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Brown adipocytes proteome upon acute adrenergic stimulation

ABSTRACT: Mice and other small mammals heavily rely on UCP1-mediated non-shivering thermogenesis in the cold, and thus the unexpected cold resistance of UCP1-knockout (UCP1KO) mice has always been and still is an unresolved mystery inextricably intertwined with alternative means of thermogenesis and futile substrate cycles. Several potentially thermogenic futile substrate cycles in adipose tissue of WT and UCP1KO mice have been reported in the literature. We hypothesized that isoproterenol treatment of brown adipocytes from UCP1KO mice would cause an immediate acceleration of futile substrate cycling, and entail a consecutive upregulation of the involved enzymes to recruit additional capacity. In this study, we analyzed changes in the proteome of wild type (WT) and UCP1KO adipocytes during acute adrenergic stimulation to detect characteristic molecular signatures, which allowed us to narrow down our search to potential candidates related to Ca2+ and lipid metabolism.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Adipose Tissue

SUBMITTER: Piero Giansanti

LAB HEAD: Bernhard Kuster

PROVIDER: PXD025854 | Pride | 2022-04-25

REPOSITORIES: Pride

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			Action	DRS
	03835_A12_P042807_U1_R1.raw	Raw
	03835_A12_P042807_U1_R2.raw	Raw
	03835_A1_P042806_R1.raw	Raw
	03835_A2_P042806_R16.raw	Raw
	03835_A3_P042806_R17.raw	Raw

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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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Brown adipocytes proteome upon acute adrenergic stimulation

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