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1. Exogenous estradiol does not regulate daily metabolic rhythms underlying diet-induced obesity in male mice

   https://doi.org/10.1371/journal.pone.0343513  

   Osborne, W Brad; Vöcking, Oliver; Alvord, Victoria M; Omotola, Oluwabukola B; Katsumata, Yuriko; Pendergast, Julie S (March 2026, PLOS One)

   Kumar, Vinay (Ed.)

   Male mice fed high-fat diet become obese, but female mice are resistant to diet-induced weight gain. We previously found that circulating estradiol in females protects their daily rhythms from disruption by high-fat feeding to prevent diet-induced obesity. The goal of this study was to determine the effects of estradiol on daily metabolic rhythms in male mice. Male C57BL/6J mice were treated with estradiol and fed high-fat diet for 2 weeks. We measured the effects of high-fat diet feeding on daily rhythms of eating behavior and locomotor activity, and on the phases, or timing, of circadian rhythms in central and peripheral tissues. We found that males treated with estradiol had lower blood glucose when fed high-fat diet than males treated with vehicle even though there were no effects of estradiol treatment on body weight and adiposity. There was no effect of estradiol on the daily rhythm of eating behavior as it was low-amplitude or arrhythmic during high-fat diet feeding in both vehicle- and estradiol-treated males. Locomotor activity rhythms were also unaffected by estradiol treatment. Likewise, the phases of circadian rhythms in the suprachiasmatic nucleus (SCN), liver, muscle, and other peripheral tissues were not altered by estradiol treatment. Thus, treatment of male mice with estradiol did not protect daily rhythms from disruption by high-fat diet, as it does in females. Together these data suggest that the mechanisms underlying sex differences in daily metabolic rhythms are complex and may require both developmental and adult exposure to hormones. 

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2. Circadian Synchrony: Sleep, Nutrition, and Physical Activity

   Healy, Kelly L.; Morris, Andrew R.; Liu, Andrew C. (October 2021, Frontiers in network physiology)

   The circadian clock in mammals regulates the sleep/wake cycle and many associated behavioral and physiological processes. The cellular clock mechanism involves a transcriptional negative feedback loop that gives rise to circadian rhythms in gene expression with an approximately 24-hour periodicity. To maintain system robustness, clocks throughout the body must be synchronized and their functions coordinated. In mammals, the master clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN is entrained to the light/dark cycle through photic signal transduction and subsequent induction of core clock gene expression. The SCN in turn relays the time-of-day information to clocks in peripheral tissues. While the SCN is highly responsive to photic cues, peripheral clocks are more sensitive to non-photic resetting cues such as nutrients, body temperature, and neuroendocrine hormones. For example, feeding/fasting and physical activity can entrain peripheral clocks through signaling pathways and subsequent regulation of core clock genes and proteins. As such, timing of food intake and physical activity matters. In an ideal world, the sleep/wake and feeding/fasting cycles are synchronized to the light/dark cycle. However, asynchronous environmental cues, such as those experienced by shift workers and frequent travelers, often lead to misalignment between the master and peripheral clocks. Emerging evidence suggests that the resulting circadian disruption is associated with various diseases and chronic conditions that further circadian desynchrony and accelerate disease progression. In this review, we discuss how sleep, nutrition, and physical activity synchronize circadian clocks and how chronomedicine may offer novel strategies for disease intervention. 

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3. Comment on “Circadian rhythms in the absence of the clock gene Bmal1 ”

   https://doi.org/10.1126/science.abe9230  

   Ness-Cohn, Elan; Allada, Ravi; Braun, Rosemary (April 2021, Science)

   null (Ed.)

   Ray et al . (Reports, 14 February 2020, p. 800) report apparent transcriptional circadian rhythms in mouse tissues lacking the core clock component BMAL1. To better understand these surprising results, we reanalyzed the associated data. We were unable to reproduce the original findings, nor could we identify reliably cycling genes. We conclude that there is insufficient evidence to support circadian transcriptional rhythms in the absence of Bmal1 . 

