three-dimensional-adipocyte-culture-as-model-to-study-cachexia

Three-Dimensional Adipocyte Culture as a Model to Study Cachexia-Induced White Adipose Tissue Remodeling

Cancer cachexia (CC) presents itself as a syndrome with multiple manifestations, causing a marked multi-organ metabolic imbalance. Recently, cachectic ...

Boston University School of Medicine

Adipose tissue fibrosis is associated with inflammation and insulin resistance in human obesity. In particular, visceral fat fibrosis is correlated with hyperlipidemia and ectopic fat accumulation. Myocardin-related transcription factor A (MRTFA) is an important coactivator that mediates the transcription of extracellular matrix and other fibrogenic genes. Here, we examine the role of MRTFA in the development of adipose tissue fibrosis and identify a signaling pathway that regulates the fate of vascular progenitors. We demonstrate that obesity induces the formation of Sca1, Sma, ITGA5 fibrogenic progenitor cells (FPCs) in adipose tissue. MRTFA deficiency in mice shifts the fate of perivascular progenitors from FPCs to adipocyte precursor cells and protects against chronic obesity-induced fibrosis and accompanying metabolic dysfunction, without a shift in energy expenditure. Our findings highlight the ITGA5-MRTFA pathway as a potential target to ameliorate obesity-associated metabolic disease.

Myocardin-Related Transcription Factor A Promotes Recruitment of ITGA5+ Profibrotic Progenitors during Obesity-Induced Adipose Tissue Fibrosis.

A recent study (Girousse et al. Cell Rep. 2019;27:323-333) shows that CXCR4 adipose progenitors (APCs) contribute to lipid spillover during high-fat feeding through their release from subcutaneous fat depots (ScATs) and migration to skeletal muscle where they differentiate into adipocytes. Pharmacological antagonism of CXCR4, which prevents the CXCL12-dependent retention of APCs in ScAT, mimics the effects of overfeeding.

Adipose Progenitor Cells Contribute to Lipid Spillover during Obesity.

Visceral white adipose tissue (vWAT) expands and undergoes extensive remodeling during diet-induced obesity. Much is known about the contribution of various stromal vascular cells to the remodeling process, but less is known of the changes that occur within the adipocyte as it becomes progressively dysfunctional. Here, we performed a transcriptome analysis of isolated vWAT adipocytes to assess global pathway changes occurring in response to a chronic high fat diet (HFD). The data demonstrate that the adipocyte responds to the HFD by adopting a fibroblast-like phenotype, characterized by enhanced expression of ECM, focal adhesion and cytoskeletal genes and suppression of many adipocyte programs most notably those associated with mitochondria. This study reveals that during obesity the adipocyte progressively becomes metabolically dysfunctional due to its acquisition of fibrogenic functions. We propose that mechano-responsive transcription factors such as MRTFA and SRF contribute to both upregulation of morphological genes as well as suppression of mitochondrial programs.

The Adipocyte Acquires a Fibroblast-Like Transcriptional Signature in Response to a High Fat Diet.

Triphenyl phosphate (TPhP) is an environmental PPARγ ligand, and growing evidence suggests that it is a metabolic disruptor. We have shown previously that the structurally similar ligand, tributyltin, does not induce brite adipocyte gene expression. Here, using in vivo and in vitro models, we tested the hypothesis that TPhP is a selective PPARγ ligand, which fails to induce brite adipogenesis. C57BL/6 J male mice were fed either a low or very high-fat diet for 13 weeks. From weeks 7-13, mice were injected intraperitoneally, daily, with vehicle, rosiglitazone (Rosi), or TPhP (10 mg/kg). Compared to Rosi, TPhP did not induce expression of browning-related genes (e.g. Elovl3, Cidea, Acaa2, CoxIV) in mature adipocytes isolated from inguinal adipose. To determine if this resulted from an effect directly on the adipocytes, 3T3-L1 cells and primary human preadipocytes were differentiated into adipocytes in the presence of Rosi or TPhP. Rosi, but not TPhP, induced expression of brite adipocyte genes, mitochondrial biogenesis and cellular respiration. Further, Rosi and TPhP-induced distinct proteomes and phosphoproteomes; Rosi enriched more regulatory pathways related to fatty acid oxidation and mitochondrial proteins. We assessed the role of phosphorylation of PPARγ in these differences in 3T3-L1 cells. Only Rosi protected PPARγ from phosphorylation at Ser273. TPhP gained the ability to stimulate brite adipocyte gene expression in the presence of the CDK5 inhibitor and in 3T3-L1 cells expressing alanine at position 273. We conclude that TPhP is a selective PPARγ modulator that fails to protect PPARγ from phosphorylation at ser273.

Triphenyl phosphate is a selective PPARγ modulator that does not induce brite adipogenesis in vitro and in vivo.

White adipose tissue (WAT) is a dynamic tissue, which responds to environmental stimuli and dietary cues by changing its morphology and metabolic capacity. The ability of WAT to undergo a beige remodeling has become an appealing strategy to combat obesity and its comorbidities. Here, by using single-cell RNA sequencing, we provide a comprehensive atlas of the cellular dynamics during beige remodeling. We reveal drastic changes both in the overall cellular composition and transcriptional states of individual cell subtypes between Adrb3- and cold-induced beiging. Moreover, we demonstrate that cold induces a myeloid to lymphoid shift of the immune compartment compared to Adrb3 activation. Further analysis showed that, Adrb3 stimulation leads to activation of the interferon/Stat1 pathways favoring infiltration of myeloid immune cells, while repression of this pathway by cold promotes lymphoid immune cell recruitment. These findings highlight that pharmacological mimetics may not provide the same beneficial effects as physiological stimuli.

Article	Year
Myocardin-Related Transcription Factor A Promotes Recruitment of ITGA5+ Profibrotic Progenitors during Obesity-Induced Adipose Tissue Fibrosis. Cell reports\| PubMed ID: 29768198	2018
Adipose Progenitor Cells Contribute to Lipid Spillover during Obesity. Trends in endocrinology and metabolism: TEM\| PubMed ID: 31153731	2019
The Adipocyte Acquires a Fibroblast-Like Transcriptional Signature in Response to a High Fat Diet. Scientific reports\| PubMed ID: 32047213	2020
Triphenyl phosphate is a selective PPARγ modulator that does not induce brite adipogenesis in vitro and in vivo. Archives of toxicology\| PubMed ID: 32683515	2020
Shifts of Immune Cell Populations Differ in Response to Different Effectors of Beige Remodeling of Adipose Tissue. iScience\| PubMed ID: 33294778	2020

Nabil Rabhi

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