Circadian clock network desynchrony promotes weight gain and alters glucose homeostasis in mice

Isa Kolbe, Brinja Leinweber, Matthias Brandenburger, Henrik Oster

In complex organisms such as mammals, circadian energy metabolism is orchestrated by an interplay of central and peripheral clocks, with a master pacemaker being located in the suprachiasmatic nucleus (SCN) and subordinate clocks in non-SCN central and peripheral tissues. Kolbe et al. used SCN pacemaker knockout mice to dissect the role of central and peripheral clock function in metabolic homeostasis. They show that a functional SCN clock is not needed to sustain metabolic health in a rhythmic environment, which is sufficient to drive behavioral and peripheral clock network rhythms. In constant conditions, however, the synchronizing capacity of the master clock becomes key for this synchronization and metabolic homeostasis.

Circadian clock network desynchrony promotes weight gain and alters glucose homeostasis in mice

Objective: A network of endogenous circadian clocks adapts physiology and behavior to recurring changes in environmental demands across the 24-hour day cycle. Circadian disruption promotes weight gain and type 2 diabetes development. In this study, we aim to dissect the roles of different tissue clocks in the regulation of energy metabolism.

Methods: We used mice with genetically ablated clock function in the circadian pacemaker of the suprachiasmatic nucleus (SCN) under different light and feeding conditions to study peripheral clock resetting and the role of the peripheral clock network in the regulation of glucose handling and metabolic homeostasis.

Results: In SCN clock-deficient mice, behavioral and non-SCN tissue clock rhythms are sustained under rhythmic lighting conditions but deteriorate quickly in constant darkness. In parallel to the loss of behavioral and molecular rhythms, the animals develop adiposity and impaired glucose utilization in constant darkness. Restoring peripheral clock rhythmicity and synchrony by time-restricted feeding normalizes body weight and glucose metabolism.

Conclusions: These data reveal the importance of an overall synchronized circadian clockwork for the maintenance of metabolic homeostasis.