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.

Epigenetic mechanisms involve the placing (writing) or removal (erasing) of histone modifications that allow heterochromatin to transition to the open, activated euchromatin state necessary for transcription. A third, less studied epigenetic pathway involves the reading of these specific histone marks once placed. The BETs (bromodomain and extraterminal-containing protein family), which includes BRD2, BRD3, and BRD4 and the testis-restricted BRDT, are epigenetic reader proteins that bind to specific acetylated lysine residues on histone tails where they facilitate the assembly of transcription complexes including transcription factors and transcriptional machinery like RNA Polymerase II. As reviewed here, considerable recent data establishes BETs as novel determinants of induced transcriptional programs in vascular cells, like endothelial cells and vascular smooth muscle cells, cardiac myocytes and inflammatory cells, like monocyte/macrophages, cellular settings where these epigenetic reader proteins couple proximal stimuli to chromatin, acting at super-enhancer regulatory regions to direct gene expression. BET inhibition, including the use of specific chemical BET inhibitors like JQ-1, has many reported effects in vivo in the cardiovascular setting, like decreasing atherosclerosis, angiogenesis, intimal hyperplasia, pulmonary arterial hypertension, and cardiac hypertrophy. At the same time, data in endothelial cells, adipocytes, and elsewhere suggest BETs also help regulate gene expression under basal conditions. Studies in the cardiovascular setting have highlighted BET action as a means of controlling gene expression in differentiation, cell identity, and cell state transitions, whether physiological or pathological, adaptive, or maladaptive. While distinct BET inhibitors are being pursued as therapies in oncology, a large prospective clinical cardiovascular outcome study investigating the BET inhibitor RVX-208 (now called apabetalone) has already been completed. Independent of this specific agent and this one trial or the numerous unanswered questions that remain, BETs have emerged as novel epigenetic players involved in the execution of coordinated transcriptional programs in cardiovascular health and disease.

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Prolonged exercise has positive metabolic effects in obese or diabetic individuals. These effects are usually ascribed to improvements in insulin sensitivity. We evaluated whether exercise also generates circulating signals that protect human and rodent β cells against endoplasmic reticulum (ER) stress and apoptosis. For this purpose, we obtained serum from humans or mice before and after an 8 wk training period. Exposure of human islets or mouse or rat β cells to human or rodent sera, respectively, obtained from trained individuals reduced cytokine (IL-1β+IFN-γ)- or chemical ER stressor-induced β-cell ER stress and apoptosis, at least in part via activation of the transcription factor STAT3. These findings indicate that exercise training improves human and rodent β-cell survival under diabetogenic conditions and support lifestyle interventions as a protective approach for both type 1 and 2 diabetes.-Paula, F. M. M., Leite, N. C., Borck, P. C., Freitas-Dias, R., Cnop, M., Chacon-Mikahil, M. P. T., Cavaglieri, C. R., Marchetti, P., Boschero, A. C., Zoppi, C. C., Eizirik, D. L. Exercise training protects human and rodent β cells against endoplasmic reticulum stress and apoptosis.