Cytoskeletal TAGLN2 is involved in gender-dependent adipose tissue expandability

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. 24 samples were analyzed: aP2_TAS (n=6); aP2_TAV (n=6); WT_TAS (n=6); WT_TAV (n=6);