Growth/differentiation factor 3 signals through ALK7 and regulates accumulation of adipose tissue and diet-induced obesity

Andersson, Olov; Korach-André, Marion; Reissmann, Eva; Ibáñez, Carlos F.; Bertolino, Philippe

doi:10.1073/pnas.0800272105

Cited by 116 publications

(147 citation statements)

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“…This indicates that those phenotypes may be the consequence of deficits in the activities of other ALK7 ligands. We have recently found that GDF-3 signals through ALK7 and regulates accumulation of adipose tissue and diet-induced obesity (14). Although neither Inh␤B Ϫ/Ϫ or Gdf3 Ϫ/Ϫ mutants show signs of reduced insulin sensitivity or liver steatosis (this study and ref.…”

Section: Discussionmentioning

confidence: 84%

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Activin B receptor ALK7 is a negative regulator of pancreatic β-cell function

Bertolino

Holmberg

Reissmann

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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113

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All major cell types in pancreatic islets express the transforming growth factor (TGF)-␤ superfamily receptor ALK7, but the physiological function of this receptor has been unknown. Mutant mice lacking ALK7 showed normal pancreas organogenesis but developed an age-dependent syndrome involving progressive hyperinsulinemia, reduced insulin sensitivity, liver steatosis, impaired glucose tolerance, and islet enlargement. Hyperinsulinemia preceded the development of any other defect, indicating that this may be one primary consequence of the lack of ALK7. In agreement with this, mutant islets showed enhanced insulin secretion under sustained glucose stimulation, indicating that ALK7 negatively regulates glucose-stimulated insulin release in ␤-cells. Glucose increased expression of ALK7 and its ligand activin B in islets, but decreased that of activin A, which does not signal through ALK7. The two activins had opposite effects on Ca 2؉ signaling in islet cells, with activin A increasing, but activin B decreasing, glucosestimulated Ca 2؉ influx. On its own, activin B had no effect on WT cells, but stimulated Ca 2؉ influx in cells lacking ALK7. In accordance with this, mutant mice lacking activin B showed hyperinsulinemia comparable with that of Alk7 ؊/؊ mice, but double mutants showed no additive effects, suggesting that ALK7 and activin B function in a common pathway to regulate insulin secretion. These findings uncover an unexpected antagonism between activins A and B in the control of Ca 2؉ signaling in ␤-cells. We propose that ALK7 plays an important role in regulating the functional plasticity of pancreatic islets, negatively affecting ␤-cell function by mediating the effects of activin B on Ca 2؉ signaling.T he signaling networks controlling metabolic processes are highly regulated and integrate the actions of both positively and negatively acting components from many different signaling pathways. Members of the transforming growth factor (TGF)-␤ superfamily, including TGF-␤s, growth and differentiation factors (GDFs), bone morphogenetic proteins (BMPs) and activins, have been implicated in the regulation of several metabolic processes. These ligands signal via distinct complexes of type I and type II receptor serine-threonine kinases, each binding to different classes of TGF-␤ ligands (1, 2). The main and most widely studied signaling pathway downstream of these receptors involves activation and nuclear translocation of Smad proteins, which in turn regulate gene transcription through multiple interactions with distinct sets of transcription factors in a cell type-specific manner (1, 2). Although less well understood, Smad-independent pathways have also been described in a variety of cell systems and involve the activation of MAP kinases, small GTPases, and Ca 2ϩ mobilization (3).Identification of cell-intrinsic factors controlling the specification and function of pancreatic endocrine cells is of major importance for understanding the regulation of blood-glucose homeostasis. The characterization of signals regul...

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Section: Discussionmentioning

confidence: 84%

“…The type I receptor ALK7 can mediate signaling by a selected group of ligands in the TGF-␤ superfamily, including Nodal (12), GDF-1 (13), GDF-3 (14) and activin B (15), all of which can also signal through the ubiquitous activin type I receptor ALK4. Unlike ALK4, however, ALK7 does not mediate activin A signaling (15,16).…”

mentioning

confidence: 99%

Activin B receptor ALK7 is a negative regulator of pancreatic β-cell function

Bertolino

Holmberg

Reissmann

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

113

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“…Given that ATMs are maintained by proliferation 20 , reduction in macrophage frequency in aged VAT may reflect an exhausted senescent-like ATM profile driven by sustained NLRP3 inflammasome activation. The most highly upregulated gene with age, growth differentiation factor-3 ( Gdf3 ), that controls adiposity 21,22 was downregulated upon ablation of Nlrp3 to the levels on par in young mice (Fig. 3b).…”

Section: Main Textmentioning

confidence: 99%

“…4a), suggesting that high levels of GDF3 inhibits lipolysis. Interestingly, age-induced increase of Pcsk6 , which cleaves and activates nodal/ALK7 to promote GDF3 signaling 22 , is also regulated by Nlrp3 (Extended Data 8a). Furthermore, ablation of Gdf3 inhibited the NLRP3 inflammasome activation in BMDMs (Fig.…”

