Brown Adipose Tissue Dysfunction Links Obesogen Exposure to Reduced Energy Expenditure and Transgenerational Obesity

Obesity has become a global health challenge, and increasing evidence suggests that environmental obesogens contribute to its prevalence. Tributyltin (TBT) is a model obesogen known to activate PPARγ and RXR and to promote transgenerational obesity in mice, but the mechanisms linking TBT exposure to impaired energy balance remain poorly defined. Brown adipose tissue (BAT) is a central regulator of energy expenditure (EE) and basal metabolic rate (BMR) through both UCP1-dependent and UCP1-independent pathways. Here, we tested whether ancestral TBT exposure disrupts BAT function across generations. To assess whether TBT alters body composition and thermogenic capacity, we measured fat and lean mass, BAT gene expression, mitochondrial abundance, and core body temperature in F1 and F3 offspring. TBT-group males accumulated more fat mass without changes in lean mass or food intake scaled to metabolic size, indicating reduced EE/BMR. Expression of BAT lineage and oxidative genes (Zic1, Ebf2, Pgc1a, Pdk4) was suppressed in TBT-group males across generations. Ucp1 expression was unchanged at baseline but decreased after high-fat diet (HFD) challenge, whereas Ucp2 and Ucp4 were reduced even at baseline. In addition, key UCP1-independent thermogenic genes involved in creatine (Slc6a8, Ckb) and calcium (Atp2a2, Itpr) futile cycles were significantly decreased, while lipid-cycle genes (Pnpla2, Abhd5) were unaffected. Mitochondrial DNA content was largely unchanged, but core body temperature was reduced in TBT-group males prior to diet challenge, confirming impaired basal thermogenesis. These findings demonstrate that ancestral TBT exposure produces male-specific and heritable defects in BAT identity and thermogenic capacity. By suppressing both UCP1-dependent and UCP1-independent pathways without altering mitochondrial abundance, TBT-group males exhibit reduced energy expenditure and basal metabolic rate. These results identify BAT dysfunction as a mechanistic link between environmental obesogen exposure and transgenerational susceptibility to obesity.