The metabolism/obesity area has had a lot of interesting findings show up over the years, many of which initially appeared promising for human therapy. Leptin, ghrelin, orexin, NPY5, AGRP, melanocortin receptors, MCH, POMC, peptide YY, 5-HT2c ligands, CB1 receptor ligands, SCD1, beta-3 agonists. . .all of them have turned out to be more complicated than they might have appeared at first. Their role in human feeding behavior and energy balance turned out to be compensated for by other signaling pathways, or they had somewhat different functions in humans than in animal models, or there were unanticipated side effects to targeting them, or they simply weren’t as important as they first appeared. The landscape is littered with these things. I’ve written about several over the years here on the blog, and none of those have gone on to set the therapeutic landscape on fire, either, as far as I can see.
That’s especially true for the various attempts to work out and/or exploit out the biochemical pathways behind the beneficial effects of exercise. It’s a truism, and I know that physicians get tired of recommending it to their patients, especially since so few of them actually follow through. But this one got to be a truism because it’s true. There is nothing in the pharmacopeia like the effects of physical activity. Just to pick one prominent example, it can drag mild cases of Type II diabetes back over the line towards normal function, while improving many other factors at the same time (cardiovascular health, bone density, lipid levels, and more). It has effects on almost every physiological system, and naturally enough, it has occurred to many people over the years that recapitulating at least some of that pharmcologically would be very, very useful.
So keep that history in mind when you read this new paper, which is nonetheless certainly worth a look. The authors report that exercise causes N-lactoyl phenylalanine to be synthesized in several cell types, and that this is responsible for many exercise-induced effects. This metabolite had been noted before in other metabolic screening efforts, and there was a 2015 report of it (and other N-lactoyl amino acids), where that team found that they were produced by cytosolic nonspecific peptidase 2 (CNDP2), an enzyme that is helpfully known in the literature by at least a dozen other names. That sounds a bit funny, since peptidases are meant to go around cleaving amide bonds, not forming them, but like several other enzyme classes, they can sometimes be run in reverse depending on the conditions (particularly local concentrations of substrates). I always imagine this happening with that car-transmission-in-reverse-gear noise, but there is as yet no evidence for that effect. A guy can hope.
This latest work is drawing a connection between a well-known exercise metabolite (lactate) and longer-term endocrine signaling. Lac-Phe is produced under exercise conditions in mice, racehorses, and humans, and just the fact that it’s being made in CNDP2-containing cells shows how wide-ranging exercise effects can be. You’d imagine this happening in muscle tissue, but it seems to be more coming from things like macrophages, monocytes, epithelial cells and others. And once Lac-Phe is released, it has effects on food intake (in diet-induced obese mice) without apparently affecting physical activity, and continued administration of it reduces fat levels, body weight, and improves glucose handling (as reducing those two almost invariably does). On the other side of the coin, mice whose CNDP2 gene was knocked out responded to exercise by eating more than their wild-type counterparts.
There are a couple of things to point out immediately. One of them is that Lac-Phe was completely ineffective when dosed orally – it’s clearly broken down like other small peptides in the gut, so if anyone tries to sell you some of it down at the vitamin store in a few months – what am I talking about, in a few weeks – then you should save your money. The second thing is that we really have no idea of how it’s working. The authors of this paper believe that there are “as yet unidentified receptors and. . .neural circuits” involved in its signaling, and you can bet that investigations are underway to track these down. But for now, the only way to get your Lac-Phe is the hard way. With exercise. Which will do all of us a lot of good.
