bims-ciryme 2022-11-13 papers

Mol Metab. 2022 Nov 02. pii: S2212-8778(22)00197-1. [Epub ahead of print] 101628

Genetic and environmental circadian disruption induce weight gain through changes in the gut microbiome.

Baraa Altaha, Marjolein Heddes, Violetta Pilorz, Yunhui Niu, Elizaveta Gorbunova, Michael Gigl, Karin Kleigrewe, Henrik Oster, Dirk Haller, Silke Kiessling.

OBJECTIVE: Internal clocks time behavior and physiology, including the gut microbiome, in a circadian (∼24 h) manner. Mismatch between internal and external time, e.g. during shift work, disrupts circadian system coordination promoting the development of obesity and type 2 diabetes (T2D). Conversely, body weight changes induce microbiota dysbiosis. The relationship between circadian disruption and microbiota dysbiosis in metabolic diseases, however, remains largely unknown.
METHODS: Core and accessory clock gene expression in different gastrointestinal (GI) tissues were determined by qPCR in two different models of circadian disruption - mice with Bmal1 deficiency in the circadian pacemaker, the suprachiasmatic nucleus (Bmal1SCNfl/-), and wild-type mice exposed to simulated shift work (SSW). Body composition and energy balance were evaluated by nuclear magnetic resonance (NMR), bomb calorimetry, food intake and running-wheel activity. Intestinal permeability was measured in an Ussing chamber. Microbiota composition and functionality were evaluated by 16S rRNA gene amplicon sequencing, PICRUST2.0 analysis and targeted metabolomics. Finally, microbiota transfer was conducted to evaluate the functional impact of SSW-associated microbiota on the host's physiology.
RESULTS: Both chronodisruption models show desynchronization within and between peripheral clocks in GI tissues and reduced microbial rhythmicity, in particular in taxa involved in short-chain fatty acid (SCFA) fermentation and lipid metabolism. In Bmal1SCNfl/- mice, loss of rhythmicity in microbial functioning associates with previously shown increased body weight, dysfunctional glucose homeostasis and adiposity. Similarly, we observe an increase in body weight in SSW mice. Germ-free colonization experiments with SSW-associated microbiota mechanistically link body weight gain to microbial changes. Moreover, alterations in expression of peripheral clock genes as well as clock-controlled genes (CCGs) relevant for metabolic functioning of the host were observed in recipients, indicating a bidirectional relationship between microbiota rhythmicity and peripheral clock regulation.
CONCLUSIONS: Collectively, our data suggest that loss of rhythmicity in bacteria taxa and their products, which likely originates in desynchronization of intestinal clocks, promotes metabolic abnormalities during shift work.

Keywords: Bile acids; Circadian rhythm; Microbiota; SCN; Shift work; Short chain fatty acids

DOI: https://doi.org/10.1016/j.molmet.2022.101628

Front Nutr. 2022 ;9 1007824

The impact of a self-selected time restricted eating intervention on eating patterns, sleep, and late-night eating in individuals with obesity.

Stacey L Simon, Jennifer Blankenship, Emily N C Manoogian, Satchidananda Panda, Douglas G Mashek, Lisa S Chow.

Background: Time restricted eating (TRE), limiting eating to a specific daily window, is a novel dietary intervention, but the mechanisms by which TRE results in weight loss remain unclear. The goal of the current study was to examine changes in eating patterns, sleep, and late-night eating, and associations with health outcomes in a secondary analysis of a 12-week self-selected TRE intervention.
Methods: Twenty participants 18-65 years with BMI ≥25 kg/m2 completed the 12-week trial. Participants randomized to TRE (n = 11) were instructed to eat during a self-selected 8-h window, while the non-TRE group (n = 9) followed their typical eating habits. All participants logged oral intake using the myCircadian Clock mobile application throughout the entire intervention. Anthropometrics, HbA1c, an oral glucose tolerance test, and 2 weeks of actigraphy monitoring were completed at pre-intervention and end-intervention. Independent samples t-tests compared differences between groups. Data are presented as mean ± standard deviation.
Results: At preintervention, late night eating was significantly associated with higher fasting glucose (r = 0.59, p = 0.006) and higher HbA1c (r = 0.46, p = 0.016). The TRE group significantly delayed the timing of the first eating occasion by 2.72 ± 1.48 h relative to wake time (p < 0.001) and advanced the timing of the last eating occasion by 1.25 ± 0.8 h relative to bedtime (p < 0.001). The non-TRE group, on average, maintained their eating pattern. Sleep measures did not change from pre- to end-intervention, however greater restriction of the eating window was associated with longer sleep duration at end-intervention (β = -0.46 [95% CI -9.2, -0.4], p = 0.03). The TRE group significantly reduced the prevalence of late night eating (eating within 2 h of bedtime) by 14 ± 6% (p = 0.028) with 63% of participants completely eliminating late night eating at end-intervention.
Conclusion: A self-selected TRE intervention significantly shifted meal timing, reduced late-night eating while prolonging sleep duration.
Trial registry: ClinicalTrials.gov, identifier: 03129581.

