A novel crosstalk between Alk7 and cGMP signaling differentially regulates brown adipocyte function

• Alk7 expression in brown adipocytes is modulated by the cGMP/PKGI signaling pathway.
• Brown adipocyte differentiation requires tight regulation of Alk7 activation.
• Alk7 signaling via SMAD3 reduces PPARγ and attenuates adipogenic differentiation.
• Alk7 enhances UCP1 expression in mature brown adipocytes.
• We found a novel crosstalk between the Alk7 and cGMP signaling pathway.

ObjectiveObesity is an enormous burden for patients and health systems world-wide. Brown adipose tissue dissipates energy in response to cold and has been shown to be metabolically active in human adults. The type I transforming growth factor β (TGFβ) receptor Activin receptor-like kinase 7 (Alk7) is highly expressed in adipose tissues and is down-regulated in obese patients. Here, we studied the function of Alk7 in brown adipocytes.MethodsUsing pharmacological and genetic tools, Alk7 signaling pathway and its effects were studied in murine brown adipocytes. Brown adipocyte differentiation and activation was analyzed.ResultsAlk7 is highly upregulated during differentiation of brown adipocytes. Interestingly, Alk7 expression is increased by cGMP/protein kinase G (PKG) signaling, which enhances brown adipocyte differentiation. Activin AB effectively activates Alk7 and SMAD3 signaling. Activation of Alk7 in brown preadipocytes suppresses the master adipogenic transcription factor PPARγ and differentiation. Stimulation of Alk7 during late differentiation of brown adipocytes reduces lipid content and adipogenic marker expression but enhances UCP1 expression.ConclusionsWe found a so far unknown crosstalk between cGMP and Alk7 signaling pathways. Tight regulation of Alk7 is required for efficient differentiation of brown adipocytes. Alk7 has differential effects on adipogenic differentiation and the development of the thermogenic program in brown adipocytes.