Wednesday, June 23, 2010

What causes people to gain or lose weight?

A while ago I finished Gary Taubes' Good Calories, Bad Calories: Fat, Carbs, and the Controversial Science of Diet and Health (GCBC). Surprisingly for a mainstream book, Good Calories, Bad Calories has, like, actual science. The horror!

I'm going to focus on Taubes' discussion and explanation of obesity, since I found that the most interesting, but he also talks about heart disease, cancer, Alzheimer's and dementia, among other things. In addition, he traces the history of the science leading up to the our current understanding of nutrition and health, how certain ideas came to be accepted, etc. This chronicling is actually quite interesting in its own right and is a major focus of the book, but I won't discuss it here.

Fat and carbohydrate metabolism

Any fully satisfying explanation for why people gain or lose weight must get down to the level of biochemistry. It isn't enough to say that "eating X makes you fat" - we need an actual mechanism by which the body chooses to store more fat in response to eating X. So what follows is a very brief overview of fat and carbohydrate metabolism, distilled from GCBC and some Wikipedia and web surfing. Disclaimer: I am not a biochemist. Please provide corrections in the comments!

During digestion carbohydrates are broken down into glucose and released into the bloodstream. Cells in the pancreas called beta cells detect glucose in the blood and secrete insulin in response. In addition to inhibiting fat metabolism, insulin promotes metabolism of glucose which brings blood sugar levels back down to normal.

Glucose not immediately used for energy is converted to glycogen and stored in the liver and muscles. If these glycogen stores are already at capacity (somewhere around 1500 calories' worth), the body converts the glucose to fat and stores it. People with type 2 diabetes are unable to synthesize and store this fat rapidly enough to maintain pace and end up excreting excess glucose in the urine.

As blood glucose levels fall below normal levels, the pancreas secretes glucagon, a hormone which signals the liver to convert glycogen back to glucose, again bringing blood sugar back to normal levels - this process is known as glycogenolysis. It seems the body prefers to use stored glycogen as energy before turning to fat metabolism, although the two sources are probably not mutually exclusive. In addition to glycogen, the liver can also syntesize glucose from other non-carbohydrate sources (gluconeogenesis), like proteins.

In addition to this energy conversion process happening in the liver, low insulin levels enable fat tissue to convert fat from its stored form (triglycerides) to free fatty acids (FFAs). These FFAs are released into the bloodstream and can be metabolized for energy. This is an active process, happening throughout the day, between meals and during sleep. In general, the body attempts to maintain a constant supply of energy to its cells despite fluctuations in the flow of fats and carbohydrates coming from digestion.

The above story is an oversimplification in several ways. Glucagon production can also be promoted and inhibited by factors other than blood sugar levels. The mere taste of something sweet can prompt insulin production, well before any sugar would be digested and enter the bloodstream. And, going one level further down, each of the above responses has an underlying biochemical mechanism. For instance, in order to be stored as fat, the FFAs in the blood must be packaged up into triglycerides. The formation of triglycerides requires the presence of a molecule called glycerol phosphate, a byproduct of carbohydrate metabolism. (Glycerol phosphate, incidentally, is produced from fructose, the "fruit" sugar, more readily than from glucose.) It's easy to imagine various scenarios where, depending on the timing of when fats and carbohydrates are released into the bloodstream after a meal and the rate at which glucose and FFAs are absorbed, we get different amounts of fat stored.

The other issue I've ignored is insulin sensitivity. Obese persons typically have higher than normal resting levels of blood sugar and insulin because their cells do not respond sufficiently to the hormone and thus fail to remove glucose from the blood. This condition is called insulin resistence, or low insulin sensitivity. Insulin resistence can lead to a vicious cycle ending in diabetes - because cells don't uptake the glucose, blood glucose remains high; beta cells in the pancreas respond to this heighted blood sugar by secreting even more insulin to compensate, which tends to increase insulin resistence further, and so on.

Technically, it's more accurate to talk about the insulin sensitivity of particular tissues in the body (when people talk about "insulin sensitivity" in general, as I did above, it's usually referring to insulin sensitivity of muscle tissue) and to take into account the relative sensitivities of these tissues. Taubes discusses this in chapter 22, page 395, where he summarizes the research of James Neel. Neel listed listed three "scenarios" by which the body might be more inclined to store rather than burn fat. I'm going to just quote Taubes' descriptions:
The first of these scenarios was what Neel called a "quick insulin trigger." By this Neel meant that the insulin-secreting cells in the pancreas are hypersensitive to the appearance of glucose in the bloodstream. They secrete too much insulin in response to the rise in blood sugar during a meal; that encourages fat deposition and induces a compensatory insulin resistence in the muslces...

