Thromboxane synthase deficiency improves insulin action and attenuates adipose tissue fibrosis.
Thromboxane A2, an arachidonic acid-derived eicosanoid generated by thromboxane synthase (TBXAS), plays critical roles in hemostasis and inflammation. However, the contribution of thromboxane A2 to obesity-linked metabolic dysfunction remains incompletely understood. Here, we used in vitro and mouse models to better define the role of TBXAS in metabolic homeostasis. We found that adipose expression of Tbxas and thromboxane A2 receptor (Tbxa2r) was significantly upregulated in genetic and dietary mouse models of obesity and diabetes. Expression of Tbxas and Tbxa2r was detected in adipose stromal cells, including macrophages. Furthermore, stimulation of macrophages with interferon-γ or resistin factors known to be upregulated in obesity induced Tbxas and Tbxa2r expression. Mice lacking Tbxas had similar weight gain, food intake, and energy expenditure. However, loss of Tbxas markedly enhanced insulin sensitivity in mice fed a low-fat diet. Improvement in glucose homeostasis was correlated with the upregulated expression of multiple secreted metabolic regulators (Ctrp3, Ctrp9, and Ctrp12) in the visceral fat depot. Following a challenge with a high-fat diet, Tbxas deficiency led to attenuated adipose tissue fibrosis and reduced circulating IL-6 levels without adipose tissue macrophages being affected; however, these changes were not sufficient to improve whole body insulin action. Together, our results highlight a novel, diet-dependent role for thromboxane A2 in modulating peripheral tissue insulin sensitivity and adipose tissue fibrosis.
Department of Physiology and Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland;
Xia
X
Lei
Department of Physiology and Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Diabetes Institute, Shanghai Clinical Center of Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China; and.
Qing
Q
Li
Department of Physiology and Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland;
Susana
S
Rodriguez
Department of Physiology and Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland;
Stefanie Y
SY
Tan
Department of Physiology and Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland;
Marcus M
MM
Seldin
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
John C
JC
McLenithan
Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Diabetes Institute, Shanghai Clinical Center of Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China; and.
Weiping
W
Jia
Department of Physiology and Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland; gwwong@jhmi.edu.
G William
GW
Wong
D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D005260:Female; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018836:Inflammation Mediators / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000235:genetics / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000172:deficiency / Q000235:genetics*
D016207:Cytokines; D018836:Inflammation Mediators; D007328:Insulin; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013930:Thromboxane-A Synthase
C1q/tumor necrosis factor-related protein; adipose tissue; diabetes; eicosanoid; fibrosis; obesity; thromboxane