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Cytoskeletal TAGLN2 is involved in gender-dependent adipose tissue expandability

ABSTRACT: The preadipocytes’ shape changes dramatically during differentiation, in parallel with lipid accumulation and cytoskeletal reorganization. Failure to do so may impact the flexibility of adipose tissue (AT) to shift between lipid storage and mobilization, leading to impaired metabolism and insulin resistance. Transgelin 2 (TAGLN2) was identified as a cytoskeletal protein expressed in AT and associated with obesity and inflammation both in mice and humans, being normalized upon weight loss. Tagln2 knockdown in preadipocytes revealed a key functional role, being required for proliferation and biosynthetic and oxidation pathways. The phenotype of gain of function in vivo (aP2-Tagln2 mice) disclosed important gender-related differences, in whom transgenic female mice over-expressing Tagln2 in AT exhibited “healthy” obesity, characterized by increased fat mass, hypertrophic adipocytes, and preserved insulin sensitivity. Conversely, transgenic males exhibited enhanced activation of T helper cells, mitochondrial dysfunction, and impaired fatty acid metabolism in AT, together with decreased insulin sensitivity and the prevalence of small adipocytes, suggestive of defective AT expandability. The metabolic relevance of TAGLN2 in humans was supported by the existence of single nucleotide polymorphisms that can modulate TAGLN2 gene expression in AT and are associated with obesity and protection from ischemic heart disease in GWAS public databases. Collectively, current findings highlight the contribution of cytoskeletal TAGLN2 to AT expansion and protection from cardiometabolic disease in a gender-dependent manner.

ORGANISM(S): Mus musculus

PROVIDER: GSE121015 | GEO | 2019/10/09

REPOSITORIES: GEO

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Project description:Background: Exposure to the endocrine-disrupting chemical bisphenol A (BPA) is correlated with obesity and promotes adipogenesis of human preadipocytes into mature adipocytes. However, the mechanism of action of BPA-induced human adipogenesis in vitro remains to be fully characterized. Methods: In this study, potential mechanisms of BPA-induced adipogenesis in primary human preadipocytes were evaluated using gene expression microarray analysis. Preadipocytes from donors with normal body mass indexes were differentiated in the presence of 50 M-BM-5M BPA or 1 M-BM-5M dexamethasone (DEX) for 48 hours. Results: Microarray analysis revealed 235 up-regulated and 138 down-regulated genes following BPA treatment, including sterol regulatory element binding factor 1 (SREBF1), a key transcription factor known to regulate many components of lipid metabolism and adipogenesis. For DEX treated preadipocytes, 1136 genes were up-regulated, including the adipogenic marker lipoprotein lipase, while 1031 genes were down-regulated. Ingenuity Pathway Analysis was used to identify functional annotations of the gene expression changes associated with response to BPA and DEX treatments. BPA exposure was associated with expression changes in the genes involved in the accumulation of triacylglycerol while DEX was linked to metabolism of triacylglycerol and cleavage of fatty acids. The analysis also revealed enrichment of genes in pathways known to be associated with BPA exposure including thyroid-receptor/retinoic X receptor (TR/RXR) activation, mammalian target of rapamycin (mTOR) signaling and cholesterol biosynthesis, whereas DEX treatment was linked to cholesterol biosynthesis and ethanol degradation. Interestingly, alterations in the mTOR pathway in response to BPA did not occur in DEX-treated preadipocytes. Conclusions: Our data suggest that potential mechanisms of action of BPA-induced adipogenesis involve SREBF1, the TR/RXR and the mTOR pathways. The study used 40 samples in total which included 5 replicates (cells from 5 unique donors) of 8 different treatments. The 8 treatments were as follows: 1) untreated (negative) control for 48 hours, 2) 25 uM BPA treated for 48 hours, 3) 50 uM BPA treated for 48 hours, 4) untreated (negative) control + insulin for 48 hours, 5) 25 uM BPA + insulin treated for 48 hours, 6) 50 uM BPA + insulin treated for 48 hours, 7) 1uM Dexamethasone + insulin treated for 48 hours, 8) 1uM Dexamethasone + insulin treated for 96 hours.

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Cytoskeletal TAGLN2 is involved in gender-dependent adipose tissue expandability

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