The central melanocortin system directly controls peripheral lipid metabolism
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
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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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 4

Effects of CNS-Mcr on WAT SNA in rats and in TKO mice.

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Effects of CNS-Mcr on WAT SNA in rats and in TKO mice. Effect of i.c.v. ...
Effect of i.c.v. administration of MTII on SNA to visceral WAT in anesthetized Sprague-Dawley rats. (A) Original records of WAT SNA at baseline and 6 hours after i.c.v. injection of vehicle (Veh) or MTII (5 nmol). (B) Time course of WAT SNA response to MTII (5 nM). There was a significant difference (P < 0.001 by 2-way repeated-measures ANOVA) between the effects of MTII and vehicle on WAT SNA. (C) Dose-response effect of MTII on WAT SNA and blockade of sympathoactivation to MTII in the presence of SHU9119. SNA represent the percent change from baseline (A and B). Data represent mean ± SEM of 5–6 rats per group. *P < 0.05 versus other groups. Effect of a 7-day i.c.v. SHU9119 infusion (5 nmol/day) on cumulative food intake (D) and body weight change (E) in WT and TKO. Controls were infused i.c.v. with saline. Effect of a 7-day i.c.v. SHU9119 infusion on epididymal WAT FAS mRNA expression (F) and FAS activity (G). Data are presented as values normalized to the housekeeping gene HPRT. Values are mean ± SEM of 5–7 animals per group. *P < 0.05 versus controls.