Section: Main Textmentioning

confidence: 99%

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

Camell

Sander

Spadaro

et al. 2017

Nature

369

352

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Catecholamine-induced lipolysis, the first step in generation of energy substrates through hydrolysis of triglycerides (TGs) 1, declines with age 2,3. The defect in mobilization of free fatty acids (FFA) in elderly is accompanied with increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. While catecholamine signaling in adipocytes is normal in elderly, how lipolysis is impaired in aging remains unknown 2,4. Here we uncover that the adipose tissue macrophages (ATMs) regulate age-related reduction in adipocyte lipolysis by lowering the bioavailability of norepinephrine (NE). Unexpectedly, unbiased whole transcriptome analyses of adipose macrophages revealed that aging upregulates genes controlling catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in aging restored catecholamine-induced lipolysis through downregulation of growth differentiation factor-3 (GDF3) and monoamine oxidase-a (MAOA) that is known to degrade NE. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing MAOA and caspase-1. Furthermore, inhibition of MAOA reversed age-related reduction in adipose tissue NE concentration and restored lipolysis with increased levels of key lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-innate signaling between sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.

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“…It is therefore likely that Prkab1, Nek8 (Supporting Information Fig. 3), Ptpr6, Ppp3r, Dlgh3, and Sbk2 are novel and specific regulators of crosspresentation, without significantly affecting MHC class II presentation.We focused on one of the hits, Acvr1c, also known as Alk7, a type I receptor for the TGF-β family of signaling molecules, implicated in the regulation of adipose tissue accumulation [10] and pancreatic β-cell function [11], but no reports on a role in immunity.By measuring protein levels in response to knockdown with different shRNAs, we found a good correlation between Acvr1c protein levels and T-cell proliferation resulting from BMDC antigen cross-presentation (Fig. 1C).…”

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confidence: 99%

RNAi screen for kinases and phosphatases that play a role in antigen presentation by dendritic cells

et al. 2012

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Effective CD8 + T-cell responses against tumor or microbial antigens that are not directly expressed in antigen-presenting cells (APCs) depend on the cross-presentation of these antigens on MHC class I in APCs. To identify signaling molecules that regulate crosspresentation, we used lentiviral-based RNA interference to test the roles of hundreds of kinases and phosphatases in this process. Our study uncovered eight previously unknown genes, consisting of one positive and seven negative regulators of antigen cross-presentation. Depletion of Acvr1c, a type I receptor for TGF-β family of signaling molecules, led to an increase in CD80 and CD86 co-stimulator surface expression and secreted IL-12 in mouse bone marrow-derived DCs, as well as antigen-specific T-cell proliferation. Keywords:Antigen cross-presentation r Dendritic cells r Kinases r Phosphatases r RNA interference Supporting Information available online IntroductionThe generation of cytotoxic T lymphocytes (CTLs) against tumor antigens of nonhematopoietic origin or viral agents that do not infect antigen-presenting cells (APCs) can be elicited in a process known as antigen cross-presentation [1]. Furthermore, the importance of this process in vivo during infection and in therapeutically generating antitumor immunity has now been established [2].Antigen cross-presentation remains poorly characterized at the molecular level. In particular, unbiased studies have not been used to dissect the process, with the exception of the work of Zou et al.[3] who used siRNAs to probe the role of 57 Rab GTPases. While Correspondence: Dr. Catarina F. Moita e-mail: lmoita@fm.ul.pt they identified 12 genes that affect cross-presentation, including the GTPase Rab3b/3c, further validation in vivo is still needed to validate these findings.To study this process, we used an arrayed library of shRNAexpressing lentiviruses to silence 691 genes (with ∼5 shRNAs targeting each gene) in DCs and identified eight genes that affect antigen cross-presentation by mouse bone marrow-derived dendritic cells (BMDCs). We also describe the initial characterization of one of the validated hits, Acvr1c, a receptor for the TGF-β family of signaling molecules. Results and discussionTo identify genes involved in cross-presentation, we applied an shRNA-based genetic screening approach [4][5][6] Immunol. 2012Immunol. . 42: 1843Immunol. -1849 signaling components and pathways in DCs that play a role in cross-presentation to primary CD8 + T cells. We mostly targeted kinases and phosphatases because they are part of most regulatory pathways and can often be inhibited with small molecules. In fact, the definition of constriction points within signaling pathways has been a successful approach when analyzing biological complexity and that these constriction points, more often than not, materialize in kinases and phosphatases. We started by developing an in vitro assay to measure antigen cross-presentation by mouse BMDCs after infection with the TRC shRNA-expressing lentivirus. C57BL/6 mice were used as do...

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Growth/differentiation factor 3 signals through ALK7 and regulates accumulation of adipose tissue and diet-induced obesity

Cited by 116 publications

References 28 publications

Activin B receptor ALK7 is a negative regulator of pancreatic β-cell function

Activin B receptor ALK7 is a negative regulator of pancreatic β-cell function

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

RNAi screen for kinases and phosphatases that play a role in antigen presentation by dendritic cells

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