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

Wankhade, Umesh D.; Lee, Ji-Hyeon; Dagur, Pradeep K.; Yadav, Hariom; Shen, Michael; Chen, Weiping; Kulkarni, Ashok B.; McCoy, J. Philip; Finkel, Toren; Cypess, Aaron M.; Rane, Sushil G.

doi:10.1016/j.molmet.2018.07.008

Cited by 39 publications

(28 citation statements)

References 64 publications

(100 reference statements)

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“…TGF-β's role in regulating apoptosis in normal and diseased cells is well known 63 . We have previously shown that TGF-β antagonism can protect mice from obesity and diabetes 60,64 . The findings here support a role for controlled TGF-β inhibition in combating β-cell apoptosis and restoring the β-cell mass in diabetes.…”

Section: Discussionmentioning

confidence: 99%

Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling

et al. 2020

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Prevailing insulin resistance and the resultant hyperglycemia elicits a compensatory response from pancreatic islet beta cells (β-cells) that involves increases in β-cell function and β-cell mass. However, the sustained metabolic stress eventually leads to β-cell failure characterized by severe β-cell dysfunction and progressive loss of β-cell mass. Whereas, β-cell dysfunction is relatively well understood at the mechanistic level, the avenues leading to loss of β-cell mass are less clear with reduced proliferation, dedifferentiation, and apoptosis all potential mechanisms. Butler and colleagues documented increased β-cell apoptosis in pancreas from lean and obese human Type 2 diabetes (T2D) subjects, with no changes in rates of β-cell replication or neogenesis, strongly suggesting a role for apoptosis in β-cell failure. Here, we describe a permissive role for TGF-β/Smad3 in β-cell apoptosis. Human islets undergoing β-cell apoptosis release increased levels of TGF-β1 ligand and phosphorylation levels of TGF-β's chief transcription factor, Smad3, are increased in human T2D islets suggestive of an autocrine role for TGF-β/Smad3 signaling in β-cell apoptosis. Smad3 phosphorylation is similarly increased in diabetic mouse islets undergoing β-cell apoptosis. In mice, β-cell-specific activation of Smad3 promotes apoptosis and loss of β-cell mass in association with β-cell dysfunction, glucose intolerance, and diabetes. In contrast, inactive Smad3 protects from apoptosis and preserves β-cell mass while improving β-cell function and glucose tolerance. At the molecular level, Smad3 associates with Foxo1 to propagate TGF-β-dependent β-cell apoptosis. Indeed, genetic or pharmacologic inhibition of TGF-β/Smad3 signals or knocking down Foxo1 protects from β-cell apoptosis. These findings reveal the importance of TGF-β/Smad3 in promoting β-cell apoptosis and demonstrate the therapeutic potential of TGF-β/Smad3 antagonism to restore β-cell mass lost in diabetes.

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Section: Discussionmentioning

confidence: 99%

Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling

et al. 2020

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“…Our data indicate that progenitor autophagy inhibition similarly favors beigeing and also minimizes adipose tissue fibrogenic potential, even in mice fed an obesogenic diet. The TGF pathway is a key actor in fibrogenesis, and some TGFb family members have been reported to modulate the development of beige adipocytes [40,41], but it is still unclear how TGFb family members/receptor pathways govern this inverse relationship. There is clinical relevance in this question because acting on both AT fibrosis (an ultimate sign of dysfunction linked to insulin resistance) and AT browning (a favorable metabolic phenotype with positive effects on glucose utilization) would be expected to positively influence metabolic health when combined.…”

