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Transcriptome profiling of brown adipocytes treated with BML-260, DMSO or ISO for revealing the BML-260 mechanism

ABSTRACT: To explore BML-260 how to increase thermogenesis, we treated brown adipocytes with BML-260 and DMSO for 1 day or 3 days after seven days' differenciation. Meanwhile, we also set ISO (isoproterenol)-treated brown adipocytes as positive control. We found that BML-260 treatment led to very significant upregulation of genes involved in oxidative phosphorylation, fatty acid beta-oxidation, and mitochondrial function.When compared to cells treated with ISO, although both showed significant upregulation of UCP1, BML-260-treated cells showed a rather distinct gene profile when compared to ISO-treated cells. This work provides evidences that BML-260 can also exert a JSP-1-independent effect in activating UCP1 and thermogenesis in adipocytes, and be potentially applied to treat obesity.

ORGANISM(S): Mus musculus

PROVIDER: GSE129791 | GEO | 2019/04/16

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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Transcriptome profiling of brown adipocytes treated with BML-260, DMSO or ISO for revealing the BML-260 mechanism

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