Circadian clock controls rhythms in ketogenesis by interfering with PPARα transcriptional network

Abstract

Ketone bodies are energy-rich metabolites and signaling molecules whose production is mainly regulated by diet. Caloric restriction (CR) is a dietary intervention that improves metabolism and extends longevity across the taxa. We found that CR induced high-amplitude daily rhythms in blood ketone bodies (beta-hydroxybutyrate [βOHB]) that correlated with liver βOHB level. Time-restricted feeding, another periodic fasting–based diet, also led to rhythmic βOHB but with reduced amplitude. CR induced strong circadian rhythms in the expression of fatty acid oxidation and ketogenesis genes in the liver. The transcriptional factor peroxisome-proliferator-activated-receptor α (PPARα) and its transcriptional target hepatokine fibroblast growth factor 21 (FGF21) are primary regulators of ketogenesis. Fgf21 expression and the PPARα transcriptional network became highly rhythmic in the CR liver, which implicated the involvement of the circadian clock. Mechanistically, the circadian clock proteins CLOCK, BMAL1, and cryptochromes (CRYs) interfered with PPARα transcriptional activity. Daily rhythms in the blood βOHB level and in the expression of PPARα target genes were significantly impaired in circadian clock–deficient Cry1,2 −/− mice. These data suggest that blood βOHB level is tightly controlled and that the circadian clock is a regulator of diet-induced ketogenesis.

Ketogenic propensity is differentially related to lipid‐induced hepatic and peripheral insulin resistance

“…35 Comparisons between reports are difficult to interpret due to differences in the strategies used to perturb βOHB levels (e.g., intravenous infusion, ketogenic diet, exogenous ketone supplement) and methods used to quantify insulin sensitivity (e.g., hyperinsulinemiceuglycemic clamp, HOMA-IR, oral glucose tolerance test). Further, circadian timing affects ketogenesis 36 and was not matched between reports, which may be particularly critical regarding peripheral glucose metabolism. 37,38 Our data supplements this prevailing literature, evidencing altered ketone body metabolism at the onset of lipid-induced insulin resistance and reporting discrete relationships between plasma βOHB and both hepatic and peripheral insulin sensitivity.…”

Sexual dimorphism of circadian liver transcriptome

“…Liver rhythmic transcriptome under AL diet was published by multiple groups, but the response of circadian transcriptome to various anti-aging feeding paradigms is a subject of ongoing research. 25 , 28 , 29 , 70 , 71 Acosta-Rodriguez et al. reported a positive effect of timed CR on transcriptomic rhythmicity and lifespan extension in male mice, 28 while Sato et al.…”

“… The transcriptomic RNAseq data have been deposited and made publicly available via the Gene Expression Omnibus repository [ GSE216416 ; GSE211975 70 ] as of the date of publication. Processed RNA-seq data is available for quick access as Tables S1 and S2 .…”

Ketones and the cardiovascular system

“…In addition, ketogenic diets have been shown to inhibit mitochondrial biogenesis and induce cardiac fibrosis 96 . The circadian clock has also been shown to control ketogenesis and contribute to changes in the blood βOHB levels 115 , so it will be important to consider time of day measurements of βOHB concentrations in subsequent studies. Together, these studies suggest that while a ketogenic diet may have some benefit for treating CV disease, much more research is needed before definitive conclusions can be drawn.…”