Smad2/3 Activation Regulates Smad1/5/8 Signaling via a Negative Feedback Loop to Inhibit 3T3-L1 Adipogenesis

• Published in: International journal of molecular sciences Vol. 22; no. 16; p. 8472
• Main Authors: Aykul, Senem, Maust, Jordan, Thamilselvan, Vijayalakshmi, Floer, Monique, Martinez-Hackert, Erik
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 06-08-2021; MDPI
• Subjects: 3T3-L1; Activin; Adipocytes; Adipogenesis; Adipose tissue; BMP; Feedback; Feedback loops; Gene expression; Growth factors; Hyperplasia; Hypertrophy; Inhibitors; Kinases; Ligands; Lipids; Metabolism; Morbidity; Negative feedback; Obesity; Precursors; Public health; Signal transduction; signaling; SMAD; Smad2 protein; TGF-β; Transforming growth factor-b; Traps
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22168472

Adipose tissues (AT) expand in response to energy surplus through adipocyte hypertrophy and hyperplasia. The latter, also known as adipogenesis, is a process by which multipotent precursors differentiate to form mature adipocytes. This process is directed by developmental cues that include members of the TGF-β family. Our goal here was to elucidate, using the 3T3-L1 adipogenesis model, how TGF-β family growth factors and inhibitors regulate adipocyte development. We show that ligands of the Activin and TGF-β families, several ligand traps, and the SMAD1/5/8 signaling inhibitor LDN-193189 profoundly suppressed 3T3-L1 adipogenesis. Strikingly, anti-adipogenic traps and ligands engaged the same mechanism of action involving the simultaneous activation of SMAD2/3 and inhibition of SMAD1/5/8 signaling. This effect was rescued by the SMAD2/3 signaling inhibitor SB-431542. By contrast, although LDN-193189 also suppressed SMAD1/5/8 signaling and adipogenesis, its effect could not be rescued by SB-431542. Collectively, these findings reveal the fundamental role of SMAD1/5/8 for 3T3-L1 adipogenesis, and potentially identify a negative feedback loop that links SMAD2/3 activation with SMAD1/5/8 inhibition in adipogenic precursors.