Melanocortin 4 receptor stimulation prevents antidepressant-associated weight gain in mice caused by long-term fluoxetine exposure
María José Ortuño, … , Jeffrey M. Friedman, Patricia Ducy
María José Ortuño, … , Jeffrey M. Friedman, Patricia Ducy
Published October 21, 2021
Citation Information: J Clin Invest. 2021;131(24):e151976. https://doi.org/10.1172/JCI151976.
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Research Article Metabolism

Melanocortin 4 receptor stimulation prevents antidepressant-associated weight gain in mice caused by long-term fluoxetine exposure

Abstract

Contrasting with the predicted anorexigenic effect of increasing brain serotonin signaling, long-term use of selective serotonin reuptake inhibitor (SSRI) antidepressants correlates with body weight (BW) gain. This adverse outcome increases the risk of transitioning to obesity and interferes with treatment compliance. Here, we show that orally administered fluoxetine (Flx), a widely prescribed SSRI, increased BW by enhancing food intake in healthy mice at 2 different time points and through 2 distinct mechanisms. Within hours, Flx decreased the activity of a subset of brainstem serotonergic neurons by triggering autoinhibitory signaling through 5-hydroxytryptamine receptor 1a (Htr1a). Following a longer treatment period, Flx blunted 5-hydroxytryptamine receptor 2c (Htr2c) expression and signaling, decreased the phosphorylation of cAMP response element–binding protein (CREB) and STAT3, and dampened the production of pro-opiomelanocortin (POMC, the precursor of α-melanocyte stimulating hormone [α-MSH]) in hypothalamic neurons, thereby increasing food intake. Accordingly, exogenous stimulation of the melanocortin 4 receptor (Mc4r) by cotreating mice with Flx and lipocalin 2, an anorexigenic hormone signaling through this receptor, normalized feeding and BW. Flx and other SSRIs also inhibited CREB and STAT3 phosphorylation in a human neuronal cell line, suggesting that these noncanonical effects could also occur in individuals treated long term with SSRIs. By defining the molecular basis of long-term SSRI–associated weight gain, we propose a therapeutic strategy to counter this effect.

Authors

María José Ortuño, Marc Schneeberger, Anoj Ilanges, François Marchildon, Kyle Pellegrino, Jeffrey M. Friedman, Patricia Ducy

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Figure 3

Acute treatment with Flx decreases the activity of DRN neurons and hypothalamic α-MSH levels.

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Acute treatment with Flx decreases the activity of DRN neurons and hypot...
(A and B) iDISCO+ whole-brain imaging and ClearMap analysis of c-Fos from compressed coronal views of the DRN (A) and hypothalamus (B) of WT female mice treated with vehicle (second column) or Flx (third column) for 2 hours (n = 5–6 mice/group). First column: ABA annotated image. Second and third columns: heatmaps. Fourth column: voxel-based statistical analysis. Regions with significantly different numbers of Fos+ cells in the Flx versus vehicle treatment conditions are highlighted. (C) IHF validation of iDISCO+ results for brain slices from WT female mice treated with vehicle or Flx for 2 hours. Graphs show the quantification of Fos+ neurons in the DRN, ARC, and PVN (n = 5–7 mice/group). (D and E) Representative images and quantification following double-IHF as indicated, in brain slices from WT female mice treated with Flx or vehicle for 2 hours (D, n = 7 mice/group; E, n = 6 mice/group). (F) Representative IHF images and levels of α-MSH in PVN neurons quantified as integrated density in brain slices from WT female mice treated with vehicle or Flx for 14 hours. Flx was then withdrawn in some of the groups as indicated (n = 12 vehicle, n = 7 mice/other groups). aq, aqueduct; 3V, third ventricle. Scale bars: 200 μm. Values represent the mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001, by unpaired Student’s t test versus vehicle (C–E) or 1-way ANOVA followed by Dunnett’s test (F).