Transglutaminases and Obesity in Humans: Association of F13A1 to Adipocyte Hypertrophy and Adipose Tissue Immune Response

Abstract

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 TGM 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 F13A1 is the only TGM family member showing significantly altered, higher expression in adipose tissue of the heavier twin. Our previous work linked adipocyte F13A1 to increased weight, body fat mass, adipocyte size, and pro-inflammatory pathways. Here, we explored further the link of F13A1 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 F13A1 (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 F13A1 in the human adipose tissue pathology, suggesting a role in the cascade that links hypertrophic adipocytes with inflammation.

Identification of differentially expressed genes and signaling pathways in gestational diabetes mellitus by integrated bioinformatics analysis

“…Previously reported studies have shown that the expression of LBP (lipopolysaccharide binding protein) [273], MC1R [274], CXCL14 [275], RGN (regucalcin) [276], NPY2R [277], MFAP5 [278], WNT5A [279], EDA (ectodysplasin A) [280], THSD7A [281], NEUROD1 [282], SLIT2 [283], PPARGC1A [219], IGF1 [144], OSR1 [284], TLR3 [285], BMP7 [286], POSTN (periostin) [287], LRP1B [288], THBS1 [289], NOTCH2 [290]. LRP1 [291], CLU (clusterin) [292], SMAD3 [91], TGFB1 [293], APP (amyloid beta precursor protein) [294], ITGB2 [295], IL6R [296], TIMP1 [297], CD47 [298], CD74 [299], RARA (retinoic acid receptor alpha) [300], DOCK2 [301], F13A1 [302], IRF7 [303], STIM1 [304], CXCR4 [305], MGLL (monoglyceride lipase) [306], M6PR [307], USP22 [308] and CASP2 [309] were mainly involved in progression of obesity, but these genes might be novel targets for GDM. Recent studies have shown that GLP1R [310], NEUROD1 [311], PPARGC1A [312], IGF1 [313], LRP1B [314], NOTCH2 [315], BAK1 [316], TLR2 [317], IL6R [318], TIMP1 [319], PIK3CD [320], PRKCA (protein kinase C alpha) [321], CXCR4 [322], RAB8A [323] and M6PR [324] are associated with GDM.…”

Factor XIII-A in Diseases: Role Beyond Blood Coagulation

“…Abdalla et al showed that angiotensin II-induced cFXIII-A activation facilitates the covalent cross-links between type 1 angiotensin receptor monomers, resulting in enhanced signaling and desensitization. This finding was associated with increased adhesion of monocytes to the endothelium in ApoE-deficient mice [ 33 ], which is one of the earliest detectable changes in atherosclerotic lesions (reviewed in [ 66 ]).…”

“…Interestingly, they have also found a positive correlation between the expression of FXIII-A and phospholipase 2A (PLA2G16) and mitogen-activated protein kinase 1 (MAPK1) genes; both genes are shown to be involved in lipolysis. Based on these findings, Kaartinen et al suggested that FXIII-A could be an important therapeutic target to control adipose tissue inflammation linked to human obesity [ 33 , 101 ].…”

“…Implicating state-of-the art, unbiased research strategies and molecular methods into FXIII-A research brought another breakthrough and opened new vistas to define its relationship to diseases, many of which were not raised previously even at the level of speculation. Whole gene expression profiling has revealed that in alternatively activated macrophages, cFXIII-A may alter the expression of genes related to immune functions and to wound response [ 32 ]; it has also shown that FXIII-A shows abundant expression levels in adipose tissue, with a suggested role in adipose tissue development [ 33 ]. Protein detection confirmed its possible intracellular substrate in the pathogenesis of atherosclerosis [ 34 ].…”

Transglutaminases Are Active in Perivascular Adipose Tissue

“…Other studies demonstrated that TG2 mediates ventricular [ 23 ] and aortic [ 24 ] contractility, stiffness, and function. Further, Kaartinen et al found that human FXIIIA1 expression is increased in adipose tissue of the heavier twin in a monozygotic pair [ 25 ]. These studies highlight the importance of understanding how TGs function in adipose tissue, and more specifically in a fat intimately associated with the vasculature, PVAT.…”