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


METHODS
Using pharmacological and genetic tools, Alk7 signaling pathway and its effects were studied in murine brown adipocytes. Brown adipocyte differentiation and activation was analyzed.


RESULTS
Alk7 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.


CONCLUSIONS
We 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.
Institute of Pharmacology and Toxicology, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany.
Aileen
A
Balkow
Institute of Pharmacology and Toxicology, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany.
Johanna
J
Jagow
Institute of Pharmacology and Toxicology, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany ; Division of Genetic and Reproductive Toxicology, Federal Institute for Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany.
Bodo
B
Haas
Institute of Pharmacology and Toxicology, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany.
Franziska
F
Siegel
Institute of Pharmacology and Toxicology, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany.
Ana
A
Kilić
Institute of Pharmacology and Toxicology, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany.
Alexander
A
Pfeifer
Activin; Alk7; Brown adipocytes; UCP1; cGMP