Protection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R

Camilla Lund, Pablo Ranea-Robles, Sarah Falk, Dylan M. Rausch, Grethe Skovbjerg, Victoria Kamma Vibe-Petersen, Nathalie Krauth, Jacob Lercke Skytte, Vasiliki Vana, Urmas Roostalu, Tune H. Pers, Jens Lund and Christoffer Clemmensen ()
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Camilla Lund: University of Copenhagen
Pablo Ranea-Robles: University of Copenhagen
Sarah Falk: University of Copenhagen
Dylan M. Rausch: University of Copenhagen
Grethe Skovbjerg: University of Copenhagen
Victoria Kamma Vibe-Petersen: University of Copenhagen
Nathalie Krauth: University of Copenhagen
Jacob Lercke Skytte: Gubra ApS
Vasiliki Vana: University of Copenhagen
Urmas Roostalu: Gubra ApS
Tune H. Pers: University of Copenhagen
Jens Lund: University of Copenhagen
Christoffer Clemmensen: University of Copenhagen

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-45223-0

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