In Neel's second scenario, there is a tendency to become slightly more insulin-resistant than would normally be the case when confronted with a given amount of insulin in the circulation. So even an appropriate insulin response to the waves of blood sugar that appear during meals will result in insulin resistance, and that in turn requires a ratcheting up of the insulin response...

Neel's third scenario is slightly more complicated, but there's evidence to suggest that this one comes closest to reality. Here an appropriate amount of insulin is secreted in response to the "excessive glucose pulses" of a modern meal, and the response of the muscle cells to the insulin is also appropriate. The defect is in the relative sensitivity of muscle and fat cells to the insulin. The muscle cells become insulin-resistent... but the fat cells fail to compensate. They remain stubbornly sensitive to insulin. So, as Neel explained, the fat tissue accumulates more and more fat, but "mobilization of stored fat would be inhibited."
Taubes doesn't offer much explanation or give any mechanism by which the insulin sensitivities of these tissues might be influenced, and he also doesn't talk about what factors other than insulin levels might affect the propensity of the body to burn rather than store fat.

There is however an interesting discussion in the book of the role of the enzyme lipoprotein lipase (LPL), which acts as a "gatekeeper" for fat storage and gets us closer to understanding what's happening. LPL acts differently in different tissue types: in fat tissue, LPL acts to break lipids housed in lipoproteins down into their component fatty acids and promotes flow of these FFAs into the fat cells where they are then repackaged as triglycerides for storage (lipoproteins serve as water-soluble transport for fats and cholesterol in the blood and are often characterized by their density - high-density lipoprotein (HDL), low density lipoprotein (LDL), etc). In muscle tissue, LPL promotes uptake of FFAs into the muscle where it can be used for energy. Differing levels of LPL activity in different parts of the body provide a good account for why men and women and even individuals tend to accumulate fat in different areas.

LPL activity is upregulated in fat tissue by insulin - this provides a possible explanation for exactly how insulin acts to promote storage of fat in the fat tissue. But it seems we don't have the full story. Quoting Taubes, pg 399:
LPL activity in fat tissue increases with weight loss on a calorie-restricted diet and it decreases in muscle tissue; both reactions will work to maintain fat in the fat tissue, regardless of any negative energy balance that may be induced by the semi-starvation diet. During exercise, LPL activity increases in muscle tissue, enhancing the absorption of fatty acids into the muscles to be burned as fuel. But when the workout is over, LPL activity in the fat tissue increases. The sensitivity of fat cells to insulin will also be "sufficiently altered," as the University of Colorado physiologist Robert Eckel has described it, so as to restock the fat tissue with whatever fat it might have surrendered.
This suggests there's more going on here - what is the mechanism by which the body affects this LPL activity and insulin sensitivity? Taubes doesn't quite close the biochemical loop here - I'm not sure if this is because the information just isn't known or that Taubes himself didn't know or chose to omit it.

Since finishing the book I've been searching for additional info; what I've read so far is vague and handwavy, but seems to indicate that Omega-3 fatty acids, low cortisol levels (cortisol is the "stress" hormone), sufficient sleep, vitamin D, and exercise all might promote (or at least prevent decline in) a tendency to mobilize fat out of the fat tissue for use as energy. But I'm still looking for more convincing accounts that get down to the biochemical nitty-gritty. Maybe I'll write another post after doing further research.

As an aside, Taubes does offer an explanation for why some people might have pancreatic cells that are more sensitive to glucose:
[A]s women of childbearing age get heavier and more of them become diabetic, they pass the metabolic consequences on to their children through what is technically known as the intrauterine environment... If the mother has high blood sugar, then the developing pancreas in the fetus will respond to this stimulus by over-producing insulin-secreting cells. "The baby is not diabetic," explains Boyd Betzger, who studies diabetes and pregnancy at Northwestern Univeristy, "but the insulin-producing cells in the pancreas are stimulated to function and grow in size and number by the environment they're in. So they start overfunctioning. That in turn leads to a baby laying down more fat, which is why the baby of a diabetic mother is typified by being a fat baby." ... This is also the most likely explanation for why children born to women who gain excessive weight during pregnancy also tend to be fatter.
I found this alarming.

Diet implications

My impression is that none of the above is particularly controversial. But what are the dietary implications of all this, particularly for someone trying to lose weight? Here there's disagreement.

