Diet-Induced Circadian Enhancer Remodeling Synchronizes Opposing Hepatic Lipid Metabolic Processes

Abstract

Overnutrition disrupts circadian metabolic rhythms by mechanisms that are not well understood. Here, we show that diet-induced obesity (DIO) causes massive remodeling of circadian enhancer activity in mouse liver, triggering synchronous high-amplitude circadian rhythms of both fatty acid (FA) synthesis and oxidation. SREBP expression was rhythmically induced by DIO, leading to circadian FA synthesis and, surprisingly, FA oxidation (FAO). DIO similarly caused a high-amplitude circadian rhythm of PPARα, which was also required for FAO. Provision of a pharmacological activator of PPARα abrogated the requirement of SREBP for FAO (but not FA synthesis), suggesting that SREBP indirectly controls FAO via production of endogenous PPARα ligands. The high-amplitude rhythm of PPARα imparted time-of-day-dependent responsiveness to lipid-lowering drugs. Thus, acquisition of rhythmicity for non-core clock components PPARα and SREBP1 remodels metabolic gene transcription in response to overnutrition and enables a chronopharmacological approach to metabolic disorders.

The importance of being rhythmic: Living in harmony with your body clocks

“…Following lentiviral transduction, cells are synchronized in vitro by various stimuli and subjected to circadian bioluminescence recording during several days. [39][40][41][42]187,190 Photomultiplier tube-based measurements are sued to conduct population analysis of cellular rhythms (upper schema), 210 taken into account when administrating metformin, 206 lipid lowering drugs, 127 inflammatory drugs targeting the glucocorticoid receptor 122,207 and many other therapeutic agents.…”

“…30,109,[112][113][114][115][116][117][118][119][120] In skeletal muscle, REV-ERBα directly represses enzymes essential for lipid and protein metabolism, along with BMAL1, which activates key regulators of lipid metabolism. 127 Additionally, the RNA-binding protein NONO situated in liver cell nuclei couples the rhythmic expression of metabolic genes with nutrient levels, with NONO-deficient mice exhibiting impaired glucose tolerance as well as lower hepatic glycogen and lipid content. 121 In the liver, REV-ERBα couples glucocorticoid signalling to energy metabolism via binding of the hepatocyte nuclear transcription factors HNF4A/HNF6.…”

“…126 Furthermore, diet-induced obesity in wild-type mice causes remodelling of the circadian liver enhancer landscape, leading to massive changes in lipid metabolism via SREBP and PPARα. 127 Additionally, the RNA-binding protein NONO situated in liver cell nuclei couples the rhythmic expression of metabolic genes with nutrient levels, with NONO-deficient mice exhibiting impaired glucose tolerance as well as lower hepatic glycogen and lipid content. 128 Advanced approaches for circadian metabolomic and lipidomic studies reveal that a large number of metabolites are oscillating around-the-clock in rodents and in human tissues, plasma and saliva.…”

Personalized medicine and circadian rhythms: Opportunities for modern society

“…In the liver, it leads to activation of lipid-related transcription factors at a specific circadian time, promoting oscillation of transcriptional pathways involved in fatty acid synthesis, fatty acid oxidation, and glycerophospholipid metabolism. Paralleling gene transcription, a number of lipid metabolites also follow a similar pattern of gain of oscillation (Eckel-Mahan et al, 2013;Guan et al, 2018). A mouse study indicated that targeting PPAR-α-a major regulator of lipid metabolism-at its peak expression with an agonist used in the clinic for hyperlipidemia resulted in greater efficacy at lowering hepatic lipid accumulation when delivered (Guan et al, 2018).…”

Liver gene regulatory networks: Contributing factors to nonalcoholic fatty liver disease

“…When comparing young versus old mice, Sato et al () observed age induced reprogramming of the circadian hepatic transcript and chromatin landscapes. However, caloric restriction, which has been associated with clock re‐setting (Guan et al, ), counteracted age‐dependent changes (S. Sato et al, ). Earlier work has also established the role of body temperature as a universal cue in mammalian circadian transcriptional regulation (Buhr, Yoo, & Takahashi, ).…”