Impact of TGFβ signaling on adipose tissue biology
Date
2022
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Abstract
The dysfunction of adipose tissue is a hallmark step in the development of metabolic diseases in obese individuals. Transforming growth factor-beta (TGFβ) ligands are higher in the serum and adipose tissue in obesity and activated TGFβ signaling is known to contribute to adipose tissue dysfunctions. However, the molecular pathways through which TGFβ regulate proliferation and myofibroblast differentiation of human adipose stem cells (hASCs) as well as metabolic and endocrine functions of human adipocytes has not been elucidated. Using a siRNA-mediated knockdown of SMAD2 and SMAD3, two downstream effector molecules, we analyzed their roles in mediating TGFβ signaling on proliferation and myofibroblast-like cell differentiation in hASCs. We also assessed the impact of TGFβ signaling on the adipokine and metabolic profile of human adipocytes using chemical inhibitors SB431542 and SIS3. Our results showed that both SMAD2 and SMAD3 significantly increased the proliferation of hASCs (p<0.001) without impacting alpha-smooth muscle actin expression, a marker of myofibroblasts. Inhibition of endogenous TGFβ signaling improved the adipokine profile of adipocytes by increasing adiponectin (p<0.001) while decreasing leptin (p<0.05) and interleukin-6 (p<0.05) secretion. Addition of TGFβ1 promoted a proinflammatory profile by increasing leptin (p<0.01) and interleukin-6 (p<0.01) secretion and inhibiting adiponectin secretion (p<0.01). Inhibition of TGFβ signaling decreased lipolysis (p<0.01) and tended to decrease lipid droplet size while enhancing mitochondrial intensity without significantly affecting OXPHOS expression in adipocytes. Our data indicates that proliferation of hASCs is not differentially regulated by SMAD2 and SMAD3 and that high TGFβ signaling contributes to adipose tissue dysfunction by increasing proliferation of adipose progenitors as well as inducing pathogenic endocrine and metabolic profiles.
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Molecular biology, Adipose tissue dysfunction, Metabolic diseases, Obesity, TGFβ signaling
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39 pages
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