Abstract
Leptin may affect central and/or peripheral timing, in addition to its well-known regulatory effects on metabolism. Here, we investigated whether leptin can impact rhythmicity of blood glucose and lipids. For that purpose, daily variations of blood glucose and lipids were compared between mice lacking functional leptin receptor (db/db) or deficient for leptin (ob/ob) and controls (db/+ and ob/+, respectively). Next, we investigated whether timed treatment with exogenous leptin in ob/ob mice could modulate blood glucose rhythm. Mice with defective leptin signaling (db/db and ob/ob) have the same phase-opposed timing in glycemia (11 and 9 h shift, respectively) compared to respective controls. By contrast, the phase of plasma lipids rhythms (e.g. triglycerides, non-esterified fatty acid – NEFA, high density lipoprotein – HDL, low density lipoprotein – LDL) remained essentially unchanged, whatever the genotype. Daily injections of leptin (1 mg/kg) in ob/ob mice during nighttime or daytime led to 1–2 h phase-advances of blood glucose rhythm and glucose arrhythmicity, respectively. These injections induced additional phase-dependent shifts of feeding rhythm (ranging from 2.6 h phase-delays to 2.6 h advances). The present study reveals a chronomodulatory role of leptin, and highlights that rhythmic leptin can be a determinant of daily variations of blood glucose and food intake, though not for lipids.
Acknowledgements
We thank S. Gourmelen and Dr. D. Sage-Ciocca for their expert assistance with animal care and actimetry, respectively. We also thank Dr. A. Malan for his invaluable help in the statistical analyses.
Declaration of Interest
The authors report no conflicts of interest. This work was supported by the Centre National de la Recherche Scientifique, University of Strasbourg (E.C., F.C. and P.P.), ProjEx H2E “Contributions of exotic animal models in the discovery of new therapeutic approaches in human pathophysiology”, University of Strasbourg (to F.C. and E.C.), the Institut de Recherches Internationales Servier (C.S.K. and B.G.L.), and a doctoral fellowship from the French Ministry of National Education and Research (E.G.).
Supplementary material available online
Supplementary Table S1-S4 and Figure S1 and S2