Always Hungry? It's Probably Not Your Insulin.

David Ludwig, MD, recently published a new book titled Always Hungry? Conquer cravings, retrain your fat cells, and lose weight permanently.  The book is getting widespread media coverage.  Ludwig is a professor of pediatrics at the Harvard Medical School and a professor of nutrition at the Harvard School of Public Health.  He's a pediatric endocrinologist, but his primary focus is research, particularly the impact of nutrition on hunger, calorie expenditure, and body weight.  Although I sometimes disagree with how he interprets evidence, he has made significant and useful contributions to the scientific literature in these areas, and I also support his efforts to find policy solutions to curb the intake of sweetened beverages and other junk foods.  In the grand scheme of things, he's an ally in the fight to improve the American diet.

Ludwig has written several high-profile op-ed pieces in recent years, both in the popular press and in scientific journals (1, 2).  He argues that our understanding of eating behavior and obesity may be all wrong, and that our focus on calories may be leading us away from the true cause of obesity: hormonal imbalance.  And the primary culprit is insulin.  You might recognize this idea, because it's similar to the one that science journalist Gary Taubes developed in his book Good Calories, Bad Calories.

According to this view, overeating is irrelevant.  We gain fat because our insulin levels are too high, leading our fat tissue to take up too much fat, and other tissues to take up too much glucose, causing our blood energy levels to drop and resulting in fat gain, hunger, and fatigue.  The ultimate cause of the problem is the rapidly-digesting carbohydrate and sugar we eat.  This idea is encapsulated by Ludwig's quote, "Overeating doesn't make you fat.  The process of getting fat makes you overeat" (3).

Here are eleven facts that may make you question this line of reasoning:

1. Overeating does make you fat.   Randomized controlled trials have shown that eating excess calories causes fat gain, whether the extra calories come from fat or carbohydrate, and regardless of their impact on insulin levels (4, 5).  If you eat too many calories, regardless of why you overate, you will gain fat (although some people are intrinsically more resistant to overeating-induced fat gain than others).  That's why overeating remains a key concept for understanding body fatness.
2. Hunger is only one of the reasons we eat.  We don't generally eat dessert because we're still hungry at the end of a meal.  We don't drink alcohol or put cream and sugar in our coffee because we're hungry.  Much of the eating we do in the affluent world has little to do with hunger-- a phenomenon researchers call "non-homeostatic eating".  
3. Blood levels of fat and glucose tend to be normal or elevated in people with obesity and high insulin, not lower (6, 7, 8).  That's because they're insulin resistant, meaning that insulin isn't doing its job of constraining blood glucose and fat levels as effectively.  Since people with obesity/overweight don't have lower circulating energy levels than lean people, this cannot explain why they eat more.  Obesity is not a condition of "internal starvation".
4. Fat cells do not have an increased affinity for fat in people with obesity and high insulin.  In fact, people with obesity and elevated insulin release fat from their fat tissue at a higher rate than lean people with lower insulin (higher total lipolysis rate; 9).  Again, this may relate to the fact that they're insulin resistant.
5. Body fatness is regulated by the brain, not by fat tissue or the pancreas.  There is a vast research literature showing that the brain regulates food intake, energy expenditure, and fat tissue metabolism to regulate the size of body fat stores (10).  There is no known mechanism intrinsic to fat tissue or the insulin-secreting pancreas that does this.  Genetic differences that impact body fatness tend to be located in genes that affect brain function, not fat tissue or insulin signaling (11, 12).
6. High insulin levels do not predict future weight gain (13, 14).  This is a basic prediction of the hypothesis that has been tested many times, and the majority of the evidence doesn't support it.
7. If high insulin were a major contributor to obesity, weight loss would be a positive feedback process.  In other words, the more weight you lost, the easier it would become to lose further weight.  This is because weight loss itself reduces insulin levels, both between and after meals (15, 16).  Yet what we observe is the opposite: weight loss becomes more difficult the more you lose, despite declining insulin levels (a negative feedback process).
8. Foods that lead to higher blood levels of glucose and insulin do not result in greater subsequent hunger.  The most comprehensive study examined 38 common foods and found no relationship between glycemic index and subsequent hunger, and an inverse relationship between insulin levels and hunger (i.e., foods that caused greater insulin release tended to be more filling; 17).
9. Diets that reduce blood glucose and insulin swings (low-glycemic) are not an effective tool for weight control.  This has been shown repeatedly in RCTs lasting longer than two months (18, 19, 20, 21, 22, 23), including an 18-month study by Ludwig's group that found a low-glycemic-load diet to provide the same weight and fat loss, and the same participant satisfaction, as a standard low-fat diet (24).  This is despite the fact that these studies often don't control for confounding dietary factors like fiber content, calorie density, protein, and/or palatability (i.e., the "low-glycemic" diet is often a whole-food-based diet).
10. Billions of people globally eat high-glycemic diets and remain lean.  Many traditional diets are very high in starch and low in fat.  If foods that promote large blood sugar and insulin spikes were the primary factor in obesity, shouldn't these people be obese?  
11. There is no evidence that our appetites increase, and our energy level drops, because our fat cells are hoovering up fat from the bloodstream.  You would think, with how often this is repeated, that there would be some kind of evidence that this process is actually happening in common obesity.  Yet despite having read a number of works by Taubes and Ludwig, I haven't found anything more concrete than speculation and analogies.  The concrete evidence I have encountered (#3 and 4 above) is at odds with the claim.

I have no doubt that the whole-food-based diet and lifestyle advice in Ludwig's book is healthy and slimming.  What I doubt is the mechanism to which he attributes these effects.

There are other hypotheses that explain why some of us are "always hungry", but these focus on the brain-- the organ that controls hunger, food motivation, body fatness, and the behaviors of food intake.  In my view, these are a better fit for the evidence.