Retinoid X Receptor Activation by the Endocrine Disruptor Tributyltin Promotes Adipose Lineage Commitment and Perturbs Adipocyte Function
The obesity epidemic has reached unsustainable proportions and threatens to bankrupt the American healthcare system. While physicians continue to prescribe diet and exercise as a panacea for obesity, mounting evidence shows that the majority of diet interventions fail. Longitudinal data suggest that Americans gain more weight in the 21st century than they did three decades ago for a given level of caloric intake and exercise, implicating an environmental insult independent of energy balance that is programming obesity risk into the population.
Mounting evidence implicates early-life exposure to industrial chemicals—of which there are tens of thousands—as an overlooked contributor to the obesity epidemic. Of particular concern are a subset of at least 1,000 chemicals, termed endocrine disrupting chemicals, that have the ability to interfere with the action of endogenous hormones in the body. Our laboratory proposed the ‘obesogen hypothesis’, which asserts that there are chemicals in the environment that can program our obesity risk, particularly when we are exposed during critical windows of development.
Our lab identified and characterized the archetypal obesogen, tributyltin (TBT), which acts through two nuclear receptors, peroxisome proliferator-activated receptor γ and retinoid X receptor (RXR), to promote the development of fat tissue. Mice exposed to TBT in utero are born with excess fat tissue and have mesenchymal stem cells (MSCs) that favor the fat lineage over bone. In vitro exposure to TBT promotes the differentiation of MSCs or 3T3-L1 cells (a preadipocyte cell line) into adipocytes in a PPARγ-dependent fashion. Incredibly, the obesogenic effects of TBT can be propagated through several generations to the F3 and F4 descendants of exposed F0 mothers.
The work described in this dissertation employs the in vitro MSC adipogenesis model to further explore the molecular mechanisms through which TBT alters the fate and function of developing stem cells. In Chapter 1, we investigate how TBT influences the earliest cell-fate decisions MSCs make during the process of lineage commitment. In Chapter 2, we examine the functionality of adipocytes differentiated in the presence TBT. In both studies, we found RXR to be indispensable in programming the obesogenic effects of TBT on the MSC compartment.