Circadian period of luciferase expression shortens with age in human mature adipocytes from obese patients

Abstract

Daily rhythms in physiology and behavior change with age. An unresolved question is to what extent such age-related alterations in circadian organization are driven by the central clock in the suprachiasmatic nucleus (SCN), modifying timing signals to contributing peripheral tissue oscillators, and are mediated by underlying changes in the local cellular oscillators themselves. Using a bioluminescence reporter approach, we sought to determine whether circadian clock function in human adipocytes from subcutaneous (SAT) and visceral (VAT) adipose tissues changes with age. SAT and VAT biopsies were obtained from obese individuals during gastric bypass surgeries [ n = 16; body mass index: 44.8 ± 11.4 kg/m; age: 44 ± 9 yr (range: 30-58)]. Cells were isolated and transduced with a lentiviral circadian reporter construct [brain and muscle aryl hydrocarbon receptor nuclear translocator-like:luciferase ( BMAL:LUC)], and bioluminescence was recorded over a period of 3 d. Human BMAL1:LUC adipocytes displayed a robust luminescence rhythm with comparable within-individual periods in mature and preadipocytes ( P > 0.05). With increasing age, the circadian period decreased in mature adipocytes ( P = 0.005) (β = 4 min/yr; P < 0.05). Our ex vivo approach indicated that ageing changes the organization of endogenous circadian oscillators in human adipocytes, independent of SCN signaling.-Kolbe, I., Carrasco-Benso, M. P., López-Mínguez, J., Luján, J., Scheer, F. A. J. L., Oster, H., Garaulet, M. Circadian period of luciferase expression shortens with age in human mature adipocytes from obese patients.

Redox changes in obesity, metabolic syndrome, and diabetes

“…This resulted in uncoupling of the clock-controlled regulated pathways of carbohydrate and lipid metabolism from the adipose tissue clock, leading to increased carbohydrate turnover and impaired glucose homeostasis [ 170 ]. In line with this work, human mature adipocytes show altered circadian rhythms in obese patients with age [ 171 ]. Similarly, a further study investigated whether the expression of clock genes in peripheral blood cells is impaired in T2DM and whether inflammatory markers are associated with circadian clock gene expression in T2DM patients.…”

Interplay between diet, exercise and the molecular circadian clock in orchestrating metabolic adaptations of adipose tissue

“…Nevertheless, in isolated adipocytes from obese patients transduced in vitro with a circadian reporter construct, the increased age of the donor correlates with a shortened circadian period in BMAL1 expression. This suggests that ageing-related development of metabolic disorders could be associated with adipose tissue clock perturbation (Kolbe et al 2019).…”

“…This suggests that ageing‐related development of metabolic disorders could be associated with adipose tissue clock perturbation (Kolbe et al . ).…”

The importance of being rhythmic: Living in harmony with your body clocks

“…47,94,138,191,192 In this context, further progress in identifying the molecular links between the circadian timing system and human pathologies is of urgent need. 42,137,161,193 One exciting and rapidly developing field, based on the understanding that the feeding time represents the most potent Zeitgeber for peripheral oscillators that orchestrate body metabolism, is chrononutrition. 81,176 Likewise, dissecting the molecular properties of the circadian oscillators in human primary cells in vitro holds promise for getting novel insights into clockwork alterations associated with differences in human chronotypes, 187 ageing 185 and pathologies.…”

“…81,176 Likewise, dissecting the molecular properties of the circadian oscillators in human primary cells in vitro holds promise for getting novel insights into clockwork alterations associated with differences in human chronotypes, 187 ageing 185 and pathologies. 42,137,161,193 One exciting and rapidly developing field, based on the understanding that the feeding time represents the most potent Zeitgeber for peripheral oscillators that orchestrate body metabolism, is chrononutrition. Beneficial effects of time-restricted feeding for weight loss and metabolic improvement have been recently established in rodents, 194,195 followed by emerging translational studies in humans.…”