Endocrine Abstracts

Obesity rate keeps growing worldwide and weighs heavily on the healthcare system because of the related metabolic disorders like diabetes. In addition to calorie-rich diet and sedentary lifestyle, environmental exposure to obesogens, endocrine disrupting chemicals (EDC) targeting adipose tissue and its function as well as central pathways regulating food intake and energy expenditure, could add to the raising obesity incidence. The flame-retardant tetrabromobisphenol A (TBBPA) is an obesogen known to target thyroid hormone signaling, which has important roles in metabolic control. TBBPA is widely used and it is detected in human samples including mother’s milk and cord blood. Thereby, babies are exposed to this EDC during the vulnerable perinatal period. We wanted to study the combined effect of perinatal TBBPA exposure and adult life Western diet (high in fat and sucrose, HFHS) to metabolic health in adulthood using C57BL/6J mice. Hypothalamus, the central regulator of many bodily functions including thyroid axis and metabolism, consists of various nuclei, each having a unique role in the central control of metabolism. In particular, two nuclei are deeply involved in metabolic regulations, the arcuate nucleus (AN) and the paraventricular nucleus (PVN). Pregnant dams received 10 mg/kg/d TBBPA or vehicle for 4 weeks (last week of gestation through end of lactation). Pups followed a HFHS diet from 2 to 6 months of age. We measured several metabolic parameters, including food intake and weight gain in the four study groups of male mice: vehicle+control diet, vehicle+HFHS diet, TBBPA+control diet and TBBPA+HFHS diet. We also compared the transcriptomes of each group to discover how the hypothalamic nuclei respond to the treatments: we used the cutting-edge technology of spatial transcriptomics (10X Genomics) adding a spatial localization to differential gene expression studies. We measured the whole transcriptome activity, mapped to the relevant hypothalamic regions, focusing more precisely the PVN (controlling thyroid axis) and the AN, to identify the specific transcriptional pathways regulated in each hypothalamic nucleus. The results allow us to determine the molecular pathways specifically affected by the different treatments in each hypothalamic nucleus involved in the central control of metabolism. This will unravel the mechanisms by which the perinatal TBBPA exposure coupled to HFHS diet interfere with the setpoint adjustment of the thyroid axis or other hormonal pathways, and therefore alter the adult’s ability to cope with a metabolic challenge.