bims-ciryme 2022-10-02 papers

Proc Natl Acad Sci U S A. 2022 Oct 04. 119(40): e2205755119

Circadian clock controls rhythms in ketogenesis by interfering with PPARα transcriptional network.

Volha Mezhnina, Oghogho P Ebeigbe, Nikkhil Velingkaar, Allan Poe, Yana Sandlers, Roman V Kondratov.

Ketone bodies are energy-rich metabolites and signaling molecules whose production is mainly regulated by diet. Caloric restriction (CR) is a dietary intervention that improves metabolism and extends longevity across the taxa. We found that CR induced high-amplitude daily rhythms in blood ketone bodies (beta-hydroxybutyrate [βOHB]) that correlated with liver βOHB level. Time-restricted feeding, another periodic fasting-based diet, also led to rhythmic βOHB but with reduced amplitude. CR induced strong circadian rhythms in the expression of fatty acid oxidation and ketogenesis genes in the liver. The transcriptional factor peroxisome-proliferator-activated-receptor α (PPARα) and its transcriptional target hepatokine fibroblast growth factor 21 (FGF21) are primary regulators of ketogenesis. Fgf21 expression and the PPARα transcriptional network became highly rhythmic in the CR liver, which implicated the involvement of the circadian clock. Mechanistically, the circadian clock proteins CLOCK, BMAL1, and cryptochromes (CRYs) interfered with PPARα transcriptional activity. Daily rhythms in the blood βOHB level and in the expression of PPARα target genes were significantly impaired in circadian clock-deficient Cry1,2-/- mice. These data suggest that blood βOHB level is tightly controlled and that the circadian clock is a regulator of diet-induced ketogenesis.

Keywords: aging; caloric restriction; circadian rhythms; fatty acid metabolism; metabolism

DOI: https://doi.org/10.1073/pnas.2205755119

Front Physiol. 2022 ;13 963449

Circadian rhythms-related disorders in diurnal fat sand rats under modern lifestyle conditions: A review.

Carmel Bilu, Haim Einat, Paul Zimmet, Noga Kronfeld-Schor.

Modern lifestyle reduces environmental rhythmicity and may lead to circadian desynchrony. We are exposed to poor day-time lighting indoors and excessive night-time artificial light. We use air-conditioning to reduce ambient temperature cycle, and food is regularly available at all times. These disruptions of daily rhythms may lead to type 2 diabetes mellitus (T2DM), obesity, cardiometabolic diseases (CMD), depression and anxiety, all of which impose major public health and economic burden on societies. Therefore, we need appropriate animal models to gain a better understanding of their etiologic mechanisms, prevention, and management.We argue that the fat sand rat (Psammomys obesus), a diurnal animal model, is most suitable for studying the effects of modern-life conditions. Numerous attributes make it an excellent model to study human health disorders including T2DM, CMD, depression and anxiety. Here we review a comprehensive series of studies we and others conducted, utilizing the fat sand rat to study the underlying interactions between biological rhythms and health. Understanding these interactions will help deciphering the biological basis of these diseases, which often occur concurrently. We found that when kept in the laboratory (compared with natural and semi-wild outdoors conditions where they are diurnal), fat sand rats show low amplitude, nocturnal or arrhythmic activity patterns, dampened daily glucose rhythm, glucose intolerance, obesity and decreased survival rates. Short photoperiod acclimation exacerbates these pathologies and further dampens behavioral and molecular daily rhythms, resulting in CMD, T2DM, obesity, adipocyte dysfunction, cataracts, depression and anxiety. Increasing environmental rhythmicity by morning bright light exposure or by access to running wheels strengthens daily rhythms, and results in higher peak-to-trough difference in activity, better rhythmicity in clock genes expression, lower blood glucose and insulin levels, improved glucose tolerance, lower body and heart weight, and lower anxiety and depression. In summary, we have demonstrated that fat sand rats living under the correspondent of "human modern lifestyle" conditions exhibit dampened behavioral and biological rhythms and develop circadian desynchrony, which leads to what we have named "The Circadian Syndrome". Environmental manipulations that increase rhythmicity result in improvement or prevention of these pathologies. Similar interventions in human subjects could have the same positive results and further research on this should be undertaken.

