Serotonin 5-HT2A receptor activity mediates adipocyte differentiation through control of adipogenic gene expression

Bangning Yu,Timothy P Foster,Diana M Battaglia,Charles D Nichols

doi:10.1038/s41598-021-98970-1

Bangning Yu, Timothy P Foster + Show 2 more

Open Access

https://doi.org/10.1038/s41598-021-98970-1

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Abstract

Serotonin 5-HT2 receptors are expressed in many tissues and play important roles in biological processes. Although the 5-HT2A receptor is primarily known for its role in central nervous system, it is also expressed in peripheral tissues. We have found that 5-HT2A receptor antagonists inhibit human subcutaneous primary adipocyte differentiation. We also show that siRNA knockdown of the 5-HT2A receptor blocks differentiation. Using gene expression analysis in combination with receptor antagonists we found that activity of 5-HT2A receptors is necessary very early in the differentiation process to mediate expression of adipogenic genes, including peroxisome proliferator-activated receptor gamma (ppar-γ), adipocyte protein 2 (aP2), adiponectin, and serine/threonine-protein kinase 1 (sgk1). We show here for the first time that 5-HT2A receptor activity is necessary for differentiation of human primary subcutaneous preadipocytes to adipocytes, and that 5-HT2A receptor activity mediates key genes related to adipogenesis during this process. Importantly, this work contributes to a greater understanding of the adipocyte differentiation process, as well as to the role of 5-HT2A receptors in peripheral tissues, and may be relevant to the development of novel therapeutic strategies targeting this receptor for the treatment of obesity related diseases.

Highlights

Serotonin 5-HT2 receptors are expressed in many tissues and play important roles in biological processes
We have found no evidence for 5-HT2C receptor expression in human preadipocytes by qRT-polymerase chain reaction (PCR), and there is no report in the literature of human preadipocytes expressing 5-HT2C receptors
Following up on our earlier work[37], we present here conclusive evidence demonstrating that 5-HT2A receptor activity is necessary for differentiation in a more relevant adipose model system: primary human subcutaneous preadipocyte to adipocyte differentiation

Summary

Introduction

Serotonin 5-HT2 receptors are expressed in many tissues and play important roles in biological processes. Some research has implicated 5-HT2A receptor activity in metabolic processes, for example, activation of 5HT2 receptors with the agonist DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), has been reported to increase plasma glucagon levels in rats[23]. This hyperglucagonemia induced by DOI is dose-dependently prevented by the 5-HT2 receptor antagonist. A different antagonist at the 5-HT2A receptor, sapogrelate, has been reported to elevate adiponectin expression and to have insulin-sensitizing e ffects[25,26,27] Taken together, these studies support the notion that 5-HT2 receptors likely play an important, but as yet undefined, role in obesity-related diseases, including diabetes. Elucidation of the role of 5-HT2A receptors is likely to provide crucial information about these processes, and potentially to lead to new therapeutic avenues

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