bims-ciryme Biomed News
on Circadian rhythms and metabolism
Issue of 2022‒05‒15
three papers selected by
Gabriela Da Silva Xavier
University of Birmingham

  1. Cell Rep. 2022 May 10. pii: S2211-1247(22)00554-X. [Epub ahead of print]39(6): 110787
      The mechanisms that generate robust ionic oscillation in circadian pacemaker neurons are under investigation. Here, we demonstrate critical functions of the mitochondrial cation antiporter leucine zipper-EF-hand-containing transmembrane protein 1 (LETM1), which exchanges K+/H+ in Drosophila and Ca2+/H+ in mammals, in circadian pacemaker neurons. Letm1 knockdown in Drosophila pacemaker neurons reduced circadian cytosolic H+ rhythms and prolonged nuclear PERIOD/TIMELESS expression rhythms and locomotor activity rhythms. In rat pacemaker neurons in the hypothalamic suprachiasmatic nucleus (SCN), circadian rhythms in cytosolic Ca2+ and Bmal1 transcription were dampened by Letm1 knockdown. Mitochondrial Ca2+ uptake peaks late during the day were also observed in rat SCN neurons following photolytic elevation of cytosolic Ca2+. Since cation transport by LETM1 is coupled to mitochondrial energy synthesis, we propose that LETM1 integrates metabolic, ionic, and molecular clock rhythms in the central clock system in both invertebrates and vertebrates.
    Keywords:  CP: Metabolism; CP: Neuroscience; caged Ca(2+) compound; circadian H(+) rhythms; clock genes; lateral neurons; mitochondrial calcium imaging; proton imaging
  2. FASEB J. 2022 May;36 Suppl 1
      Circadian rhythm disruption increases cardiometabolic disease risk. For example, night shift workers have an increased risk of developing metabolic syndrome, hypertension, and endothelial dysfunction. Loss of Bmal1, an essential circadian clock gene, impairs cardiometabolic rhythms and promotes endothelial dysfunction. We hypothesized that chronic light cycle disruption increases fat mass, blunts metabolic rhythms, and leads to cardiovascular disease in adult mice dependent on the molecular circadian clock. Littermate wild type (WT) and global Bmal1-KO mice (5-7 month old males) were maintained on a standard light/dark cycle (control, 12-h light, 12-h dark) or a chronic circadian disruption protocol (CCD,10-h light, 10-h dark for 14-18 weeks) with food and water available ad libitum. Food intake over 24-h was similar between all groups. Body weight was similar between WT control and WT CCD mice whereas weight was lower in Bmal1-KO mice with control and CCD conditions (p<0.01 WT vs Bmal1-KO, n=3-4). Body composition measured by quantitative magnetic resonance revealed lower fat mass in Bmal1-KO control as well as both WT CCD and Bmal1-KO CCD mice compared to WT on the control schedule (p<0.01 WT control vs WT CCD; p=0.02 WT vs Bmal1-KO; n=3-4). Lean mass was not different between control and CCD WT mice but was lower in Bmal1-KO mice regardless of light cycle (p<0.01 WT vs Bmal1-KO; n=3-4). Total body water was similar in control and CCD WT mice but significantly lower in both control and CCD Bmal1-KO mice (p<0.01 WT vs Bmal1-KO; n=3-4). Respiratory exchange ratio measured by indirect calorimetry during light and dark phases was not significantly different between groups although both groups of KO mice were significantly higher than controls (p=0.04; n=3-4). As expected, there was a light-dark phase difference in energy expenditure (EE) in WT control mice, whereas the light-dark phase difference in EE was absent in WT CCD mice (p=0.05 WT control dark vs light; p>0.05 WT CCD dark vs. light; n=3-4). Bmal1-KO control mice lacked a light-dark phase difference in EE. CCD did not affect the EE light-dark phase difference in Bmal1-KO mice. Aortic stiffness, measured by pulse wave velocity, was similar in WT under control and CCD and in Bmal1-KO mice in both conditions (p>0.05). Systolic blood pressure (tail-cuff) was similar in WT control and CCD mice, yet lower in both control and CCD Bmal1-KO mice (p=0.02 WT control vs Bmal1-KO; p=0.04 WT CCD vs Bmal1-KO CCD; n=4-5). In isolated vessels, aortic endothelial-dependent relaxation was not impaired by CCD in WT mice but attenuated in both control and CCD Bmal1-KO mice (p<0.01; n=4-5). Endothelial-independent relaxation was similar between all groups. In conclusion, we found that CCD decreases fat mass in older adult WT mice and dampens EE rhythm, while Bmal1-KO mice have reduced fat and lean mass, total water, and blunted EE rhythm regardless of light cycle. These data suggest that metabolic changes due to light cycle disruption may be dependent on the molecular clock.
  3. Int J Mol Sci. 2022 Apr 23. pii: 4679. [Epub ahead of print]23(9):
      Uncoupling of metabolism and circadian activity is associated with an increased risk of a wide spectrum of pathologies. Recently, insulin and the closely related insulin-like growth factor I (IGF-I) were shown to entrain feeding patterns with circadian rhythms. Both hormones act centrally to modulate peripheral glucose metabolism; however, whereas central targets of insulin actions are intensely scrutinized, those mediating the actions of IGF-I remain less defined. We recently showed that IGF-I targets orexin neurons in the lateral hypothalamus, and now we evaluated whether IGF-I modulates orexin neurons to align circadian rhythms with metabolism. Mice with disrupted IGF-IR activity in orexin neurons (Firoc mice) showed sexually dimorphic alterations in daily glucose rhythms and feeding activity patterns which preceded the appearance of metabolic disturbances. Thus, Firoc males developed hyperglycemia and glucose intolerance, while females developed obesity. Since IGF-I directly modulates orexin levels and hepatic expression of KLF genes involved in circadian and metabolic entrainment in an orexin-dependent manner, it seems that IGF-I entrains metabolism and circadian rhythms by modulating the activity of orexin neurons.
    Keywords:  IGF-I; central control of metabolism; circadian activity; feeding entrainment; orexin