Endospanin 1 silencing in the hypothalamic arcuate nucleus contributes to sustained weight loss of high fat diet obese mice.
Leptin targets specific receptors (OB-R) expressed in the hypothalamus to regulate energy balance. Leptin decreases food intake in normal weight individuals, but this effect is blunted in obese subjects who are characterized by a state of leptin resistance. The prevention of leptin resistance is one of the major goals of obesity research. Recently, we identified endospanin 1 as a negative regulator of OB-R, which by interacting with OB-R retains the receptor inside the cell. We show here that in obese mice endospanin 1 is upregulated in the hypothalamic arcuate nucleus (ARC), the major brain structure involved in body weight regulation, suggesting that endospanin 1 is implicated in obesity development and/or the installation of leptin resistance. In contrast, silencing of endospanin 1 with lentiviral vectors in the ARC of obese mice fully restores leptin responsiveness when combined with a switch to ad libitum fed chow diet. The recovery of central leptin sensitivity is accompanied by sustained body weight loss and amelioration of blood lipid parameters and steatosis. Collectively, our results define endospanin 1 as a novel therapeutic target against obesity.
1] Inserm, U1016, Institut Cochin, Paris, France [2] CNRS UMR 8104, Paris, France [3] University Paris Descartes, Sorbonne Paris Cite, Paris, France.
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Vauthier
1] Inserm, U1016, Institut Cochin, Paris, France [2] CNRS UMR 8104, Paris, France [3] University Paris Descartes, Sorbonne Paris Cite, Paris, France.
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Swartz
1] Inserm, U1016, Institut Cochin, Paris, France [2] CNRS UMR 8104, Paris, France [3] University Paris Descartes, Sorbonne Paris Cite, Paris, France.
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Chen
1] Inserm, U1016, Institut Cochin, Paris, France [2] CNRS UMR 8104, Paris, France [3] University Paris Descartes, Sorbonne Paris Cite, Paris, France.
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Roujeau
1] Inserm, U1016, Institut Cochin, Paris, France [2] CNRS UMR 8104, Paris, France [3] University Paris Descartes, Sorbonne Paris Cite, Paris, France.
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Pagnon
UMR 7091, University Paris Pierre et Marie Curie (UPMC), CNRS, NewVectys, Paris, France.
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Mallet
UMR 7091, University Paris Pierre et Marie Curie (UPMC), CNRS, NewVectys, Paris, France.
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Sarkis
1] Inserm, U1016, Institut Cochin, Paris, France [2] CNRS UMR 8104, Paris, France [3] University Paris Descartes, Sorbonne Paris Cite, Paris, France.
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Jockers
1] Inserm, U1016, Institut Cochin, Paris, France [2] CNRS UMR 8104, Paris, France [3] University Paris Descartes, Sorbonne Paris Cite, Paris, France.
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Dam
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015431:Weight Loss
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D008055:Lipids; C484581:Obrgrp protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse