Essential roles of four-carbon backbone chemicals in the control of metabolism

Abstract

The increasing incidence of obesity worldwide and its related cardiometabolic complications is an urgent public health problem. While weight gain results from a negative balance between the energy expenditure and calorie intake, recent research has demonstrated that several small organic molecules containing a four-carbon backbone can modulate this balance by favoring energy expenditure, and alleviating endoplasmic reticulum stress and oxidative stress. Such small molecules include the bacterially produced short chain fatty acid butyric acid, its chemically produced derivative 4-phenylbutyric acid, the main ketone body D-β-hydroxybutyrate - synthesized by the liver - and the recently discovered myokine β-aminoisobutyric acid. Conversely, another butyrate-related molecule, α-hydroxybutyrate, has been found to be an early predictor of insulin resistance and glucose intolerance. In this minireview, we summarize recent advances in the understanding of the mechanism of action of these molecules, and discuss their use as therapeutics to improve metabolic homeostasis or their detection as early biomarkers of incipient insulin resistance.

Keywords: Butyric acid; D-β-hydroxybutyrate; Histone deacetylases; Histone deacetylases inhibitors; Insulin resistance

Core tip: Recent research demonstrated that the four-carbon molecule butyrate, and butyrate-related molecules (4-phenylbutyric acid, D-β-hydroxybutyrate and β-aminoisobutyric acid), act as modulators of metabolism, favoring energy expenditure. Conversely, another butyrate-related molecule, α-hydroxybutyrate, is an early predictor of insulin resistance and glucose intolerance. In this minireview, we summarize the recent progress in the understanding of the mechanism of action of these molecules and discuss their possible therapeutic use to improve metabolic homeostasis and their usefulness as early biomarkers for insulin resistance.