Hedgehog signaling via Gli2 prevents obesity induced by high-fat diet in adult mice

Shi, Yu; Long, Fanxin

doi:10.7554/elife.31649

Cited by 57 publications

(52 citation statements)

References 35 publications

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“…This signalling pathway involves the binding of extracellular Hh protein to a cell surface receptor complex consisting of Patched (Ptch) and Smoothened (Smo). Smo then activates a cascade of intracellular signals resulting in the activation of target genes by Gli family transcription factors (Gli 1, 2, and 3) [75]. Adipocyte differentiation is prevented through the specific inhibition of C/EBPα and PPARγ [35].…”

Section: Hedgehog Signalling Pathwaymentioning

confidence: 99%

Adipogenesis: A Complex Interplay of Multiple Molecular Determinants and Pathways

Ambele

Dhanraj

Giles

2020

IJMS

183

146

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The formation of adipocytes during embryogenesis has been largely understudied. However, preadipocytes appear to originate from multipotent mesenchymal stromal/stem cells which migrate from the mesoderm to their anatomical localization. Most studies on adipocyte formation (adipogenesis) have used preadipocytes derived from adult stem/stromal cells. Adipogenesis consists of two phases, namely commitment and terminal differentiation. This review discusses the role of signalling pathways, epigenetic modifiers, and transcription factors in preadipocyte commitment and differentiation into mature adipocytes, as well as limitations in our understanding of these processes. To date, a limited number of transcription factors, genes and signalling pathways have been described to regulate preadipocyte commitment. One reason could be that most studies on adipogenesis have used preadipocytes already committed to the adipogenic lineage, which are therefore not suitable for studying preadipocyte commitment. Conversely, over a dozen molecular players including transcription factors, genes, signalling pathways, epigenetic regulators, and microRNAs have been described to be involved in the differentiation of preadipocytes to adipocytes; however, only peroxisome proliferator-activated receptor gamma has proven to be clinically relevant. A detailed understanding of how the molecular players underpinning adipogenesis relate to adipose tissue function could provide new therapeutic approaches for addressing obesity without compromising adipose tissue function.

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Section: Hedgehog Signalling Pathwaymentioning

confidence: 99%

Adipogenesis: A Complex Interplay of Multiple Molecular Determinants and Pathways

Ambele

Dhanraj

Giles

2020

IJMS

183

146

View full text Add to dashboard Cite

show abstract

“…Shh inhibits adipocyte differentiation by diverting preadipocytes away from adipogenesis (15), which is implicated in the development of white adipose tissue (16). The Hh-Gli2 axis drives lipogenesis in adipocytes, leading to increased obesity in adult mice (17). Moreover, Shh-related ciliopathy is involved in obesity, cognitive impairment, and limb deformities, which has been defined as Bardet-Biedl syndrome in humans (18).…”

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confidence: 99%

Sonic hedgehog signaling instigates high-fat diet–induced insulin resistance by targeting PPARγ stability

Yao

Liu

Xiao

et al. 2019

Journal of Biological Chemistry

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Obesity is a major risk for patients with chronic metabolic disorders including type 2 diabetes. Sonic hedgehog (Shh) is a morphogen that regulates the pancreas and adipose tissue formation during embryonic development. Peroxisome proliferator-activated receptor ␥ (PPAR␥) is a member of the nuclear receptor superfamily and one of the most important regulators of insulin action. Here, we evaluated the role and mechanism of Shh signaling in obesity-associated insulin resistance and characterized its effect on PPAR␥. We showed that Shh expression was up-regulated in subcutaneous fat from obese mice. In differentiated 3T3-L1 and primary cultured adipocytes from rats, recombinant Shh protein and SAG (an agonist of Shh signaling) activated an extracellular signal-regulated kinase (ERK)-dependent noncanonical pathway and induced PPAR␥ phosphorylation at serine 112, which decreased PPAR␥ activity. Meanwhile, Shh signaling degraded PPAR␥ protein via binding of PPAR␥ to neural precursor cell-expressed developmentally down-regulated protein 4-1 (NEDD4-1). Furthermore, vismodegib, an inhibitor of Shh signaling, attenuated ERK phosphorylation induced by a high fat diet (HFD) and restored PPAR␥ protein level, thus ameliorating glucose intolerance and insulin resistance in obese mice. Our finding suggests that Shh in subcutaneous fat decreases PPAR␥ activity and stability via activation of an ERK-dependent noncanonical pathway, resulting in impaired insulin action. Inhibition of Shh may serve as a potential therapeutic approach to treat obesity-related diabetes.

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“…In this study, we found that LAMA2 regulates osteogenesis and adipogenesis of MSCs via modulating the hedgehog signaling pathway. The hedgehog signaling pathway is involved in bone formation and in osteogenic and adipogenic differentiation of MSCs which indicates that targeted regulation of hedgehog signaling is a potential target for the treatment of bonerelated diseases such as osteoporosis and fracture healing [19,20,[43][44][45][46][47].…”

Section: Discussionmentioning

confidence: 99%

LAMA2 regulates the fate commitment of mesenchymal stem cells via hedgehog signaling

Zhu¹,

Zhang²,

Gu³

et al. 2020

Stem Cell Res Ther

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Background: Bone defects are a common clinical condition that has gained an increasing amount of attention in recent years. Causes of bone defect include tumors, inflammation, and fractures. Bone tissue engineering is a novel treatment of bone defect, and human mesenchymal stem cells (hMSCs) are the ideal seed cells for bone tissue engineering due to their multi-lineage differentiation potential and immunogenicity. The laminin α2 (LAMA2) gene encodes the α2 subunit of laminins. Mutations in this gene have been reported to cause muscular dystrophy, but thus far no studies have elucidated the role of LAMA2 in the fate choices of MSCs. Here, we aimed to investigate the critical role of LAMA2 in the osteogenesis and adipogenesis of mesenchymal stem cells (MSCs). Methods: We investigated LAMA2 function in osteogenic and adipogenic differentiation of MSCs in vitro and in vivo through loss-and gain-of-function experiments. In addition, molecular mechanism was clarified by Western blot and siRNA. Results: Our results demonstrated that LAMA2 was a critical regulator for fate commitment of MSCs. Both in vitro and in vivo studies indicate that LAMA2 inhibits osteogenesis and promotes adipogenesis. Mechanistically, we found that LAMA2 regulated osteogenesis and adipogenesis of MSCs by modulating the hedgehog signaling pathway. Conclusions: The present work confirms that LAMA2 is a new molecular target for MSC-based bone regeneration.

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Hedgehog signaling via Gli2 prevents obesity induced by high-fat diet in adult mice

Cited by 57 publications

References 35 publications

Adipogenesis: A Complex Interplay of Multiple Molecular Determinants and Pathways

Adipogenesis: A Complex Interplay of Multiple Molecular Determinants and Pathways

Sonic hedgehog signaling instigates high-fat diet–induced insulin resistance by targeting PPARγ stability

LAMA2 regulates the fate commitment of mesenchymal stem cells via hedgehog signaling

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