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 7

Cotreatment with Lcn2 can block the long-term effects of Flx on feeding and BW.

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Cotreatment with Lcn2 can block the long-term effects of Flx on feeding ...
(A–E) WT female mice were treated for 5 weeks with vehicle or Flx and then with vehicle, Flx, or Flx plus Lcn2 for 5 additional days (n = 4–5 mice/group). (A) Schema of the experimental design. (B) Cumulative food intake. (C) Percentage of BW on the last day of cotreatment relative BW on day 0 of cotreatment. (D) Percentage of WAT content relative to BW. (E) Fat content relative to BW. (F–J) WT female mice were treated for 4 days with vehicle, Flx, Lcn2, or both drugs as indicated (n = 10 mice/group). (F) Cumulative food intake. (G) Percentage of BW on the last day of treatment relative to BW on day 0. (H) Percentage of WAT content relative to BW. (I) Fat content relative to BW. (J) Marble-burying test. Values represent the mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001, for vehicle versus Flx; †P ≤ 0.05 and †††P ≤ 0.001, for Flx compared with Flx+Lcn2+. Two-way ANOVA (B and F) or 1-way ANOVA (C–E and G–J) followed by Tukey’s test.