Circadian phenotyping of obese and diabetic db/db mice
Résumé
Growing evidence links metabolic disorders to circadian alterations. Genetically obese db/db mice,
lacking the long isoform of leptin receptor, are a recognized model of type 2 diabetes. In this study, we
aimed at characterizing the potential circadian alterations of db/db mice in comparison to db/þ control
mice. By using telemetry devices, we first reported arrhythmicity in general activity of most db/db mice
under both lightedark cycle and constant darkness, while their rhythm of body temperature is less
dramatically disrupted. Water access restricted to nighttime restores significant rhythmicity in behaviorally
arrhythmic db/db mice, indicating a masking effect of polydipsia when water is available ad
libitum. Endogenous period of temperature rhythm under constant dark conditions is significantly
increased (þ30 min) in db/db compared with db/þ mice. Next, we studied the oscillations of clock
proteins (PER1, PER2 and BMAL1) in the suprachiasmatic nuclei (SCN), the site of the master clock, and
detected no difference according to the genotype. Furthermore, c-FOS and P-ERK1/2 expression in
response to a light pulse in late night was significantly increased (þ80 and þ55%, respectively) in the SCN
of these diabetic mice. We previously showed that, in addition to altered activity rhythms, db/db mice
exhibit altered feeding rhythm. Therefore, we investigated daily patterns of clock protein expression in
medial hypothalamic oscillators involved in feeding behavior (arcuate nucleus, ventro- and dorso-medial
hypothalamic nuclei). Compared with db/þ mice, very subtle or no difference in oscillations of PER1 and
BMAL1 is found in the medial hypothalamus. Although we did not find a clear link between altered
hypothalamic clockwork and behavioral rhythms in db/db mice, our results highlight a lengthened
endogenous period and altered photic integration in these genetically obese and diabetic mice