This is a short paper on ketogenesis and is well wroth a read imo. Very accessible even to the layperson. Interestingly, the ketone acetoacetate is the preferred substrate for fuel, chosen above even glucose. The liver is the only place ketones are synthesized, and the liver itself cannot oxidize ketones, it can only release them.
I was one of the people who thought that the switch for ketogenesis was simply the depletion of oxaloacetate in the liver mitochondria, but this is not true. Apparently the signal for ketogenesis is glucagon, aswell as a decrease in Malonyl-CoA in the liver. Once the glucagon signal hits the liver, the rate-limiting step for ketogenesis is simply the amount of fats reaching the liver from the adipose tissue. The liver will burn fats and generate ketones as fast as it can.
Anyway, just read the paper. !
Calorie restriction increases fatty acid synthesis and whole body fat oxidation rates
This is another fascinating paper, I havent seen it discussed elsewhere, if memory serves.....
The paper is another fantastic demonstration of the futility of calorie restriction in attempting to lose weight. ( although that was not the objective of the study ). Mice subjected to 30% calorie restriction achieved a lower bodyweight,
After an initial 1- to 2-wk period of weight loss, CR mice reestablish a state of energy balance in which fat mass is preserved or even increased.
The paper talks about the nutrient balancing hypothesis, and that to remain weight stable, the food quotient must match the respiratory quotient. I.E. if you eat 300g carbs and 100g fats per day, then you must also oxidize 300g of carbs and 100g of fats per day to remain weight stable. If you burnt 150g of fat per day in that example, then the theory says you would lose fat mass.
So what happened in this study was that, the 30% calorie restricted mice were only allowed to eat 92mg of fat per day, but the researchers found the mice were oxidizing 367mg of fat per day. Thats a calorie deficit of 275mg of fat per day, so the question was, why werent the mice losing weight? Why where they weight stable? They were in calorie deficit!
Well, the researchers found that the adipose tissue ( not the liver ) of the calorie restricted mice were actually synthesizing the missing 275mg of fat per day!.
In addition, in the first 3 h postfeeding, endogenously synthesized palmitate accumulated in the subcutaneous depot five times faster in calorie restricted mice than in ad-libitum controls,
Glucose is likely the predominant substrate for FA synthesis in the adipose tissue. Consistent with adipose playing a role in FA synthesis, Wetter et al. (45) demonstrated that glucose uptake is increased in adipose tissue of calorie-restricted rats.
immediately after food was provided, fatty-acid synthase enzyme expression increased 50-fold in calorie restricted mice, leading to values nearly threefold higher than ad-libitum controls
Anyway, as I spoke of before, calorie restriction increases AgRP, this in turn blocks MC4R signalling. Maybe whats happening is that a lack of MC4R signalling in adipose tissue leads to elevated FA synthesis in white adipocytes? Well, even if this is not the mechanism, the point remains, 30% calorie restriction increases FA synthesis in your adipocytes.
But what about 20% calorie restriction? Maybe I can lose weight there without the FA synthesis? Or 15%??
MAYBE THERES A MAGIC NUMBER THAT ALLOWS ME TO LOSE WEIGHT WITHOUT THE NEGATIVE EFFECTS OF CALORIE RESTRICTION??!?!