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Fibroblast growth factors induce preadipocyte UCP1 expression and imprint on post-differentiation white and brown adipocyte function

ABSTRACT: Objective: The presence of uncoupling protein 1 (Ucp1) is a hallmark of thermogenic adipocytes and enables heat production by dissipating energy from mitochondrial proton motive force as heat. The purpose of its recently discovered presence in preadipocytes in response to certain fibroblast growth factors (FGFs) remains elusive. Methods: In this study, we systematically investigated the potential of all paracrine FGFs to invoke Ucp1 expression in murine preadipocytes derived from interscapular brown and inguinal white adipose tissue. Results: The factors FGF2, FGF4, FGF8, and FGF9 induced Ucp1 expression in undifferentiated preadipocytes, with FGF2 acting most potently and rapidly. This premature Ucp1 induction did not translate into increased Ucp1 protein abundance or thermogenic activity after full adipogenic differentiation. Notably, preadipocyte treatment with FGFs and parallel Ucp1 expression led to a sustained suppression of interferon-stimulated genes after differentiation. Preadipocyte Ucp1 was required and sufficient for this lasting imprint. Conclusion: Thus, FGF-induced Ucp1 expression in preadipocytes programs a lasting post-differentiation anti-inflammatory status.

ORGANISM(S): Mus musculus

PROVIDER: GSE306079 | GEO | 2025/08/22

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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Fibroblast growth factors induce preadipocyte UCP1 expression and imprint on post-differentiation white and brown adipocyte function

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