Keywords: eating patterns; intermittent fasting; obesity; sleep; time restricted eating

DOI: https://doi.org/10.3389/fnut.2022.1007824

Neurobiol Sleep Circadian Rhythms. 2022 Nov;13 100083

Mood phenotypes in rodent models with circadian disturbances.

Kiyomichi Imamura, Toru Takumi.

Many physiological functions with approximately 24-h rhythmicity (circadian rhythms) are generated by an internal time-measuring system of the circadian clock. While sleep/wake cycles, feeding patterns, and body temperature are the most widely known physiological functions under the regulation of the circadian clock, physiological regulation by the circadian clock extends to higher brain functions. Accumulating evidence suggests strong associations between the circadian clock and mood disorders such as depression, but the underlying mechanisms of the functional relationship between them are obscure. This review overviews rodent models with disrupted circadian rhythms on depression-related responses. The animal models with circadian disturbances (by clock gene mutations and artifactual interventions) will help understand the causal link between the circadian clock and depression.

Keywords: CMS, chronic mild stress; Circadian; Clock gene; D1R-MSN, dopamine 1 receptor-expressing medium spiny neurons; DG, dentate gyrus; DSPS, delayed sleep phase syndrome; Depression; EMS, ethyl methane sulfonate; FASPS, familial advanced sleep phase syndrome; LAN, light-at-night; LHb, lateral habenula; MAOA, monoamine oxidase A; MDD, major depressive disorder; Mood disorder; NAc, nucleus accumbens; PHb, perihabenular nucleus; SCN, suprachiasmatic nucleus; Sleep disorder; VTA, ventral tegmental area; ipRGCs, intrinsically photosensitive retinal ganglion cells; vLGN/IGL, ventral lateral geniculate nucleus and intergeniculate leaflet

DOI: https://doi.org/10.1016/j.nbscr.2022.100083

Diabetes. 2022 Nov 08. pii: db220238. [Epub ahead of print]

Impaired Diurnal Pattern of Meal Tolerance and Insulin Sensitivity in Type 2 Diabetes: Implications for Therapy.

Yogesh Yadav, Davide Romeres, Claudio Cobelli, Chiara Dalla Man, Rickey Carter, Ananda Basu, Rita Basu.

To assess the diurnal patterns of postprandial glucose tolerance and insulin sensitivity, 19 type 2 diabetes [8F; 60±11 yrs.; BMI: 32±5 kg/m2] and 19 anthropometrically matched non-diabetic (ND) subjects [11 F; 53±12 yrs.; BMI: 29±5 kg/m2] were studied during breakfast (B), lunch (L), and dinner (D) with identical mixed meals (75 gm carbs) on three consecutive days in a randomized Latin square design. Three stable isotopes of glucose were utilized to estimate meal fluxes and mathematical models used for estimating indices of insulin action and beta cell function. Post meal glucose excursions were higher at D vs B and D vs L in type 2 diabetes (p<0.05) while in ND they were higher at D vs. B (p=0.025) and L vs B (P=0.04). Insulin iAUC was highest at B as compared to L and D in type 2 diabetes while there were no differences observed in ND. Disposition Index (DI) was higher at B than at L (p<0.01) and D (p<0.001) in ND subjects while DI was low with unchanging pattern across B-L-D in type 2 diabetes. Furthermore, between meal differences in beta cell responsivity to glucose (φ) and insulin sensitivity (SI) were concurrent with changes in DI within groups. Fasting and post meal glucose, insulin, C-peptide concentrations, along with estimates of endogenous glucose production (EGP), rate of glucose disappearance (Rd), SI, Φ, hepatic extraction of insulin (HE), insulin secretion rate, extracted insulin and DI were altered in type 2 diabetes compared to ND (P < 0.011 for all).The data shows diurnal pattern of postprandial glucose tolerance in overweight otherwise glucose tolerant ND individuals differs from overweight type 2 diabetes. The results not only provide valuable insight into management strategies for better glycemic control in people with type 2 diabetes but also improved understanding of daytime glucose metabolism in overweight individuals without impaired glucose tolerance or overt diabetes.

DOI: https://doi.org/10.2337/db22-0238

Nat Commun. 2022 Nov 08. 13(1): 6742

Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice.

Cryptochromes are negative transcriptional regulators of the circadian clock in mammals. It is not clear how reducing the level of endogenous CRY1 in mammals will affect circadian rhythm and the relation of such a decrease with apoptosis. Here, we discovered a molecule (M47) that destabilizes Cryptochrome 1 (CRY1) both in vitro and in vivo. The M47 selectively enhanced the degradation rate of CRY1 by increasing its ubiquitination and resulted in increasing the circadian period length of U2OS Bmal1-dLuc cells. In addition, subcellular fractionation studies from mice liver indicated that M47 increased degradation of the CRY1 in the nucleus. Furthermore, M47-mediated CRY1 reduction enhanced oxaliplatin-induced apoptosis in Ras-transformed p53 null fibroblast cells. Systemic repetitive administration of M47 increased the median lifespan of p53-/- mice by ~25%. Collectively our data suggest that M47 is a promising molecule to treat forms of cancer depending on the p53 mutation.

DOI: https://doi.org/10.1038/s41467-022-34582-1