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Transglutaminases TG2 and FXIII-A have recently been linked to adipose tissue biology and obesity, however, human studies for TG family members in adipocytes have not been conducted. In this study, we investigated the association of <i>TGM</i> family members to acquired weight gain in a rare set of monozygotic (MZ) twins discordant for body weight, i.e., heavy–lean twin pairs. We report that <i>F13A1</i> is the only <i>TGM</i> family member showing significantly altered, higher expression in adipose tissue of the heavier twin. Our previous work linked adipocyte <i>F13A1</i> to increased weight, body fat mass, adipocyte size, and pro-inflammatory pathways. Here, we explored further the link of <i>F13A1</i> to adipocyte size in the MZ twins via a previously conducted TWA study that was further mined for genes that specifically associate to hypertrophic adipocytes. We report that differential expression of <i>F13A1</i> (ΔHeavy–Lean) associated with 47 genes which were linked via gene enrichment analysis to immune response, leucocyte and neutrophil activation, as well as cytokine response and signaling. Our work brings further support to the role of <i>F13A1</i> in the human adipose tissue pathology, suggesting a role in the cascade that links hypertrophic adipocytes with inflammation.