bims-ciryme 2023-02-19 papers

Proc Natl Acad Sci U S A. 2023 Feb 21. 120(8): e2218510120

Time of day determines postexercise metabolism in mouse adipose tissue.

Logan A Pendergrast, Leonidas S Lundell, Amy M Ehrlich, Stephen P Ashcroft, Milena Schönke, Astrid L Basse, Anna Krook, Jonas T Treebak, Lucile Dollet, Juleen R Zierath.

The circadian clock is a cell-autonomous transcription-translation feedback mechanism that anticipates and adapts physiology and behavior to different phases of the day. A variety of factors including hormones, temperature, food-intake, and exercise can act on tissue-specific peripheral clocks to alter the expression of genes that influence metabolism, all in a time-of-day dependent manner. The aim of this study was to elucidate the effects of exercise timing on adipose tissue metabolism. We performed RNA sequencing on inguinal adipose tissue of mice immediately following maximal exercise or sham treatment at the early rest or early active phase. Only during the early active phase did exercise elicit an immediate increase in serum nonesterified fatty acids. Furthermore, early active phase exercise increased expression of markers of thermogenesis and mitochondrial proliferation in inguinal adipose tissue. In vitro, synchronized 3T3-L1 adipocytes showed a timing-dependent difference in Adrb2 expression, as well as a greater lipolytic activity. Thus, the response of adipose tissue to exercise is time-of-day sensitive and may be partly driven by the circadian clock. To determine the influence of feeding state on the time-of-day response to exercise, we replicated the experiment in 10-h-fasted early rest phase mice to mimic the early active phase metabolic status. A 10-h fast led to a similar lipolytic response as observed after active phase exercise but did not replicate the transcriptomic response, suggesting that the observed changes in gene expression are not driven by feeding status. In conclusion, acute exercise elicits timing-specific effects on adipose tissue to maintain metabolic homeostasis.

Keywords: adipose tissue; circadian rhythm; exercise; lipolysis; metabolism

DOI: https://doi.org/10.1073/pnas.2218510120

Proc Natl Acad Sci U S A. 2023 Feb 21. 120(8): e2214062120

The circadian demethylation of a unique intronic deoxymethylCpG-rich island boosts the transcription of its cognate circadian clock output gene.

Nisha Misra, Manohar Damara, Tao Ye, Pierre Chambon.

We demonstrate that there is a tight functional relationship between two highly evolutionary conserved cell processes, i.e., the circadian clock (CC) and the circadian DNA demethylation-methylation of cognate deoxyCpG-rich islands. We have discovered that every circadian clock-controlled output gene (CCG), but not the core clock nor its immediate-output genes, contains a single cognate intronic deoxyCpG-rich island, the demethylation-methylation of which is controlled by the CC. During the transcriptional activation period, these intronic islands are demethylated and, upon dimerization of two YY1 protein binding sites located upstream to the transcriptional enhancer and downstream from the deoxyCpG-rich island, store activating components initially assembled on a cognate active enhancer (a RORE, a D-box or an E-box), in keeping with the generation of a transcriptionally active condensate that boosts the initiation of transcription of their cognate pre-mRNAs. We report how these single intronic deoxyCpG-rich islands are instrumental in such a circadian activation/repression transcriptional process.

Keywords: YY1 protein; circadian DNA demethylation-methylation; circadian clock (CC); circadian transcription; intronic deoxyCpG islands

DOI: https://doi.org/10.1073/pnas.2214062120

Proc Natl Acad Sci U S A. 2023 Feb 21. 120(8): e2213075120

The HP1α protein is mandatory to repress the circadian clock and its output genes during the 12 h period of transcriptional repression.

Nisha Misra, Manohar Damara, Pierre Chambon.

The transcriptional repressions driven by the circadian core clock repressors RevErbα, E4BP4, and CRY1/PER1 involve feedback loops which are mandatory for generating the circadian rhythms. These repressors are known to bind to cognate DNA binding sites, but how their circadian bindings trigger the cascade of events leading to these repressions remain to be elucidated. Through molecular and genetic analyses, we now demonstrate that the chromatin protein HP1α plays a key role in these transcriptional repressions of both the circadian clock (CC) genes and their cognate output genes (CCGs). We show that these CC repressors recruit the HP1α protein downstream from a repressive cascade, and that this recruitment is mandatory for the maintenance of both the CC integrity and the expression of the circadian genes. We further show that the presence of HP1α is critical for both the repressor-induced chromatin compaction and the generation of "transcriptionally repressed biomolecular hydrophobic condensates" and demonstrates that HP1α is mandatory within the CC output genes for both the recruitment of DNA methylating enzymes on the intronic deoxyCpG islands and their subsequent methylation.