First, Taubes' argument: merely restricting calories is not the most effective way to lose weight. As mentioned above, most people who are overweight have some level of insulin resistance and higher-than-normal levels of circulating insulin. We might say that the base insulin level in the blood and insulin sensitivities of the fat cells and muscles together determine an equilibrium for amount of fat stored. Restricting calories without a commensurate decrease in base insulin levels (or increase in muscle insulin sensitivity, or decreased fat tissue insulin sensitivity) won't change this equilibrium. With no more fat available for metabolism than before but fewer calories available in the diet, the body has no way of maintaining its previous energy expenditure. The result is low energy and persistent hunger. According to this view, hunger is not the cause of obesity but merely a symptom of an underlying metabolic problem (see metabolic syndrome).

It seems obvious, then, that the way to encourage fat loss is to eat less foods that promote an insulin response - that is, refined and easily digestible carbohydrates like sugar, potatoes, white bread, and other starches. This has the effect of decreasing insulin levels, allowing more stored fat to be used for energy. This fat is, to the body, indistinguishable from fat coming from the diet, and has the same effect on appetite as if it were coming from the diet. Since the body is extracting adequate energy from its fat stores, there's no increased feelings of hunger despite the restriction in dietary calories. A corollary of all this is that dietary fat does not itself make a person fat and eating a low fat diet (which implies increasing carbs assuming we keep calories constant) is probably a very bad way to lose weight, since insulin levels may actually increase under such a regime.

There's more to Taubes' argument but this is the basic idea. I highly recommend reading chapters 22 and 24 of GCBC for more detail. They can be read independently from the rest of the book.

I've been searching for good rebuttals to Taubes, but so far haven't found any. Many people seem annoyed that Taubes would even suggest anything contradicting the conventional wisdom of diet and health and don't engage honestly with his arguments. For instance, consider Michael Fumento's article in Reason, discussing the earlier (2002) article by Taubes that led to the book deal (Taubes' response and Fumento's follow up; there's also this excellent interview with Taubes discussing how the article evolved and some of his more controversial decisions). Fumento is quite angry and in my opinion misrepresents Taubes, whose goal was to get people to take seriously an alternative hypothesis of obesity. Here's Taubes in his response to George Bray (Bray's review and discussion by Michael Eades):
One goal of GCBC is to motivate investigators in this field to take a more rigorous, strictly scientific approach to their research, rather than taking critical issues on faith because they agree with their preconceptions. The book attempts to establish that compelling evidence indeed exists for an alternative hypothesis of obesity, and that the disorder is fundamentally caused by the influence of carbohydrates on insulin and insulin on fat accumulation, not by eating too much or sedentary behaviour as has been dogma for decades.
In the afterword of GCBC, Taubes is also quite explicit about the fact that he simply wants people to take the alternative hypothesis seriously and even suggests an experimental design that would test the theory.

Many responses, such as Bray's, bring up the first law of thermodynamics which states in a closed system energy can be neither created nor destroyed. This is true but irrelevant - the body is not a closed system. In response to increased consumption of calories, the body can: 1) excrete excess calories as waste 2) burn more calories by increasing activity, generating additional heat, or even simply allowing more heat to escape the skin, or 3) store more fat. Likewise, in response to decreased consumption of calories, the body can 1) lower energy expenditure in numerous ways or 2) convert fat or protein to energy. Given how much discretion the body has over these pathways, much of it involuntary or subconscious, it is implausible to assume we can hold all other variables constant while decreasing or increasing calorie intake. Robert McLeod also elaborates on this in his review. Also see Michael Eades' discussion.

A more substantive criticism is Taubes doesn't devote adequate attention to determining what factors promote or inhibit insulin sensitivity and fat metabolism in general, or at least emphasizing that these are critical questions. There obviously is more to the story here - in addition to the questions raised above regarding LPL activity, we know that some individuals can consume large amounts of sugar and carbs without becoming fat. What is the reason for this? Simply saying it's "genetic" or there exists a "set-point" is not an explanation (and Taubes trashes the whole set-point concept so I doubt he'd accept such an "explanation") - ultimately, there must be some biochemical mechanism, and if there is such a mechanism it could potentially be influenced in some way by diet or exercise.

GCBC also fails to fully close the loop in the explanation of weight gain, energy levels, and hunger. We need to know the mechanisms by which the body increases or decreases energy expenditure and hunger. It seems that the hormone leptin plays a major role here (article on Mark's Daily Apple, follow up, Stephen Guyenet's discussion of leptin resistance), but Taubes doesn't discuss it much at all.

Overall, though, I highly recommend the book.


Linc said...

Insulin is not the only hormone that influences fat loss. It's not even the most important one. Please read Mastering Leptin for a scientifically thorough deep dive into all that influences fat gain/loss.

Paul Chiusano said...

@Linc - from what I have read so far, leptin seems more important for regulating hunger and possibly energy expenditure... it seems it doesn't (directly) regulate whether fat flows into or out of fat tissue like insulin does. What is your understanding? Can you give any sort of summary of what you know?