Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Laboratory of Molecular Genetics, Howard Hughes Medical Institute and.
J Clin Invest. 2021 Dec 15;131(24). doi: 10.1172/JCI151976.
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.
与增加大脑血清素信号预测的厌食效果相反，长期使用选择性 5-羟色胺再摄取抑制剂（SSRI）抗抑郁药与体重（BW）增加相关。这种不良后果增加了向肥胖过渡的风险，并干扰了治疗依从性。在这里，我们表明，口服给予氟西汀（Flx），一种广泛使用的 SSRI，通过在 2 个不同时间点和通过 2 个不同的机制增强健康小鼠的食物摄入来增加 BW。在数小时内，Flx 通过触发 5-羟色胺受体 1a（Htr1a）的自动抑制信号来降低脑干血清素能神经元的活性。在较长的治疗期间，Flx 减弱了 5-羟色胺受体 2c（Htr2c）的表达和信号传导，降低了 cAMP 反应元件结合蛋白（CREB）和 STAT3 的磷酸化，并抑制了下丘脑神经元中促黑皮质素原（POMC，α-黑素细胞刺激素[α-MSH]的前体）的产生，从而增加了食物摄入。因此，通过用 Flx 和脂联素 2 共同处理小鼠来对外源刺激黑皮质素 4 受体（Mc4r），这是一种通过该受体进行的厌食激素信号，使进食和 BW 正常化。Flx 和其他 SSRI 还抑制了人类神经元细胞系中 CREB 和 STAT3 的磷酸化，这表明这些非典型效应也可能发生在长期接受 SSRI 治疗的个体中。通过定义长期 SSRI 相关体重增加的分子基础，我们提出了一种治疗策略来对抗这种作用。
