Fig. 8: Graphical representation of GDF3’s mechanism of action on adipocytes. | Nature Communications

Fig. 8: Graphical representation of GDF3’s mechanism of action on adipocytes.

From: Acute regulation of murine adipose tissue lipolysis and insulin resistance by the TGFβ superfamily protein GDF3

Fig. 8

GDF3 binds to its heteromeric receptors on the adipocyte cell surface, which triggers a cascade of signaling responses leading to the phosphorylation of Smad2 and 3. Phospho-Smad2/3 then bind to Smad4, enter the nucleus and bind to the promoter region of the gene Adrb3 which encodes the β-3-adrenergic receptor (β3-AR), priming the cell to increase Adrb3 expression in response to thermogenic stimulation through norepinephrine (NE) or its analogs like Isoproterenol. Upon thermogenic stimulation, adipocytes pre-exposed to GDF3 increase β3-AR expression which leads to increased cellular cAMP levels because of increased adenylyl cyclase (AC) enzyme activity. Increased cAMP levels lead to increased protein kinase A (PKA) activity which leads to the phosphorylation of downstream targets like hormone sensitive lipase (HSL), located on the surface of adipocyte lipid droplets. This leads to the breakdown of adipocyte triglycerides (TG) into free fatty acids (FFA) that are released from the cells. Created in BioRender. Banks, A. (2025) https://BioRender.com/v394jid.

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