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 1

Long-term oral treatment with Flx increases BW and adiposity by specifically enhancing food intake.

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Long-term oral treatment with Flx increases BW and adiposity by specific...
(A) Percentage of BW relative to day 0 in WT female mice treated with vehicle or Flx for 6 weeks (plain gray bars, n = 8–9 mice/group, representative of 6 independent experiments) or 12 weeks (hatched bars, n = 7 mice/group). (B) Percentage of WAT content relative to BW at the end of the 6-week (n = 6–8 mice/group) and 12-week (n = 7 mice/group) treatment periods. (C and E) WT females treated with vehicle or Flx for 6 weeks. (C) Energy expenditure measured by VO2, VCO2, heat production, and locomotor activity recorded over the last 3 days of treatment (n = 7 mice/group). (D) Core body temperature (T) at the end of the treatment period (n = 6–8 mice/group). (E) Cumulative food intake measured over the last 5 days of treatment (n = 6–7 mice/group; data are representative of 2 independent experiments). Values represent the mean ± SEM. **P ≤ 0.01 and ***P ≤ 0.001, by 2-way ANOVA followed by Šidák’s test (A and B, locomotion activity in C), ANCOVA (C, except for locomotor activity), and paired Student’s t test (E) versus vehicle. ##P ≤ 0.01 and ###P ≤ 0.001, by Student’s t test for Flx versus vehicle, analyzed for each time point.