Cited by 396Regulation of Appetite and ObesityAdipose Tissue and MetabolismAdipokines, Inflammation, and Metabolic Diseases

The central melanocortin system directly controls peripheral lipid metabolism

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Nogueiras, Ruben, Wiedmer, Petra, Perez-Tilve, Diego, Veyrat-Durebex, Christelle, Keogh, Julia M., Sutton, Gregory M., Pfluger, Paul T., Castaneda, Tamara R. +18 more·2007·Journal of Clinical Investigation

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.

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  • Reduced melanocortin signaling promotes insulin sensitivity and glucose uptake in white adipose tissue but reduces glucose utilization in brown adipose tissue and muscle, favoring increased triglyceride synthesis and storage in the body.

    “while reduced melanocortin signaling promotes insulin sensitivity and glucose uptake in WAT, it reduces glucose utilization in BAT and muscle (131), favoring increased TG synthesis and storage in the body.”

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Authors
Nogueiras, R., Wiedmer, P., Perez-Tilve, D., Veyrat-Durebex, C., Keogh, J. M., Sutton, G. M., Pfluger, P. T., Castaneda, T. R., Neschen, S., Hofmann, S. M., Howles, P. N., Morgan, D. A., Benoit, S. C., Szanto, I., Schrott, B., Schürmann, A., Joost, H.-G., Hammond, C., Hui, D. Y., Woods, S. C., Rahmouni, K., Butler, A. A., Farooqi, I. S., O’Rahilly, S., Rohner-Jeanrenaud, F., & Tschöp, M. H.
Affiliations
  • German Institute of Human Nutrition (DE)
  • Addenbrooke's Hospital (GB)
  • Pennington Biomedical Research Center (US)
  • University of Cincinnati (US)
  • University of Iowa (US)
  • Eli Lilly (United States) (US)
Corresponding author
Tschöp, Matthias H.
Venue
Journal of Clinical Investigation
Published
2007-11-01
Volume
117
Issue
11
Pages
3475-3488
ISSN
0021-9738 (ISSN-L)
OpenAlex
W2151831322
Cited by
396
References
71
Citations by year
2026: 4 · 2025: 14 · 2024: 11 · 2023: 9 · 2022: 9 · 2021: 10 · 2020: 19 · 2019: 17 · 2018: 16 · 2017: 25 · 2016: 26 · 2015: 27 · 2014: 24 · 2013: 29 · 2012: 36
FWCI
10.61
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Science Foundation
  • University of Cincinnati
  • Wellcome Trust (068086)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (105889, 3100A0)
  • Medical Research Council
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
melanocortin system, melanocortin-4 receptor, obesity, lipid metabolism, white adipose tissue, nutrient partitioning, triglyceride synthesis, lipid mobilization, insulin sensitivity, glucose uptake, brown adipose tissue, sympathetic nervous system, respiratory quotient, loss-of-function mutations
MeSH terms
Adipose Tissue, alpha-MSH, Animals, Behavior, Animal, Central Nervous System, Eating, Glucose, Humans, Insulin, Melanocyte-Stimulating Hormones, Signal Transduction, Rats, Sprague-Dawley, Adipocytes, Mice, Knockout, Receptors, Melanocortin, Receptor, Melanocortin, Type 4, Lipid Metabolism, Mice, Rats, Melanocortins

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