Section: Beyond a Primary Role Of Progenitor Autophagy Status In Fibrmentioning

confidence: 99%

Autophagy inhibition blunts PDGFRA adipose progenitors’ cell-autonomous fibrogenic response to high-fat diet

et al. 2020

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Adipose tissue (AT) fibrosis in obesity compromises adipocyte functions and responses to intervention induced-weight loss. It is driven by AT progenitors with dual fibro/adipogenic potential, but pro-fibrogenic pathways activated in obesity remain to be deciphered. To investigate the role of macroautophagy/autophagy in AT fibrogenesis, we used Pdgfra-Cre Ert2 transgenic mice to create conditional deletion of Atg7 alleles in AT progenitor cells (Atg7 cKO) and examined sex-dependent, depotspecific AT remodeling in high-fat diet (HFD)-fed mice. Atg7 cKO mice had markedly decreased extracellular matrix (ECM) gene expression in visceral, subcutaneous and epicardial adipose depots compared to Atg7 lox/lox littermates. ECM gene program regulation by autophagy inhibition occurred independently of changes in the mass of fat tissues or adipocyte numbers of specific depots, and could be mimicked in cultured preadipocytes treated with pharmacological or siRNA-mediated autophagy disruptors. We found that autophagy inhibition promotes global cell-autonomous remodeling of the paracrine TGF-BMP family landscape, whereas ECM gene modulation was independent of the autophagic regulation of GTF2IRD1. The progenitor-specific mouse model of Atg7 inhibition confirms requirement of autophagy for white/beige adipocyte turnover, and combined to in vitro experiments, reveal progenitor autophagy dependence for AT fibrogenic response to HFD, through paracrine remodeling of TGF-BMP factors balance.

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“…The TGFβ pathway has emerged as a critical anti-adipogenic player through the Smad 2/3 activation (33)(34)(35). Deletion of TGFβ receptor 1 in mice has been shown to promote brown-like adipogenesis within white adipose tissue, thus supporting a model where TGFβ receptor signaling plays a role in regulating the pool of BAPs (36). The Smad2/3 pathway was found to be active during hiPSC-BAP differentiation, suggesting that bioactive TGFβ family members were secreted, which might lock differentiation (24).…”

Section: Critical Role Of the Tgfβ Pathway In Hipsc-ba Progenitor Difmentioning

confidence: 96%

“…Figure 1 illustrates the regulation of brown-like adipocyte generation from hPSCs by the retinoic acid and TGFβ pathways. Wankhade and colleagues proposed that negative regulation of PGE2/Cox-2 by TGFβ is involved in the recruitment of brown-like adipose progenitors (36). Interestingly, inhibition of the TGFβ pathway is not a prerequisite for adult adipose tissue-derived adipose progenitor differentiation.…”

Section: Critical Role Of the Tgfβ Pathway In Hipsc-ba Progenitor Difmentioning

confidence: 99%

Human Pluripotent Stem Cells: A Relevant Model to Identify Pathways Governing Thermogenic Adipocyte Generation

Yao¹,

Dani²,

Dani³

2020

Front. Endocrinol.

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Brown and brown-like adipocytes (BAs) are promising cell targets to counteract obesity thanks to their potential to drain and oxidize circulating glucose and triglycerides. However, the scarcity of BAs in human adults is a major limitation for energy expenditure based therapies. Enhanced characterization of BA progenitor cells (BAPs) and identification of critical pathways regulating their generation and differentiation into mature BAs would be an effective way to increase the BA mass. The identification of molecular mechanisms involved in the generation of thermogenic adipocytes is progressing substantially in mice. Much less is known in humans, thus highlighting the need for an in vitro model of human adipocyte development. Pluripotent stem cells (PSCs), i.e., embryonic stem cells and induced pluripotent stem cells, help gain insight into the different phases in the development of multiple cell types. We will discuss the capacity of human PSCs to differentiate into BAs in this review. Several groups, including ours, have reported low spontaneous adipocyte generation from PSCs. However, factors governing the differentiation of induced pluripotent stem cell-derived BA progenitors cells were recently identified, and the TGFβ signaling pathway has a pivotal role. The development of new relevant methods, such as the differentiation of hPSC-BAPs into 3D adipospheres to better mimick the lobular structure of human adipose tissue, will also be discussed. Differentiation of human PSCs into thermogenic adipocytes at high frequency provides an opportunity to characterize new targets for anti-obesity therapy.

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

Cited by 39 publications

References 64 publications

Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling

Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling

Autophagy inhibition blunts PDGFRA adipose progenitors’ cell-autonomous fibrogenic response to high-fat diet

Human Pluripotent Stem Cells: A Relevant Model to Identify Pathways Governing Thermogenic Adipocyte Generation

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