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Reduced representation bisulfite sequencing (RRBS) of brown adipose tissue from postnatal day 12 mice perinatally exposed to vehicle or DDT

ABSTRACT: The insecticide dichlorodiphenyltrichloroethane (DDT) and its persistent metabolite, dichlorodiphenyldichloroethylene (DDE), have been associated with increased adiposity and obesity in rodent and human studies. These lipophilic pollutants accumulate in adipose tissue and it is theorized that their exposure leads to decreased decrease energy expenditure through the impairment of thermogenesis in brown adipose tissue. We hypothesized that impaired thermogenesis is due to persistent epigenetic modifications of brown adipose tissue. To address this, we exposed C57BL/6J mice to DDT from gestational day 11.5 to postnatal day 5 and isolated brown adipose tissue for RRBS from one offspring per litter when mice reached postnatal day 12 (n=20 DDT litters and 22 vehicle litters). DNA methylation levels in brown adipose tissue of mice perinatally exposed to vehicle or DDT were determined using RRBS. Analyses of differential methylation and KEGG pathway enrichment were performed.

ORGANISM(S): Mus musculus

PROVIDER: GSE255231 | GEO | 2024/10/05

REPOSITORIES: GEO

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Project description:Non-shivering thermogenesis in adipocytes is mediated by brown adipose tissue, purportedly through the sole action of uncoupling protein 1 (UCP1). The physiological relevance of UCP1-dependent thermogenesis has primarily been inferred from the attenuation of thermogenic output of mice genetically lacking Ucp1 from birth (germline Ucp1-/-). However, germline Ucp1-/- mice harbor secondary changes within brown adipose tissue beyond UCP1, such as reduced electron transport chain abundance. We show here that these secondary changes also encompass reduced expression of genes regulating fuel liberation, changes that would attenuate the capacity of any thermogenic pathway. Therefore, the quantitative contribution of UCP1-dependent and -independent thermogenesis is not fully understood. To mitigate the potentially confounding ancillary changes to brown adipose tissue of germline Ucp1-/- mice, we constructed mice with inducible adipocyte-selective disruption of Ucp1. We find that, while germline Ucp1-/- mice succumb to cold-induced hypothermia with complete penetrance, most mice with inducible deletion of Ucp1 maintain homeothermy in the cold. However, inducible adipocyte-selective co-deletion of Ucp1 and creatine kinase B (Ckb, an effector of UCP1-independent thermogenesis) exacerbates cold-intolerance, indicative of a negative genetic interaction and thus a parallel thermogenic function. We find no evidence for impairments in insulation or non-shivering thermogenesis in skeletal muscle that would drive this phenotype. Furthermore, following UCP1 deletion or UCP1/CKB co-deletion from mature adipocytes, moderate cold exposure triggers the regeneration of mature adipocytes that coordinately restore UCP1 and CKB to brown adipose tissue, providing further evidence of their parallel thermogenic relationship. Our findings suggest that thermogenic adipocytes utilize non-paralogous protein redundancy – through UCP1 and CKB – to promote cold-induced energy dissipation.

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Reduced representation bisulfite sequencing (RRBS) of brown adipose tissue from postnatal day 12 mice perinatally exposed to vehicle or DDT

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