Metabolic and Signaling Roles of Ketone Bodies in Health and Disease

Abstract

Ketone bodies play significant roles in organismal energy homeostasis, serving as oxidative fuels, modulators of redox potential, lipogenic precursors, and signals, primarily during states of low carbohydrate availability. Efforts to enhance wellness and ameliorate disease via nutritional, chronobiological, and pharmacological interventions have markedly intensified interest in ketone body metabolism. The two ketone body redox partners, acetoacetate and D-β-hydroxybutyrate, serve distinct metabolic and signaling roles in biological systems. We discuss the pleiotropic roles played by both of these ketones in health and disease. While enthusiasm is warranted, prudent procession through therapeutic applications of ketogenic and ketone therapies is also advised, as a range of metabolic and signaling consequences continue to emerge. Organ-specific and cell-type-specific effects of ketone bodies are important to consider as prospective therapeutic and wellness applications increase.

Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosis

“…We tested a possibility of whether HMGCS2 OE-mediated improvement against hepatosteatosis was mediated via the non-ketogenic, ‘moonlighting’ effect of HMGCS2, particularly transcriptional regulation via direct interaction with PPARα, a key transcription factor of FAO, thereby promoting its target gene expression [ 9 , 19 , [85] , [86] , [87] ]. However, contrary to previous findings [ 85 , 86 ], we found that PPARα downstream target genes involved in FAO (e.g., Ppara , Cpt1a , Mcad ) were upregulated in Hmgcs2 -KO livers ( Figure 2 O) and downregulated in HMGCS2 -overexpressed livers ( Figure 6 I).…”

“…Moreover, the shift from a prenatal carbohydrate-enriched environment (dependent on placental glucose transfer) to a postnatal fat-enriched environment (dependent on breast milk), promotes ketogenesis and a consequential reliance on ketone bodies as primary energy substrates in neonates [ [13] , [14] , [15] , [16] , [17] ]. In addition to their fat-metabolizing and energy-generating capacity, ketone bodies provide other health benefits, including protection from inflammation and oxidative stress [ 9 , 18 , 19 ]. As such, ketogenic diets [ [20] , [21] , [22] , [23] ] and ketone ester formulations [ 24 ] have gained popularity for stimulating weight loss [ 10 , 25 ] and improving metabolic disorders (i.e., T2D, obesity, NAFLD).…”

Detecting de novo Hepatic Ketogenesis Using Hyperpolarized [2-13C] Pyruvate

“…Hepatic ketone production serves to provide a readily oxidizable substrate for multi-organ energy homeostasis (Puchalska and Crawford, 2021). Canonically, β-oxidation has been assumed to provide the vast majority of acetyl-CoA used for ketone production (Puchalska and Crawford, 2017).…”

Ketone body oxidation increases cardiac endothelial cell proliferation

“…This results in a surplus of acetyl‐CoA in hepatic mitochondria whenever FAO‐derived acetyl‐CoA exceeds flux through the TCA cycle. Under these circumstances, acetyl‐CoA molecules are enzymatically converted into the ketone bodies acetoacetate and β‐hydroxybutyrate (Puchalska & Crawford, 2021 ). In the healthy, fed state serum ketone body (acetoacetate and β‐hydroxybutyrate) concentrations in humans are low (50–200 µM).…”