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4. Overlapping Central Clock Network Circuitry Regulates Circadian Feeding and Activity Rhythms in Drosophila

   https://doi.org/10.1177/07487304241263734  

   Saurabh, Sumit; Meier, Ruth J; Pireva, Liliya M; Mirza, Rabab A; Cavanaugh, Daniel J (October 2024, Journal of Biological Rhythms)

   The circadian system coordinates multiple behavioral outputs to ensure proper temporal organization. Timing information underlying circadian regulation of behavior depends on a molecular circadian clock that operates within clock neurons in the brain. In Drosophila and other organisms, clock neurons can be divided into several molecularly and functionally discrete subpopulations that form an interconnected central clock network. It is unknown how circadian signals are coherently generated by the clock network and transmitted across output circuits that connect clock cells to downstream neurons that regulate behavior. Here, we have exhaustively investigated the contribution of clock neuron subsets to the control of two prominent behavioral outputs in Drosophila: locomotor activity and feeding. We have used cell-specific manipulations to eliminate molecular clock function or induce electrical silencing either broadly throughout the clock network or in specific subpopulations. We find that clock cell manipulations produce similar changes in locomotor activity and feeding, suggesting that overlapping central clock circuitry regulates these distinct behavioral outputs. Interestingly, the magnitude and nature of the effects depend on the clock subset targeted. Lateral clock neuron manipulations profoundly degrade the rhythmicity of feeding and activity. In contrast, dorsal clock neuron manipulations only subtly affect rhythmicity but produce pronounced changes in the distribution of activity and feeding across the day. These experiments expand our knowledge of clock regulation of activity rhythms and offer the first extensive characterization of central clock control of feeding rhythms. Despite similar effects of central clock cell disruptions on activity and feeding, we find that manipulations that prevent functional signaling in an identified output circuit preferentially degrade locomotor activity rhythms, leaving feeding rhythms relatively intact. This demonstrates that activity and feeding are indeed dissociable behaviors, and furthermore suggests that differential circadian control of these behaviors diverges in output circuits downstream of the clock network. 

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5. Multiscale Time-resolved Analysis Reveals Remaining Behavioral Rhythms in Mice Without Canonical Circadian Clocks

   https://doi.org/10.1177/07487304221087065  

   Morris, Megan; Yamazaki, Shin; Stefanovska, Aneta (June 2022, Journal of Biological Rhythms)

   Circadian rhythms are internal processes repeating approximately every 24 hours in living organisms. The dominant circadian pacemaker is synchronized to the environmental light-dark cycle. Other circadian pacemakers, which can have noncanonical circadian mechanisms, are revealed by arousing stimuli, such as scheduled feeding, palatable meals and running wheel access, or methamphetamine administration. Organisms also have ultradian rhythms, which have periods shorter than circadian rhythms. However, the biological mechanism, origin, and functional significance of ultradian rhythms are not well-elucidated. The dominant circadian rhythm often masks ultradian rhythms; therefore, we disabled the canonical circadian clock of mice by knocking out Per1/2/3 genes, where Per1 and Per2 are essential components of the mammalian light-sensitive circadian mechanism. Furthermore, we recorded wheel-running activity every minute under constant darkness for 272 days. We then investigated rhythmic components in the absence of external influences, applying unique multiscale time-resolved methods to analyze the oscillatory dynamics with time-varying frequencies. We found four rhythmic components with periods of ∼17 h, ∼8 h, ∼4 h, and ∼20 min. When the ∼17-h rhythm was prominent, the ∼8-h rhythm was of low amplitude. This phenomenon occurred periodically approximately every 2-3 weeks. We found that the ∼4-h and ∼20-min rhythms were harmonics of the ∼8-h rhythm. Coupling analysis of the ridge-extracted instantaneous frequencies revealed strong and stable phase coupling from the slower oscillations (∼17, ∼8, and ∼4 h) to the faster oscillations (∼20 min), and weak and less stable phase coupling in the reverse direction and between the slower oscillations. Together, this study elucidated the relationship between the oscillators in the absence of the canonical circadian clock, which is critical for understanding their functional significance. These studies are essential as disruption of circadian rhythms contributes to diseases, such as cancer and obesity, as well as mood disorders. 

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