Environmental
endocrine disruptors are implicated as putative contributors to the burgeoning
metabolic disease epidemic.
Tolylfluanid (TF) is a commonly detected fungicide in Europe, and previous in vitro and ex vivo work has identified it as a potent
endocrine disruptor with the capacity to promote adipocyte differentiation and induce adipocytic
insulin resistance, effects likely resulting from activation of
glucocorticoid receptor signaling. The present study extends these findings to an in vivo mouse model of dietary TF exposure. After 12 weeks of consumption of a normal chow diet supplemented with 100 parts per million TF, mice exhibited increased
body weight gain and an increase in total fat mass, with a specific augmentation in visceral adipose depots. This increased adipose accumulation is proposed to occur through a reduction in lipolytic and
fatty acid oxidation gene expression. Dietary TF exposure induced
glucose intolerance,
insulin resistance, and metabolic inflexibility, while also disrupting diurnal rhythms of energy expenditure and food consumption. Adipose tissue endocrine function was also impaired with a reduction in serum
adiponectin levels. Moreover, adipocytes from TF-exposed mice exhibited reduced
insulin sensitivity, an effect likely mediated through a specific down-regulation of
insulin receptor substrate-1 expression, mirroring effects of ex vivo TF exposure. Finally, gene set enrichment analysis revealed an increase in adipose
glucocorticoid receptor signaling with TF treatment. Taken together, these findings identify TF as a novel in vivo
endocrine disruptor and obesogen in mice, with dietary exposure leading to alterations in energy homeostasis that recapitulate many features of the
metabolic syndrome.