Keywords: circadian DNA methylation–demethylation; circadian clock; circadian transcription; circadian transcriptional repression; intronic deoxyCpG-Islands

DOI: https://doi.org/10.1073/pnas.2213075120

JCI Insight. 2023 Feb 14. pii: e166618. [Epub ahead of print]

Gastric bypass alters diurnal feeding behavior and reprograms hepatic clock to regulate endogenous glucose flux.

Yuanchao Ye, Marwa Abu El Haija, Reine Obeid, Hussein Herz, Liping Tian, Benjamin Linden, Yi Chu, Deng Fu Guo, Daniel C Levine, Jonathan Cedernaes, Kamal Rahmouni, Joseph Bass, Mohamad Mokadem.

The molecular clock machinery regulates several homeostatic rhythms, including glucose metabolism. We previously demonstrated that Roux-en Y Gastric Bypass (RYGB) has a weight-independent effect on glucose homeostasis, and transiently reduces food intake. In this study we investigate the effects of RYGB on diurnal eating behavior as well as its effects on the molecular clock, and its requirement for the metabolic effects of this bariatric procedure in obese mice. We find that RYGB reverses the high fat diet-induced disruption in diurnal eating pattern during the early post-surgery phase of food reduction. "Dark-cycle" pair-feeding experiments improved glucose tolerance to the level of bypass-operated animals during the physiologic "fasting" phase (Zeitgeber ZT2), but not the "feeding" phase (ZT14). Using a clock gene reporter mouse model (mPer2Luc), we reveal that RYGB induces a liver-specific phase shift in peripheral clock oscillation with no changes to the central clock activity within the suprachiasmatic nucleus (SCN). In addition, we show that weight loss effects are attenuated in obese ClockΔ19 mutant mice post-RYGB that also fail to improve glucose metabolism after surgery, specifically hepatic glucose production. We conclude that RYGB reprograms the peripheral clock within the liver early after surgery to alter diurnal eating behavior and regulate hepatic glucose flux.

Keywords: Endocrinology; Gluconeogenesis; Glucose metabolism; Metabolism

DOI: https://doi.org/10.1172/jci.insight.166618

Function (Oxf). 2023 ;4(2): zqad001

Adrenal-Specific KO of the Circadian Clock Protein BMAL1 Alters Blood Pressure Rhythm and Timing of Eating Behavior.

Hannah M Costello, G Ryan Crislip, Kit-Yan Cheng, I Jeanette Lynch, Alexandria Juffre, Phillip Bratanatawira, Annalisse Mckee, Ryanne S Thelwell, Victor M Mendez, Charles S Wingo, Lauren G Douma, Michelle L Gumz.

Brain and muscle ARNT-like 1 (BMAL1) is a core circadian clock protein and transcription factor that regulates many physiological functions, including blood pressure (BP). Male global Bmal1 knockout (KO) mice exhibit ∼10 mmHg reduction in BP, as well as a blunting of BP rhythm. The mechanisms of how BMAL1 regulates BP remains unclear. The adrenal gland synthesizes hormones, including glucocorticoids and mineralocorticoids, that influence BP rhythm. To determine the role of adrenal BMAL1 on BP regulation, adrenal-specific Bmal1 (ASCre/+ ::Bmal1) KO mice were generated using aldosterone synthase Cre recombinase to KO Bmal1 in the adrenal gland zona glomerulosa. We confirmed the localization and efficacy of the KO of BMAL1 to the zona glomerulosa. Male ASCre/+ ::Bmal1 KO mice displayed a shortened BP and activity period/circadian cycle (typically 24 h) by ∼1 h and delayed peak of BP and activity by ∼2 and 3 h, respectively, compared with littermate Cre- control mice. This difference was only evident when KO mice were in metabolic cages, which acted as a stressor, as serum corticosterone was increased in metabolic cages compared with home cages. AS Cre/+ ::Bmal1 KO mice also displayed altered diurnal variation in serum corticosterone. Furthermore, these mice have altered eating behaviors where they have a blunted night/day ratio of food intake, but no change in overall food consumed compared with controls. Overall, these data suggest that adrenal BMAL1 has a role in the regulation of BP rhythm and eating behaviors.

Keywords: Blood pressure; adrenal gland; brain and muscle ARNT-like 1; circadian rhythms; corticosterone; feeding

DOI: https://doi.org/10.1093/function/zqad001