Journal of Lipid Research
Volume 55, Issue 10, October 2014, Pages 2022-2032
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Research Articles
Inhibition of the central melanocortin system decreases brown adipose tissue activity[S]

https://doi.org/10.1194/jlr.M045989Get rights and content
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The melanocortin system is an important regulator of energy balance, and melanocortin 4 receptor (MC4R) deficiency is the most common monogenic cause of obesity. We investigated whether the relationship between melanocortin system activity and energy expenditure (EE) is mediated by brown adipose tissue (BAT) activity. Therefore, female APOE*3-Leiden.CETP transgenic mice were fed a Western-type diet for 4 weeks and infused intracerebroventricularly with the melanocortin 3/4 receptor (MC3/4R) antagonist SHU9119 or vehicle for 2 weeks. SHU9119 increased food intake (+30%) and body fat (+50%) and decreased EE by reduction in fat oxidation (−42%). In addition, SHU9119 impaired the uptake of VLDL-TG by BAT. In line with this, SHU9119 decreased uncoupling protein-1 levels in BAT (−60%) and induced large intracellular lipid droplets, indicative of severely disturbed BAT activity. Finally, SHU9119-treated mice pair-fed to the vehicle-treated group still exhibited these effects, indicating that MC4R inhibition impairs BAT activity independent of food intake. These effects were not specific to the APOE*3-Leiden.CETP background as SHU9119 also inhibited BAT activity in wild-type mice. We conclude that inhibition of central MC3/4R signaling impairs BAT function, which is accompanied by reduced EE, thereby promoting adiposity. We anticipate that activation of MC4R is a promising strategy to combat obesity by increasing BAT activity.

energy expenditure
liver
triglycerides
very low density lipoprotein
white adipose tissue

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This work was supported by ‘the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences’ for the GENIUS project ‘Generating the best evidence-based pharmaceutical targets for atherosclerosis’ (CVON2011-19). P. C. N. Rensen is an Established Investigator of the Netherlands Heart Foundation (Grant 2009T038).

    Abbreviations:

    [14C]CO

    [14C]cholesteryl oleate

    [3H]TO

    glycerol tri[3H]oleate

    BAT

    brown adipose tissue

    CREB

    cAMP response element-binding protein

    EE

    energy expenditure

    FFM

    fat-free mass

    gWAT

    gonadal white adipose tissue

    iBAT

    interscapular brown adipose tissue

    MC3/4R

    melanocortin 3/4 receptor

    MC4R

    melanocortin 4 receptor

    p-CREB

    phosphorylated cAMP response element-binding protein

    PL

    phospholipid

    RER

    respiratory exchange ratio

    SR-BI

    scavenger receptor class B type I

    TC

    total cholesterol

    TH

    tyrosine hydroxylase

    UCP-1

    uncoupling protein-1

    WAT

    white adipose tissue

[S]

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of two figures.