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TGF-? receptor 1 regulates progenitors that promote browning of white fat.

ABSTRACT: OBJECTIVE:Beige/brite adipose tissue displays morphological characteristics and beneficial metabolic traits of brown adipose tissue. Previously, we showed that TGF-? signaling regulates the browning of white adipose tissue. Here, we inquired whether TGF-? signals regulated presumptive beige progenitors in white fat and investigated the TGF-? regulated mechanisms involved in beige adipogenesis. METHODS:We deleted TGF-? receptor 1 (T?RI) in adipose tissue (T?RIAdKO mice) and, using flow-cytometry based assays, identified and isolated presumptive beige progenitors located in the stromal vascular cells of white fat. These cells were molecularly characterized to examine beige/brown marker expression and to investigate TGF-? dependent mechanisms. Further, the cells were transplanted into athymic nude mice to examine their adipogenesis potential. RESULTS:Deletion of T?RI promotes beige adipogenesis while reducing the detrimental effects of high fat diet feeding. Interaction of TGF-? signaling with the prostaglandin pathway regulated the appearance of beige adipocytes in white fat. Using flow cytometry techniques and stromal vascular fraction from white fat, we isolated presumptive beige stem/progenitor cells (iBSCs). Upon genetic or pharmacologic inhibition of TGF-? signaling, these cells express high levels of predominantly beige markers. Transplantation of T?RI-deficient stromal vascular cells or iBSCs into athymic nude mice followed by high fat diet feeding and stimulation of ?-adrenergic signaling via CL316,243 injection or cold exposure promoted robust beige adipogenesis in vivo. CONCLUSIONS:T?RI signals target the prostaglandin network to regulate presumptive beige progenitors in white fat capable of developing into beige adipocytes with functional attributes. Controlled inhibition of T?RI signaling and concomitant PGE2 stimulation has the potential to promote beige adipogenesis and improve metabolism.

SUBMITTER: Wankhade UD

PROVIDER: S-EPMC6158128 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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TGF-β receptor 1 regulates progenitors that promote browning of white fat.

Wankhade Umesh D UD Lee Ji-Hyeon JH Dagur Pradeep K PK Yadav Hariom H Shen Michael M Chen Weiping W Kulkarni Ashok B AB McCoy J Philip JP Finkel Toren T Cypess Aaron M AM Rane Sushil G SG

Molecular metabolism 20180727

<h4>Objective</h4>Beige/brite adipose tissue displays morphological characteristics and beneficial metabolic traits of brown adipose tissue. Previously, we showed that TGF-β signaling regulates the browning of white adipose tissue. Here, we inquired whether TGF-β signals regulated presumptive beige progenitors in white fat and investigated the TGF-β regulated mechanisms involved in beige adipogenesis.<h4>Methods</h4>We deleted TGF-β receptor 1 (TβRI) in adipose tissue (TβRI<sup>AdKO</sup> mice) ...[more]

PMID: 30100246

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Project description:ObjectiveBrown and beige adipocytes in humans and rodents are specialized to burn lipids for heat generation as a natural defense against cold and obesity, which is advantageous to metabolic homeostasis. MicroRNAs as another regulatory layer to regulate metabolic homeostasis attracted a lot of attentions. Our previous work revealed microRNA (miR)-203 as a brown adipocyte-enriched microRNA involved in brown adipocytes development. However, the potential role of miR-203 in adipose tissue metabolic homeostasis has not been determined in vivo. In this study, we investigate the potential role of miR-203 in subcutaneous white adipose tissue (sub-WAT) browning and metabolic homeostasis.MethodsWe investigated the relationship between miR-203 and energy homeostasis in adipose tissue from cold exposed, high fat diet (HFD) fed, ob/ob and db/db mice. The functions of miR-203 on sub-WAT browning were validated through miR-203 knockdown or overexpression. The miR-203 targeted signal pathway was screened by RNAseq analysis. Luciferase report assay, western blot, and qPCR were performed to establish the miR-203 related upstream and downstream signal pathway in vivo and in vitro. The functions of miR-203 on obesity and metabolic homeostasis were validated through GTT/ITT and western blot on high fat diet-induced obesity in C57 mice. ELISA was used to determine the concentration of IFN-γ. Flow cytometry analysis was performed to determine the infiltration of macrophages in adipose tissue.ResultsMiR-203 expression positively correlates with energy expenditure, and overexpression of miR-203 could enhance sub-WAT browning in normal diet (ND) condition. Mechanistically, the expression of miR-203 is activated by cAMP-dependent C/EBPβ up-regulation. Subsequently, miR-203 inhibits IFN-γ signal pathway activation by directly targeting Lyn, which is an activator of Jak1-Stat1. Moreover, the forced expression of miR-203 could improve insulin sensitivity and resist high fat diet-induced obesity by inhibiting IFN-γ.ConclusionsMicroRNA-203 (miR-203) promotes white adipose tissue browning in cold exposed mice and improves glucose tolerance in HFD fed mice by repressing IFN-γ. Since miR-203 is activated by cAMP-dependent C/EBPβ up-regulation and directly represses IFN-γ signal pathway, we declare that miR-203 acts as a messenger between cAMP signal pathway and IFN-γ signal pathway.

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TGF-? receptor 1 regulates progenitors that promote browning of white fat.

Publications

TGF-β receptor 1 regulates progenitors that promote browning of white fat.

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