Protection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R
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Protection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R. / Lund, Camilla; Ranea-Robles, Pablo; Falk, Sarah; Rausch, Dylan M; Skovbjerg, Grethe; Vibe-Petersen, Victoria Kamma; Krauth, Nathalie; Skytte, Jacob Lercke; Vana, Vasiliki; Roostalu, Urmas; Pers, Tune H; Lund, Jens; Clemmensen, Christoffer.
In: Nature Communications, Vol. 15, 1192, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Protection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R
AU - Lund, Camilla
AU - Ranea-Robles, Pablo
AU - Falk, Sarah
AU - Rausch, Dylan M
AU - Skovbjerg, Grethe
AU - Vibe-Petersen, Victoria Kamma
AU - Krauth, Nathalie
AU - Skytte, Jacob Lercke
AU - Vana, Vasiliki
AU - Roostalu, Urmas
AU - Pers, Tune H
AU - Lund, Jens
AU - Clemmensen, Christoffer
N1 - © 2024. The Author(s).
PY - 2024
Y1 - 2024
N2 - Overfeeding triggers homeostatic compensatory mechanisms that counteract weight gain. Here, we show that both lean and diet-induced obese (DIO) male mice exhibit a potent and prolonged inhibition of voluntary food intake following overfeeding-induced weight gain. We reveal that FGF21 is dispensable for this defense against weight gain. Targeted proteomics unveiled novel circulating factors linked to overfeeding, including the protease legumain (LGMN). Administration of recombinant LGMN lowers body weight and food intake in DIO mice. The protection against weight gain is also associated with reduced vascularization in the hypothalamus and sustained reductions in the expression of the orexigenic neuropeptide genes, Npy and Agrp, suggesting a role for hypothalamic signaling in this homeostatic recovery from overfeeding. Overfeeding of melanocortin 4 receptor (MC4R) KO mice shows that these mice can suppress voluntary food intake and counteract the enforced weight gain, although their rate of weight recovery is impaired. Collectively, these findings demonstrate that the defense against overfeeding-induced weight gain remains intact in obesity and involves mechanisms independent of both FGF21 and MC4R.
AB - Overfeeding triggers homeostatic compensatory mechanisms that counteract weight gain. Here, we show that both lean and diet-induced obese (DIO) male mice exhibit a potent and prolonged inhibition of voluntary food intake following overfeeding-induced weight gain. We reveal that FGF21 is dispensable for this defense against weight gain. Targeted proteomics unveiled novel circulating factors linked to overfeeding, including the protease legumain (LGMN). Administration of recombinant LGMN lowers body weight and food intake in DIO mice. The protection against weight gain is also associated with reduced vascularization in the hypothalamus and sustained reductions in the expression of the orexigenic neuropeptide genes, Npy and Agrp, suggesting a role for hypothalamic signaling in this homeostatic recovery from overfeeding. Overfeeding of melanocortin 4 receptor (MC4R) KO mice shows that these mice can suppress voluntary food intake and counteract the enforced weight gain, although their rate of weight recovery is impaired. Collectively, these findings demonstrate that the defense against overfeeding-induced weight gain remains intact in obesity and involves mechanisms independent of both FGF21 and MC4R.
KW - Male
KW - Mice
KW - Animals
KW - Receptor, Melanocortin, Type 4/genetics
KW - Obesity/genetics
KW - Weight Gain
KW - Fibroblast Growth Factors/genetics
KW - Body Weight/physiology
U2 - 10.1038/s41467-024-45223-0
DO - 10.1038/s41467-024-45223-0
M3 - Journal article
C2 - 38331907
VL - 15
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 1192
ER -
ID: 382506502