Chronic circadian desynchronization of feeding-fasting rhythm generates alterations in daily glycemia, LDL cholesterolemia and microbiota composition in mice

Abstract

IntroductionThe circadian system synchronizes behavior and physiology to the 24-h light– dark (LD) cycle. Timing of food intake and fasting periods provide strong signals for peripheral circadian clocks regulating nutrient assimilation, glucose, and lipid metabolism. Mice under 12 h light:12 h dark (LD) cycles exhibit behavioral activity and feeding during the dark period, while fasting occurs at rest during light. Disruption of energy metabolism, leading to an increase in body mass, was reported in experimental models of circadian desynchronization. In this work, the effects of chronic advances of the LD cycles (chronic jet-lag protocol, CJL) were studied on the daily homeostasis of energy metabolism and weight gain.MethodsMale C57 mice were subjected to a CJL or LD schedule, measuring IPGTT, insulinemia, microbiome composition and lipidemia.ResultsMice under CJL show behavioral desynchronization and feeding activity distributed similarly at the light and dark hours and, although feeding a similar daily amount of food as compared to controls, show an increase in weight gain. In addition, ad libitum glycemia rhythm was abolished in CJL-subjected mice, showing similar blood glucose values at light and dark. CJL also generated glucose intolerance at dark in an intraperitoneal glucose tolerance test (IPGTT), with increased insulin release at both light and dark periods. Low-density lipoprotein (LDL) cholesterolemia was increased under this condition, but no changes in HDL cholesterolemia were observed. Firmicutes/Bacteroidetes ratio was analyzed as a marker of circadian disruption of microbiota composition, showing opposite phases at the light and dark when comparing LD vs. CJL.DiscussionChronic misalignment of feeding/fasting rhythm leads to metabolic disturbances generating nocturnal hyperglycemia, glucose intolerance and hyperinsulinemia in a IPGTT, increased LDL cholesterolemia, and increased weight gain, underscoring the importance of the timing of food consumption with respect to the circadian system for metabolic health.

Chronic jet lag reduces motivation and affects other mood-related behaviors in male mice

“…Similar results as here were found in rats, such as anhedonia and increased anxiety, using an advancing CJL protocol that also decreased hippocampal neurogenesis and impaired learning and memory ( Herzog et al, 2017 ; Horsey et al, 2020 ). In addition, unlike previous results from the laboratory ( Casiraghi et al, 2016 ; Trebucq et al, 2023 ), CJL did not increase body weight. Other works using CJL protocols also failed to report changes in body weight ( Preuss et al, 2008 ; Chen et al, 2021 ), nevertheless, internal desynchronization can still take place at both the organ and the molecular levels ( Wolff et al, 2013 ; Siddique et al, 2022 ).…”

“…The lack of a stable phase of entrainment of the SCN clock with the LD cycle generates desynchronization of outputs controlling key circadian organizers, as activity/feeding—rest/fasting behavioral rhythms, hypothalamic nuclei controlling sleep/arousal, temperature, energy metabolism, hypothalamic-pituitary-adrenal (HPA) neuroendocrine axis controlling stress, etc. Uncoupling the circadian phase of activity/feeding-rest/fasting rhythms from central and peripheral control of energy metabolism increase the risk of metabolic alterations ( Trebucq et al, 2023 ), which can be considered to increase the risk for depressive states ( Gu et al, 2021 ). Similar CJL protocols show disruption of daily homeostasis in brain energy metabolism (i.e., glucose disposal/usage), increasing mood disorders without affecting sleep duration ( Gao et al, 2020 ; Siddique et al, 2022 ).…”

“…The misalignment between the circadian system and the light/dark schedule is related to excessive fatigue, decreased cognition and mood, gastrointestinal despair, and diminished psychomotor coordination. Chronic circadian disruption, such as the case of chronic jet lag (CJL), increases the risk for several pathologies, including cancer, metabolic alterations leading to diabetes and obesity, metabolic syndrome, cardiovascular diseases, and premature mortality ( Davidson et al, 2006 ; Maywood et al, 2006 ; Golombek et al, 2013 ; Aiello et al, 2020 ; Horsey et al, 2020 ; Trebucq et al, 2023 ). Indeed, CJL can be seen as a shift work model in which individuals experience resynchronization to light/dark cycles for extended periods.…”

Desincronizados: a la hora no señalada

“…Esto nos llevó a establecer un modelo más general sobre el impacto de la alteración de los ciclos de luz y oscuridad en la homeostasis y metabolismo (Plano et al, 2017). Más recientemente encontramos efectos directos de la desincronización crónica en el metabolismo de la glucosa, la colesterolemia y la microbiota de los animales (Trebucq et al, 2023).…”