The central melanocortin system directly controls peripheral lipid metabolism
Ruben Nogueiras, … , Françoise Rohner-Jeanrenaud, Matthias H. Tschöp
Ruben Nogueiras, … , Françoise Rohner-Jeanrenaud, Matthias H. Tschöp
Published September 20, 2007
Citation Information: J Clin Invest. 2007;117(11):3475-3488. https://doi.org/10.1172/JCI31743.
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Research Article Metabolism

The central melanocortin system directly controls peripheral lipid metabolism

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.

Authors

Ruben Nogueiras, Petra Wiedmer, Diego Perez-Tilve, Christelle Veyrat-Durebex, Julia M. Keogh, Gregory M. Sutton, Paul T. Pfluger, Tamara R. Castaneda, Susanne Neschen, Susanna M. Hofmann, Philip N. Howles, Donald A. Morgan, Stephen C. Benoit, Ildiko Szanto, Brigitte Schrott, Annette Schürmann, Hans-Georg Joost, Craig Hammond, David Y. Hui, Stephen C. Woods, Kamal Rahmouni, Andrew A. Butler, I. Sadaf Farooqi, Stephen O’Rahilly, Françoise Rohner-Jeanrenaud, Matthias H. Tschöp

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Figure 5

Lack of endogenous Mc4r affects WAT metabolism.

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Lack of endogenous Mc4r affects WAT metabolism. (A) Relative abundance o...
(A) Relative abundance of LPL mRNA in WAT of Mc4r-KO and WT mice. FAS, SCD-1, and ACC were also analyzed but did not show statistical difference (data not shown). Data are presented as values normalized to the housekeeping gene HPRT. Values are mean ± SEM of 6–8 animals per group. *P < 0.05. (B and C) Basal and insulin-stimulated PKB activity as assessed by Western blot analysis of Ser473 phosphorylation of PKB (B) and measurement of PKB kinase activity (C) was increased in WAT of Mc4r-KO mice compared with WT littermates. Phosphorylation of FoxO1 on Ser256, an important transcription factor target of PKB, was also increases in the basal and insulin-stimulated state in Mc4r-KO mice. For the experiments represented in B and C, 6-week-old pre-obese Mc4r-KO mice and WT B6 controls were fasted overnight and then administered saline or 1 U/kg insulin, and PKB and FoxO1 phosphorylation and/or activity were measured as described previously (42).