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OXPHOS-Arachidonic acid-PPAR signalosome controls brown adipocyte peroxisomal function.

ABSTRACT: Brown adipose tissue plays a crucial role in modulating whole-body energy expenditure through the thermogenic function of its mitochondrial respiratory chain. Pharmacological interventions targeting this function hold significant therapeutic promise. Thus, gaining a comprehensive understanding of the pathophysiological regulation of brown adipose tissue is imperative for future therapeutic applications. In this study, we investigated the metabolic mechanisms underlying the regulation of mature brown adipocyte function by the mitochondrial respiratory chain. Our findings indicate that deficiency in mitochondrial complex I in mature brown adipocytes leads to lipidomic remodeling. This remodeling results in an increase in arachidonic acid content and prostaglandin E2 (PGE2) production, leading to reduced transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARγ) and peroxisome proliferator-activated receptor alpha (PPARα) and alterations in the content of PPAR activator complexes, which consequently result in reduced brown adipocyte thermogenesis and peroxisomal gene expression in mature brown adipocyte. In summary, our study elucidates that the mitochondrial-derived arachidonic acid signal regulates brown adipocyte thermogenesis and peroxisome biogenesis by modulating the PPAR activator complex."

ORGANISM(S): Mus musculus

PROVIDER: GSE266292 | GEO | 2024/05/03

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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OXPHOS-Arachidonic acid-PPAR signalosome controls brown adipocyte peroxisomal function.

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