or declined since 2000 and physical activity has increased moderately, even as obesity rates continue to rise. These trends require consideration of alternative causal explanations, including those related to metabolic dysfunction.
> Clinical trials
A recent meta-analysis reported no difference in long-term weight loss between macronutrient-focused diets, cited by the MBE. While other meta-analyses comparing low-carb versus high-carb diets suggest a significant, albeit modest, advantage for the former. Despite this, interpretation of evidence tends to confuse effectiveness with behavioral implementation.
The MBE authors recognized the need for trials of at least several months in duration, noting that even small differences in energy expenditure and macronutrient balance can theoretically lead to significant differences in body weight and composition if diets are maintained for extended periods.
> Drugs
A dominant role for insulin in adipocyte physiology, including lipogenesis and lipolysis, has been recognized for decades. In patients with diabetes, insulin and drugs that increase insulin secretion or action on adipose tissue metabolism cause weight gain.
Some of these effects may involve other mechanisms compatible with MBE, such as reduction in glycosuria. However, weight loss induced by drugs that reduce secretion suggests that the action of insulin on fat storage observed in rodents occurs in humans.
The MBE considers the efficacy of GLP-1 receptor agonists for obesity as evidence against MIC, because this incretin acutely potentiates glucose-stimulated insulin secretion. However, GLP-1 has other relevant biological actions, including reducing the rate of gastric emptying (which reduces the glycemic response).
To summarize the evidence related to the two models, animal data demonstrate that excessive fat deposition can evidently be dissociated from energy intake, which contradicts a fundamental premise of MBE. In animal models involving not only diet but also brain pathways thought to mediate food intake, obesity can occur without increased food intake.
However, human data have important methodological limitations that have thus far prevented a definitive test of the two models. To advance science, studies of adequate duration and complementary designs will be needed.
> Clinical translation and public adoption
Both sides of this debate agree that fundamental changes in the food environment have driven the obesity pandemic. The new EBM’s focus on such a wide range of dietary factors offers little innovative practical insight.
Of particular concern, no causal relationships with chronic weight gain have been demonstrated for dietary factors addressed by the EBM other than those also involving pathways related to the MCI (sugar, which is high in glucose and fructose; fiber, which reduces the GI of carbohydrates ingested together; and protein, which reduces the GI of carbohydrates ingested together and stimulates glucagon secretion).
The remaining dietary goals specific to MBE include: energy density (acute changes in energy density affect short-term intake), dietary fat (focus on reducing fat in the diet), and food processing (diet “ ultra-processed” versus “unprocessed” diet).
> Confused clash of paradigms
Maintaining contrast between these competing models is critical to clarifying thinking, informing a research agenda, and identifying effective means of prevention and treatment.
The MBE authors claim that the MCI has abandoned fundamental precepts, referring to previous “adipocentric” formulations that claimed to consider only the actions of insulin in adipose tissue. However, this characterization was not made by the proponents of the ICM and offers a false distinction. The control of adipose tissue biology by multiple hormonal, autonomic, and other influences has been recognized for decades.
Even as the provenance of the MCI is criticized, the MBE has important deficiencies, including:
- Lack of explicit testable hypotheses. How will key steps along the causal pathway be interrogated? What studies will differentiate the proposed causal pathway (overeating leads to chronic weight gain) from the contrasting MCI hypothesis?
- While arguing that opponents of MBE confuse physics with pathophysiology, its authors claim that it incorporates physiological mechanisms underlying energy partitioning such that overall energy imbalances are reflected primarily as fat imbalances, regardless of fat composition. the diet.
- Lack of mechanisms that involve key components of the model. How does the new MBE explain the rapid weight gain at the population level and the large variations within individuals over time?
- Disregard of well-established metabolic mechanisms.
- Difficulty explaining the natural history of obesity.
- Confidence in assumptions that do not differentiate between models.
| Conclusions |
For intractable public health problems, the purpose of scientific models is to guide the design of informative research and, by helping to elucidate causal mechanisms, to suggest effective approaches to prevention or treatment. The new MEE does neither. At a minimum, future formulations should:
1- Specify mechanistically oriented and testable predictions that examine the causal pathway.
2- Explain why metabolic responses defend the increase in BMI at the population level.
3- Demonstrate how the calorie-independent effects of diet suggested by clinical research and demonstrated by animal models can be integrated into this model.
A constructive clash of paradigms can be facilitated by the recognition that evidence for one model in certain experimental settings does not invalidate the other model in all settings, and that the pathogenesis of obesity in humans may involve elements of both.
Finally, we emphasize that this clash of ideas should not delay action in public health. Refined grains and added sugars comprise about a third of energy intake in the US and Europe.
Both models point to these highly processed carbohydrates , although for different reasons, as primary drivers of weight gain. Regardless of how this debate evolves, there is now common ground on the need to replace these products with minimally processed carbohydrates or healthy fats in the prevention and treatment of obesity.
