TWO Competing Theories of Why We Get Fat: A Breakthrough

Is it carbs or the calories that make us fat? The debate comes to top journal, Nature Metabolism.

Last week, the journal Nature Metabolism published the latest chapter in the ongoing debate about why we get fat. The article, on which I was a co-author along with 15 influential obesity researchers, was titled “On the pathogenesis of obesity: causal models and missing pieces of the puzzle.”

It is the first article of its kind — revolutionary, in its way — but we hope not the last.

The article focuses on the two major competing hypotheses of obesity — the conventional thinking, which is known as the Energy Balance Model (EBM), and the challenger, the carbohydrate-insulin model (CIM). The EBM blames obesity ultimately on how much we eat. The CIM blames it on what our bodies do with what we eat, a process that is dominated by the effect of carbohydrates on the hormone insulin. These competing models are compared in detail side-by-side, as equals, which has never before happened in the century-plus history of meaningful research on the cause of obesity.

The article is the product of a September 2023 invite-only workshop hosted by the Novo Nordisk Foundation (NNF) in Copenhagen. NNF, as Wikipedia explains, “is a self-governing entity with no owners, focusing on long-term ownership of the Novo Group (Novo Nordisk and Novozymes) while combining business and philanthropy with scientific, humanitarian and social purposes.” Because Novo Nordisk, the pharmaceutical company, produces many of the new GLP1 obesity and diabetes drugs, NNF is now the wealthiest charitable foundation in the world.

The attendees of the September workshop included researchers promoting and defending the two conflicting perspectives, some who were not exactly agnostic but near enough, and several promoting other hypotheses (a virus hypothesis and the protein leverage hypothesis, most notably).

Kevin Hall, who is the most influential obesity researcher at the National Institutes in Health, was in attendance. So was John Speakman, who holds joint appointments in Scotland and China and is a leading figure in the obesity research community. Hall and Speakman are the most outspoken proponents of energy balance thinking and the most actively critical of the CIM.

To their credit, Hall and Speakman are among the tiny minority of obesity researchers who actually believe that the energy balance model of obesity needs to be defended. Most of the research community, as with physicians and public health authorities, believe that this perspective is essentially ordained by the laws of physics — we get fat because we consume more calories than we expend — and so there’s no need to either think critically about it or defend it. What could be more obvious? If nothing else, the Nature Metabolism paper establishes that neither the thoughtful proponents of the energy balance model nor its critics believe this ordainment by physical law to be true.

The CIM proponents in attendance included David Ludwig of Harvard and the University of Copenhagen (where he is on sabbatical leave), Mark Friedman of the Monell Chemical Senses Center in Philadelphia, and me. The meeting was organized by Arne Astrup (NNF and U. of Copenhagen), who may be the most influential nutrition and obesity researcher in Europe. His U. of Copenhagen colleague Faidon Magkos was lead author on the paper and was given the thorny task of getting the attendees, with their inherently contradictory beliefs and perspectives, to agree and eventually sign off on what the paper would say. It was not exactly a herding-cats situation but something like it.¹

“The workshop did not aspire to reach consensus on what causes obesity,” as the Nature Metabolism article described it,

but rather the intent was to (1) operationally define commonly used terms…, (2) delineate the structure of each model and overlay suggested routes and causal pathways on top of a common physiological background of energy metabolism and body weight regulation, (3) discuss the importance of purported causal factors for weight gain, (4) brainstorm on the key scientific questions that need to be answered and (5) outline the general principles of appropriate experiments to test between the relevant hypotheses. Ultimately, the goal of the workshop was to help resolve controversies and drive the field forward and thereby serve the scientific community and the public.

The article goes onto describe the models and summarize the conclusions we reached; what we agree upon, what we don’t, and what needs to be done to establish reliable knowledge.

The article and the workshop are vitally important for one reason that was not discussed explicitly in the paper. This is why we need to revisit the obesity issue so soon after the last chapter, which I discussed in Unsettled Science (here), in early July, and why we’ll have to continue revisiting this issue in the future. Allow me to digress.

Among my favorite articles in the scientific literature, one considered a landmark in the discussion of scientific method, was first published in the journal Science in 1890: “The Method of Multiple Working Hypothesis.” Its author was T.C. Chamberlin, perhaps the most prominent geologist of the era and later a president of the American Association for the Advancement of Science. (Among other work, Chamberlin is credited with early thinking on the effect of atmospheric carbon dioxide on climate.) Chamberlin published a revised version of the article in 1897, and it was republished multiple times through the 1960s. (You can read the 1965 version of the 1890 paper here.)

T.C. Chamberlin

Chamberlin’s paper is a lesson about how to do science right, how to maximize the possibility that researchers will actually get the correct answer so that reliable knowledge can be established. His method, as described in the subtitle, is about the need to avoid the “dangers of parental affection for a favorite theory.” It is also a warning to researchers about the consequences of this kind of parental affection: i.e., doing what regrettably comes most naturally in science (as in life), which is embracing a favored hypothesis as true before we have the rigorous evidence necessary to do so.

This is what Chamberlin calls the “method of the ruling theory” (also, which I like, the “habit of precipitate explanation”). He believes, as do I and most philosophers of science, that the ruling theory method will inevitably lead to a situation in which all data and observations are interpreted in the light of this ruling theory alone and either made to fit the theory or rejected as irrelevant if they don’t. Here’s Chamberlin on the extraordinary damage that comes from this way of thinking:

The theory then rapidly rises to a position of control in the processes of the mind and observation; induction and interpretation are guided by it. From an unduly favored child it readily grows to be a master and leads its author whithersoever it will… Briefly summed up, the evolution is this: a premature explanation passes first into a tentative theory, then into an adopted theory, and lastly into a ruling theory.

When this last stage has been reached, unless the theory happens perchance to be the true one, all hope of the best results is gone. To be sure, truth may be brought forth by an investigator dominated by a false ruling idea. His very errors may indeed stimulate investigation on the part of others. But the condition is scarcely the less unfortunate.

Chamberlin’s solution is for researchers to start by considering their ideas not as theories but only working hypotheses and then to consider it their obligation to generate as many alternative hypotheses as possible: hence, the method of multiple working hypotheses, the more the better:

Conscientiously followed, the method of the working hypothesis is an incalculable advance upon the method of the ruling theory, but it has some serious defects. One of these takes concrete form… in the ease with which the hypothesis becomes a controlling idea. To avoid this grave danger, the method of multiple working hypotheses is urged. It differs from the simple working hypothesis in that it distributes the effort and divides the affections. It is thus in some measure protected against the radical defect of the two other methods. In developing the multiple hypotheses, the effort is to bring up into view every rational explanation of the phenomenon in hand and to develop every tenable hypothesis relative to its nature, cause, or origin, and to give to all of these as impartially as possible a working form and a due place in the investigation. The investigator thus becomes the parent of a family of hypotheses; and by his parental relations to all is morally forbidden to fasten his affections unduly upon any one.

So what’s the relevance to obesity?