The melanocortin-4 receptor integrates circadian light cues and metabolism.
The melanocortin system directs diverse physiological functions from coat color to body weight homoeostasis. A commonality among melanocortin-mediated processes is that many animals modulate similar processes on a circannual basis in response to longer, summer days, suggesting an underlying link between circadian biology and the melanocortin system. Despite key neuroanatomical substrates shared by both circadian and melanocortin-signaling pathways, little is known about the relationship between the two. Here we identify a link between circadian disruption and the control of glucose homeostasis mediated through the melanocortin-4 receptor (Mc4r). Mc4r-deficient mice exhibit exaggerated circadian fluctuations in baseline blood glucose and glucose tolerance. Interestingly, exposure to lighting conditions that disrupt circadian rhythms improve their glucose tolerance. This improvement occurs through an increase in glucose clearance by skeletal muscle and is food intake and body weight independent. Restoring Mc4r expression to the paraventricular nucleus prevents the improvement in glucose tolerance, supporting a role for the paraventricular nucleus in the integration of circadian light cues and metabolism. Altogether these data suggest that Mc4r signaling plays a protective role in minimizing glucose fluctuations due to circadian rhythms and environmental light cues and demonstrate a previously undiscovered connection between circadian biology and glucose metabolism mediated through the melanocortin system.
Departments of Internal Medicine (D.M.A., J.H., N.O., J.S., J.W.P., R.J.S., D.A.S., D.P.-T.) and Psychiatry (R.M., S.C.W., J.P.H.), University of Cincinnati, Cincinnati, Ohio 45237; and Department of Surgery (D.M.A., R.J.S., D.A.S.), University of Michigan, Ann Arbor, Michigan 48109.
Deanna M
DM
Arble
Jenna
J
Holland
Nickki
N
Ottaway
Joyce
J
Sorrell
Joshua W
JW
Pressler
Rachel
R
Morano
Stephen C
SC
Woods
Randy J
RJ
Seeley
James P
JP
Herman
Darleen A
DA
Sandoval
Diego
D
Perez-Tilve
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002940:Circadian Rhythm / Q000235:genetics*; D003463:Cues; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D008029:Lighting; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
D001786:Blood Glucose; C574273:MC4R protein, mouse; D044105:Receptor, Melanocortin, Type 4