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.
Author contributions: P.D. and M.A.L. designed research; P.D., K.U., M.L., and M.A. performed research; P.D. and M.J.E. contributed new reagents/analytic tools; P.D., C.J., and M.A.L. analyzed data; and P.D. and M.A.L. wrote the paper. Reviewers: D.P.M.,
Most cells of the body contain molecular clocks, but the requirement of peripheral clocks for rhythmicity, and their effects on physiology, are not well understood. Here we show that deletion of core clock components REV-ERBα and β in adult mouse hepatocytes disrupted diurnal rhythms of a subset of liver genes and altered the diurnal rhythm of de novo lipogenesis. Liver function is also influenced by non-hepatocytic cells, and the loss of hepatocyte REV-ERBs remodeled the rhythmic transcriptomes and metabolomes of multiple cell types within the liver. Finally, alteration of food availability demonstrated the hierarchy of the cell-intrinsic hepatocyte clock mechanism and the feeding environment. Together, these studies reveal previously unsuspected roles of the hepatocyte clock in the physiological coordination of nutritional signals and cell-cell communication controlling rhythmic metabolism.
(1) Background: Pancreatic iron deposition has been found in the progression of type 2 diabetes (T2DM); however, whether ferroptosis contributes to the dysfunction of pancreatic β cells (PBC) remains enigmatic. Moreover, the potential protective effect of quercetin is also elusive; (2) Methods: T2DM mice model was established by multiple low dose streptozocin (STZ) injection, after which quercetin was intervened for 4 months; (3) Results: Substantially normalized glucose tolerance, diabetic symptoms, homeostasis model assessment for insulin resistance (HOMA-IR), and homeostasis model assessment for β cell (HOMA-β) index in comparison with the findings of T2DM control. Distorted pancreatic islets and especially shrunken mitochondria with cristae loss in PBC were observed in T2DM mice, which was ameliorated by quercetin. Meanwhile, quercetin lowered the iron level particularly in the islet in T2DM mice. In spite of compensatory xCT up-regulation, T2DM molding depleted glutathione (GSH), down-regulated glutathione peroxidase 4 (GPX4), and induced oxidative stress in pancreatic tissue, which was abolished partially by quercetin. More importantly, insulin secretion was worsened by ferroptosis-inducing erastin or RAS-selective lethal compounds 3 (RSL-3). Quercetin, ferroptosis inhibitor ferrostatin-1 and iron-chelating deferoxamine, rescued cell viability when cells were challenged with high-glucose; (4) Conclusions: Our findings identify that ferroptosis contributes to the PBC loss and dysfunction. Quercetin exerts beneficial effects on T2DM potentially by inhibiting pancreatic iron deposition and PBC ferroptosis, highlighting promising control strategies of T2DM by quercetin.
The heart is a highly metabolic organ that uses multiple energy sources to meet its demand for ATP production. Diurnal feeding-fasting cycles result in substrate availability fluctuations which, together with increased energetic demand during the active period, impose a need for rhythmic cardiac metabolism. The nuclear receptors REV-ERBα and β are essential repressive components of the molecular circadian clock and major regulators of metabolism. To investigate their role in the heart, here we generated mice with cardiomyocyte (CM)-specific deletion of both Rev-erb s, which died prematurely due to dilated cardiomyopathy. Loss of Rev-erbs markedly downregulated fatty acid oxidation genes prior to overt pathology, which was mediated by induction of the transcriptional repressor E4BP4, a direct target of cardiac REV-ERBs. E4BP4 directly controls circadian expression of Nampt and its biosynthetic product NAD + via distal cis -regulatory elements. Thus, REV-ERB-mediated E4BP4 repression is required for Nampt expression and NAD + production by the salvage pathway. Together, these results highlight the indispensable role of circadian REV-ERBs in cardiac gene expression, metabolic homeostasis and function.
Recent advances in transcriptome sequencing have made it possible to distinguish ubiquitously expressed long non-coding RNAs (UE lncRNAs) from tissue-specific lncRNAs (TS lncRNAs), thereby providing clues to their cellular functions. Here, we assembled and functionally characterized a consensus lncRNA transcriptome by curating hundreds of RNA-seq datasets across normal human tissues from 16 independent studies. In total, 1,184 UE and 2,583 TS lncRNAs were identified. These different lncRNA populations had several distinct features. Specifically, UE lncRNAs were associated with genomic compaction and highly conserved exons and promoter regions. We found that UE lncRNAs are regulated at the transcriptional level (with especially strong regulation of enhancers) and are associated with epigenetic modifications and post-transcriptional regulation. Based on these observations we propose a novel way to predict the functions of UE and TS lncRNAs through analysis of their genomic location and similarities in epigenetic modifications. Our characterization of UE and TS lncRNAs may provide a foundation for lncRNA genomics and the delineation of complex disease mechanisms.
The striatum comprises multiple subdivisions and neural circuits that differentially control motor output. The islands of Calleja (IC) contain clusters of densely-packed granule cells situated in the ventral striatum, predominantly in the olfactory tubercle (OT). Characterized by expression of the D3 dopamine receptor, the IC are evolutionally conserved, but have undefined functions. Here we show that optogenetic activation of OT D3 neurons robustly initiates self-grooming in mice while suppressing other ongoing behaviors. Conversely, optogenetic inhibition of these neurons halts ongoing grooming, and genetic ablation reduces spontaneous grooming. Furthermore, OT D3 neurons show increased activity before and during grooming and influence local striatal output via synaptic connections with neighboring OT neurons (primarily spiny projection neurons, SPNs), whose firing rates display grooming-related modulation. Our study uncovers a novel role of the ventral striatum’s IC in regulating motor output and has important implications for the neural control of grooming.
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