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

Abstract

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.

Regulation of metabolic homeostasis by the TGF‐β superfamily receptor ALK7

“…Thus, BAT and WAT have not only different functions but also different developmental origins. In spite of this, and similar to white adipocytes, expression of mRNA encoding ALK7 is negligible in BAT SVF and increases during differentiation of brown adipocyte progenitors isolated from the BAT interscapular depot and it is maximal in fully differentiated brown adipocytes [41,121]. Treatments that enhance brown adipocyte differentiation, such as cGMP, also increase expression of mRNA encoding ALK7 [121].…”

“…In spite of this, and similar to white adipocytes, expression of mRNA encoding ALK7 is negligible in BAT SVF and increases during differentiation of brown adipocyte progenitors isolated from the BAT interscapular depot and it is maximal in fully differentiated brown adipocytes [41,121]. Treatments that enhance brown adipocyte differentiation, such as cGMP, also increase expression of mRNA encoding ALK7 [121]. In contrast, ALK7 expression is undetectable in BAT progenitors [41], suggesting that effects attributed to ALK7 in these cells through treatment with activin ligands or ALK7 over-expression [121] most likely reflect the function of endogenous ALK4 receptors, which are abundant in precursor cells of all adipose tissues [Lee and Ib añez, in preparation].…”

“…Treatments that enhance brown adipocyte differentiation, such as cGMP, also increase expression of mRNA encoding ALK7 [121]. In contrast, ALK7 expression is undetectable in BAT progenitors [41], suggesting that effects attributed to ALK7 in these cells through treatment with activin ligands or ALK7 over-expression [121] most likely reflect the function of endogenous ALK4 receptors, which are abundant in precursor cells of all adipose tissues [Lee and Ib añez, in preparation].…”

GPR180 is a component of TGFβ signalling that promotes thermogenic adipocyte function and mediates the metabolic effects of the adipocyte-secreted factor CTHRC1

“…However, our data indicate that CTHRC1 acting through GPR180, does not affect formation of human adipocytes, but specifically promotes brown adipocyte activity and adipocyte browning, which could be attributed to low GPR180 expression in progenitor cells and its abundance in mature adipocytes. Activin, another ligand of TGFβ family which can signal via SMAD3, was shown to enhance UCP1 expression in mature murine adipocytes 46 and to increase energy expenditure by stimulation of BAT thermogenesis 47 . Interestingly, TGFβ2 treatment was recently also shown to upregulate UCP1 expression and increase glucose uptake in BAT 48 .…”

Activin receptor-like kinase 7 silencing alleviates cardiomyocyte apoptosis, cardiac fibrosis, and dysfunction in diabetic rats

“…11–18 Recent studies have shown that the nonsense mutation of ALK7 ameliorates fat accumulation and obesity-induced glucose intolerance and insulin resistance. 9,19–22 These observations lead to the suggestion that the activation of ALK7 contributes to abnormalities of lipometabolism and insulin sensitivity which are important triggers of DCM. 3,4,23,24 Our previous study showed that the silencing of ALK7 attenuated high glucose-induced cardiomyocyte apoptosis in vitro.…”