Mimicking Signaling from Exercise and Fasting in One Molecule
The metabolic responses to exercise and calorie restriction are so sweeping that there are many, many possible avenues by which drugs can mimic some of the effects. Researchers here try to get closer to the roots of these beneficial responses by using a molecule that will trigger the same reactions as two circulating signal molecules known to be important in regulating the response to exercise and fasting. This seems a reasonable strategy to try to capture a larger fraction of the benefits of exercise and fasting, but of course much more work is needed in order to see how this approach matches up to the sizable number of existing exercise mimetic and calorie restriction mimetic interventions.
Elevation of the plasma levels of (S)-lactate (Lac) and/or (R)-beta-hydroxybutyrate (BHB) occurs naturally in response to strenuous exercise and prolonged fasting, respectively, resulting in millimolar concentrations of these two metabolites. It is increasingly appreciated that Lac and BHB have wide-ranging beneficial physiological effects, suggesting that novel nutritional solutions, compatible with high-level and/or sustained consumption, which allow direct control of plasma levels of Lac and BHB, are of strong interest.
In this study, we present a molecular hybrid between (S)-lactate and the BHB-precursor (R)-1,3-butanediol in the form of a simple ester referred to as LaKe. We show that LaKe can be readily prepared on the kilogram scale and undergoes rapid hydrolytic conversion under a variety of physiological conditions to release its two constituents. Oral ingestion of LaKe, in rats, resulted in dose-dependent elevation of plasma levels of Lac and BHB triggering expected physiological responses such as reduced lipolysis and elevation of the appetite-suppressing compound N-L-lactoyl-phenylalanine (Lac-Phe).