Quote so you don't have to visit X: --- “Calories in / calories out” is bullshit. You can make mice eat 4x the calories and end up the same body weight, as l

Quote so you don't have to visit X: --- “Calories in / calories out” is bullshit. You can make mice eat 4x the calories and end up the same body weight, as long as the calories are from soda.¹ Scientists restricted one amino acid (isoleucine) in mice. This made them eat twice as much, have ~75% less fat mass, and live 33% longer.² The metabolic rate increases in response to protein-deficient overfeeding works in large part thru a circulating factor called FGF21.³ This explains the lifespan increase and lower body weight despite higher food intake, as we saw the same thing in genetically-modified mice that over-express FGF21.⁴ The mice that ate more and weighed less had much more FGF21. We have data showing up to a 44x increase FGF21 in response to protein deficient overfeeding in humans.⁵ There was individual variation, though, and some had a blunted increase in energy expenditure from FGF21 and gained more weight. FGF21 can be induced to match energy intake, though, as in ref 5. However, if the liver sees more calories than the rest of the body (i.e., MCT + fructose), whole body energy expenditure can increase more than food intake thru FGF21 over-induction,⁶ lowering bodyweight. (The liver releases FGF21) This suggests a high calorie low protein paradigm, with plenty of sugar and MCTs, would be ideal for weight loss without restricting calories, so long as the human doesn’t have a blunted metabolic response to FGF21. While the proponents of the “calories in / calories out” idea claim it's just thermodynamics, they use it as an argument to eat less. This is an implicit assumption that only “calories in” is flexible and calories out is inflexible. The name “calories in / calories out” now means “calories in is the only thing that matters.” Mouse data show clear interventional evidence that you can change the metabolic rate to change weight outcomes. Human data shows that these mechanisms are conserved, but no one has done the necessary ‘randomized controlled trials’ because the dietary interventions are anti-paradigmatic: lower protein in the context of a high calorie, sugary diet. I don’t expect these trials to pass IRB review, so you must go forward and be n=1.