Keywords: circadian desynchrony; circadian rhythms; depression; diabetes; diurnality; fat sand rats

DOI: https://doi.org/10.3389/fphys.2022.963449

Sci Immunol. 2022 Sep 30. 7(75): eabl7641

Tregs in visceral adipose tissue up-regulate circadian-clock expression to promote fitness and enforce a diurnal rhythm of lipolysis.

Tianli Xiao, P Kent Langston, Andrés R Muñoz-Rojas, Teshika Jayewickreme, Mitchell A Lazar, Christophe Benoist, Diane Mathis.

Regulatory T cells (Tregs) in nonlymphoid organs provide critical brakes on inflammation and regulate tissue homeostasis. Although so-called "tissue Tregs" are phenotypically and functionally diverse, serving to optimize their performance and survival, up-regulation of pathways related to circadian rhythms is a feature they share. Yet the diurnal regulation of Tregs and its consequences are controversial and poorly understood. Here, we profiled diurnal variations in visceral adipose tissue (VAT) and splenic Tregs in the presence and absence of core-clock genes. VAT, but not splenic, Tregs up-regulated their cell-intrinsic circadian program and exhibited diurnal variations in their activation and metabolic state. BMAL1 deficiency specifically in Tregs led to constitutive activation and poor oxidative metabolism in VAT, but not splenic, Tregs. Disruption of core-clock components resulted in loss of fitness: BMAL1-deficient VAT Tregs were preferentially lost during competitive transfers and in heterozygous TregBmal1Δ females. After 16 weeks of high-fat diet feeding, VAT inflammation was increased in mice harboring BMAL1-deficient Tregs, and the remaining cells lost the transcriptomic signature of bona fide VAT Tregs. Unexpectedly, VAT Tregs suppressed adipocyte lipolysis, and BMAL1 deficiency specifically in Tregs abrogated the characteristic diurnal variation in adipose tissue lipolysis, resulting in enhanced suppression of lipolysis throughout the day. These findings argue for the importance of the cell-intrinsic clock program in optimizing VAT Treg function and fitness.

DOI: https://doi.org/10.1126/sciimmunol.abl7641

Methods Mol Biol. 2022 ;2550 391-411

Methods to Assess Melatonin Receptor-Mediated Phase-Shift and Re-entrainment of Rhythmic Behaviors in Mouse Models.

Grant C Glatfelter, Jennifer Sosa, Randall L Hudson, Margarita L Dubocovich.

The neurohormone melatonin facilitates entrainment of biological rhythms to environmental light-dark conditions as well as phase-shifts of circadian rhythms in constant conditions via activation of the MT1 and/or MT2 receptors expressed within the suprachiasmatic nucleus of the hypothalamus. The efficacy of melatonin and related agonists to modulate biological rhythms can be assessed using two well-validated mouse models of rhythmic behaviors. These models serve as predictive measures of therapeutic efficacy for treatment of circadian phase disorders caused by internal (e.g., clock gene mutations, blindness, depression, seasonal affective disorder) or external (e.g., shift work, travel across time zones) causes in humans. Here we provide background and detailed protocols for quantitative assessment of the magnitude and efficacy of melatonin receptor ligands in mouse circadian phase-shift and re-entrainment paradigms. The utility of these models in the discovery of novel therapeutics acting on melatonin receptors will also be discussed.

Keywords: Entrainment; Jet lag; Melatonin; Melatonin receptors; Phase-shift; Rhythmic behaviors

DOI: https://doi.org/10.1007/978-1-0716-2593-4_39