UC Irvine

Abstract: Tributyltin (TBT) is a synthetic chemical widely used in industrial and commercial applications. TBT exposure has been proven to elicit obesogenic effects. Gestational exposure led to increased white adipose tissue depot size in exposed (F1, F2) animals and in unexposed generations (F3, F4), an example of transgenerational inheritance. TBT exerts these effects, in part, by increasing the number and size of white adipocytes, by altering the fate of multipotent mesenchymal stromal stem cells to favor the adipocyte lineage, by altering adipokine secretion and by modulating chromatin structure. Adipose tissue resident macrophages are critical regulators in adipose tissue; however, the effects of TBT on adipose tissue macrophages remained unclear. Here we investigated the effects of TBT on macrophages and consequent impacts on adipocyte function. TBT significantly enhanced palmitate-induced inflammatory gene expression in mouse bone marrow derived macrophages and this effect was attenuated by antagonizing action of the nuclear receptor, PPARγ. TBT-treated macrophages decreased lipid accumulation in white adipocytes differentiated from MSCs accompanied by increased expression of lipolysis genes. Lastly, ancestral TBT exposure increased Tnf expression in adipose tissue resident macrophages in both exposed (F2) and unexposed (F3) generations, suggesting that TBT exposure led to an inherited predisposition toward inflammatory adipose tissue macrophages that can manipulate adipose tissue function. These findings provide new insights into the interplay between adipocytes and adipose tissue macrophages in obesity, further establishing a role for obesogens such as TBT in the development of obesity-related metabolic disorders.