Endothelin-1 Stimulates the Growth of Visceral and Subcutaneous Human Preadipocytes through Similar and Alternative Signaling Pathways via Type A and Type B Endothelin Receptors: Potential Implications for Therapeutic Strategies for Obesity and Metabolic Disorders

TL;DR

Endothelin-1 promotes the growth of human preadipocytes through shared and unique signaling pathways, offering new insights for obesity and metabolic disorder treatments.

Contribution

The study reveals distinct and shared signaling pathways through which ET-1 stimulates growth in visceral and subcutaneous preadipocytes.

Findings

ET-1 stimulates growth of visceral and subcutaneous preadipocytes via ETAR and ETBR.

AMPK, PKC, and STAT3 are common signaling components in ET-1-induced growth.

ERK and c-JUN are unique to ETBR signaling in visceral preadipocytes.

Abstract

Endothelin-1 (ET-1), a potent vasoconstrictor, plays multifaceted roles in cellular growth, differentiation, and metabolic regulation. Elevated plasma levels of ET-1 have been observed in obesity, in which ET-1 regulates adipogenesis and the endocrine activity of fat cells. Human white adipocytes are central to energy storage and endocrine regulation. However, relatively little is known about the involvement of the ET-1 signaling pathway in the growth of human white preadipocytes (HWPs). Dysfunction or dysregulation of HWPs may contribute to the development of obesity and associated diseases. Therefore, we investigated the cellular signaling mechanisms in HWPs, focusing on the cellular and functional basis of the actions of ET-1. In this study, signaling protein levels, cell proliferation, and the numbers of visceral and subcutaneous HWPs were measured by immunoblotting and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and trypan blue exclusion assays. Both ET type A receptor (ETAR) and ET type B receptor (ETBR) antagonists inhibited the ET-1-induced growth of visceral HWPs and the phosphorylation of AMPK, PKC, and STAT3 in these cells. The ETBR antagonist alone blocked the ET-1-induced phosphorylation of ERK and c-JUN. Pretreatment with specific inhibitors of AMPK, ERK, JNK, STAT3, and PKC prevented ET-1-induced cell proliferation and attenuated the phosphorylation of AMPK, ERK, c-JUN, STAT3, and PKC induced by ET-1. Similar ETAR- and ETBR-dependent and AMPK- and ERK-dependent effects of ET-1 on the growth of primary subcutaneous HWPs were observed. In summary, the transduction of growth-related ET-1 signals in HWPs could occur through similar (e.g., AMPK, PKC, and JAK2/STAT3) or different (e.g., ERK and JNK/c-JUN) pathways. These distinct signaling pathways, along with the optimization of pathway-specific inhibitors, have potential implications for the future management of obesity and metabolic disorders.

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