Journal article
The central melanocortin system directly controls peripheral lipid metabolism
The Journal of clinical investigation, Vol.117(11), pp.3475-3488
11/01/2007
DOI: 10.1172/JCI31743
PMCID: PMC1978426
PMID: 17885689
Abstract
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.
Details
- Title: Subtitle
- The central melanocortin system directly controls peripheral lipid metabolism
- Creators
- Ruben Nogueiras - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USAPetra Wiedmer - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USADiego Perez-Tilve - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USAChristelle Veyrat-Durebex - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USAJulia M Keogh - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USAGregory M Sutton - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USAPaul T Pfluger - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USATamara R Castaneda - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USASusanne Neschen - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USASusanna M Hofmann - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USAPhilip N Howles - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USADonald A Morgan - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USAStephen C Benoit - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USAIldiko Szanto - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USABrigitte Schrott - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USAAnnette Schürmann - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USAHans-Georg Joost - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USACraig Hammond - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USADavid Y Hui - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USAStephen C Woods - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USAKamal Rahmouni - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USAAndrew A Butler - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USAI. Sadaf Farooqi - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USAStephen O’Rahilly - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USAFrançoise Rohner-Jeanrenaud - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USAMatthias H Tschöp - Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.117(11), pp.3475-3488
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/JCI31743
- PMID
- 17885689
- PMCID
- PMC1978426
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Language
- English
- Date published
- 11/01/2007
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984040221302771
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