Are BHB-Amino Acids the Missing Link to Keto Weight Loss?

How do ketogenic diets decrease appetite, contributing to weight loss? And why might some people respond more strongly to the appetite-suppressant effects of ketogenic diets and lose more weight than other people? And are you a keto responder? We're going to review new exciting data and answer these questions. Now, this research just published in the journal Cell documents the discovery of a whole new class of anti-obesity metabolites, the BHB amino acids. Okay, what the heck are these, the BHB amino acids? Well, when your body's carbohydrate stores run low, either from a very low carbohydrate ketogenic diet or from fasting, the body makes ketone bodies, namely the ketone body beta-hydroxybutyrate, or BHB for short, which is fuel for the brain and other organs. And increasing levels of this ketone body, BHB, defines the metabolic state of ketosis, which defines a ketogenic diet. Metabolic state of ketosis, ketogenic diet, makes sense. Now, while BHB is itself a potent signaling molecule, like a hormone, this new research shows it can also be transformed. Into something entirely new. Specifically, the enzyme carnosine dipeptidase 2, or CNDP2 for short, combines BHB with amino acids, the building blocks of proteins, to make BHB amino acids, this new class of metabolites. Now, of note, and for some medical background, this CNDP2 enzyme was previously known because it makes a compound called LAC-PH, which you might have heard of. It's a combination of lactate and phenylalanine, and this compound is thought to mediate some of the anti-obesity effects of the diabetes drug metformin as well as exercise. But CNDP2 appears to be a multipurpose enzyme, kind of like a Swiss Army knife enzyme, and it can also combine BHB, the ketone body, with amino acids to make the BHB amino acids, the most common of which is BHB and phenylalanine, or BHB-Phy, although there are others. And this pathway importantly appears to be conserved in mice and human beings. Now, here are the high-level points you should know before we dig into some of the nuances. BHB amino acid levels increase in response to ketogenic diets or fasting, or exogenous ketone supplements. There's many ways to get into ketosis, and they all increase BHB amino acid levels. And BHB amino acids activate different brain regions to reduce food intake and promote weight loss. Okay, that was the high level. Now for some more details. Although BHB amino acids are made in humans and present in human blood, To demonstrate causality, it's helpful to use mouse models. So the researchers found that direct administration of a ketone supplement, in this case a ketone ester, or BHB-Fe itself directly decreased food intake and prevented weight gain in a mouse model. However, and really importantly, mice who had been genetically modified to have their CNDP2 gene knocked out and thus could not generate their own BHB amino acids, their own BHB fee, when given a ketone ester supplement, they did not respond to ketone supplementation with appetite suppression. The effect was abolished. So to reinforce the point, ketone supplementation and/or a ketogenic diet contributed to relative weight loss in animals with functional CNDP2 who could make BHB fee or BHB amino acids. But when the ability to make BHB amino acids was eliminated by gene knockout, so too were the appetite-reducing and anti-obesogenic effects of ketones. And this suggests that ketogenic interventions, be it fasting or ketogenic diet or supplement, at least in part act to reduce appetite through the generation of BHB amino acids. And the researchers also found that BHB amino acids, BHB-fee, activate various brain regions in the hypothalamus and the brainstem that control feeding. However, and interestingly, the neuron populations identified appear largely distinct from those activated by LAC-fee, that other molecule we talked about, and don't appear to act through other appetite-suppressing pathways that were assessed in this study, including the GLP-1 pathway, which relates to that whole new generation of obesity weight loss drugs. Thus, how exactly the BHB amino acids reduce appetite and contribute to weight loss by acting in the brain remains a neurobiological mystery. But high level and in review, these data reveal how a secondary metabolite of ketone body metabolism, BHB-Fe and the BHB amino acids, acts to reduce appetite by acting on the brain, leading to weight loss. But we're not done. Of interest and clinical consequence, it's very possible— I want to highlight this— that there are variations in the human CNDP2 gene, and this could lead some people to respond more strongly to ketogenic interventions— diet, fasting, or supplementation— with more or less appetite reduction. And this could be an explanation, or a partial explanation, for why ketogenic diets may work better to suppress appetite in some and not others. Granted, it's not the whole picture. Ketogenic diets have also been shown to increase the excretion of fat calories in your poop through changes in microbiome and bile acid metabolism. If you want more on that, see this video. And they can increase energy expenditure and change mitochondrial dynamics. So many mechanisms. So I don't mean to pretend that this new paper represents the answer, the be-all end-all to how ketogenic diets cause weight loss and why some people might be more responsive than others. However, this is a tremendous advance because it shows for the first time that the combination of ketones with other simple biomolecules Here, amino acids, the building blocks of proteins, have tremendous biological importance and deserve further study. I certainly hope the biomedical community will invest in this research. It's all quite exciting, and I can't wait to see what we learn next. But now let me know, how is your appetite affected by a ketogenic diet, or if you've tried it, ketone supplements. Are you a keto responder or not? Let me know in the comments, and as always, stay curious, and I'm excited for the next one.