The central melanocortin system directly controls peripheral lipid metabolism.
Disruptions of the melanocortin signaling system have been linked to obesity. We investigated a possible role of the central nervous melanocortin system (CNS-Mcr) in the control of adiposity through effects on nutrient partitioning and cellular lipid metabolism independent of nutrient intake. We report that pharmacological inhibition of melanocortin receptors (Mcr) in rats and genetic disruption of Mc4r in mice directly and potently promoted lipid uptake, triglyceride synthesis, and fat accumulation in white adipose tissue (WAT), while increased CNS-Mcr signaling triggered lipid mobilization. These effects were independent of food intake and preceded changes in adiposity. In addition, decreased CNS-Mcr signaling promoted increased insulin sensitivity and glucose uptake in WAT while decreasing glucose utilization in muscle and brown adipose tissue. Such CNS control of peripheral nutrient partitioning depended on sympathetic nervous system function and was enhanced by synergistic effects on liver triglyceride synthesis. Our findings offer an explanation for enhanced adiposity resulting from decreased melanocortin signaling, even in the absence of hyperphagia, and are consistent with feeding-independent changes in substrate utilization as reflected by respiratory quotient, which is increased with chronic Mcr blockade in rodents and in humans with loss-of-function mutations in MC4R. We also reveal molecular underpinnings for direct control of the CNS-Mcr over lipid metabolism. These results suggest ways to design more efficient pharmacological methods for controlling adiposity.
Nogueiras
Ruben
R
Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio 45237, USA.
Wiedmer
Petra
P
Perez-Tilve
Diego
D
Veyrat-Durebex
Christelle
C
Keogh
Julia M
JM
Sutton
Gregory M
GM
Pfluger
Paul T
PT
Castaneda
Tamara R
TR
Neschen
Susanne
S
Hofmann
Susanna M
SM
Howles
Philip N
PN
Morgan
Donald A
DA
Benoit
Stephen C
SC
Szanto
Ildiko
I
Schrott
Brigitte
B
Schürmann
Annette
A
Joost
Hans-Georg
HG
Hammond
Craig
C
Hui
David Y
DY
Woods
Stephen C
SC
Rahmouni
Kamal
K
Butler
Andrew A
AA
Farooqi
I Sadaf
IS
O'Rahilly
Stephen
S
Rohner-Jeanrenaud
Françoise
F
Tschöp
Matthias H
MH
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002490:Central Nervous System / Q000378:metabolism*; D004435:Eating; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism; D053486:Melanocortins / Q000378:metabolism*; D009074:Melanocyte-Stimulating Hormones / Q000008:administration & dosage / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism; D044101:Receptors, Melanocortin; D015398:Signal Transduction / Q000502:physiology*; D000521:alpha-MSH / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism
D007328:Insulin; D053486:Melanocortins; D044105:Receptor, Melanocortin, Type 4; D044101:Receptors, Melanocortin; C105974:acetyl-norleucyl(4)-(aspartyl(5)-histidyl(6)-phenylalanyl(7)-arginyl(8)-tryptophyl(9)-lysyl(10))cyclo-alpha-MSH(4-10)amide; C103272:SHU 9119; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones; D005947:Glucose