Using trehalose to prevent and treat metabolic function: effectiveness and mechanisms

Abstract

Purpose of review: Trehalose is a disaccharide with manifold industrial, commercial and biomedical uses. In the decade following its initial definition as an autophagy-inducing agent, significant advances have been realized in regard to the applicable clinical and preclinical contexts in which trehalose can be deployed. Moreover, the mechanisms by which trehalose exerts its metabolic effects are only beginning to gain clarity. In this review, we will highlight the most recent advances regarding the effectiveness and mechanisms of trehalose actions in metabolic disease, and discuss barriers and opportunities for this class of compounds to advance as a clinical therapeutic.

Recent findings: Trehalose reduced cardiometabolic disease burden in diet-induced and genetic models of atherosclerosis, dyslipidemia, hepatic steatosis and insulin tolerance and glucose tolerance. The mechanism by which these effects occurred were pleiotropic, and involved activation of fasting-like processes, including autophagic flux and transcription factor EB. These mechanisms depend heavily on route of administration and disease-specific context. Host and microbial trehalase activity is likely to influence trehalose efficacy in a tissue-dependent manner.

Summary: Trehalose and its analogues are promising cardiometabolic therapeutic agents with pleiotropic effects across tissue types. It is likely that we are only beginning to uncover the broad efficacy and complex mechanisms by which these compounds modulate host metabolism.

Figure 1.

Metabolic effects of trehalose in multiple tissue types. Trehalose inhibits atherosclerotic plaque formation and secondary cardiomyopathies. Moreover, trehalose activates fasting signaling, reduces hepatic steatosis and activates adipose tissue browning. Gut microbial and brush border trehalases are likely to limit trehalose maximal trehalose efficacy as a metabolic therapeutic agent, which creates an opportunity for trehalose analogues that resist – or even inhibit – trehalase activity.