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Single-nucleus RNA-sequencing reveals NRF1/NFE2L1 as a key determining metabolic state and fate decision of brown adipocytes in mice [bulk RNA-seq]

ABSTRACT: Brown adipose tissue (BAT) is a major site of nonshivering thermogenesis (NST) in mammals and might play an important role in human obesity and energy homeostasis. Recent single-cell/nucleus RNA-sequencing studies have revealed heterogeneity in thermogenesis among brown adipocytes, such as the findings of low thermogenesis and regulated thermogenesis in brown adipocytes. Activating and enhancing function adipocytes (BAC) has acquired attention as a possible therapeutic intervention for metabolic diseases. Nuclear factor-erythroid 2-related factor 1 (NFE2L1, also known as Nrf1), a CNC-bZIP protein, is a master regulator of multiple cellular functions and responds to various stress in many cells and tissues. NFE2L1 acts as a guardian role in BAC function providing increased proteometabolic quality control for adapting to cold or obesity. Our previous studies demonstrated that NFE2L1-dependent lipolytic activity is crucial for white adipose tissue (WAT) plasticity and lipid homeostasis. To further clarify the role of NFE2L1 in adipocytes, we focused on the phenotype and gene expression profiling of BAT in adipocyte-specific Nfe2l1-knockout [Nfe2l1(f)-KO] mice. We found that deletion of Nfe2l1 decreased core body temperature and cold intolerance under cold exposure. Compared with floxed mice, the BAT of Nfe2l1(f)-KO mice expressed substantially lower levels of many genes related to lipolysis, thermogenesis, oxidative capacity of mitochondria, cellular respiration while higher genes related to inflammation, pyroptosis. By snRNA-seq, we found that Nfe2l1-knockout resulted in increased antigen processing and presentation (APP), necroptosis and NOD-like receptor signal pathway (NOD) signaling pathways in most subpopulations of BAC, with devastating effects on a normal subpopulation of BAC with low thermogenesis and high necroptosis genes expression. Absent of Nfe2l1 impairs the function of BAC, causing a morphological “whitening” phenotype with adipocyte hypertrophy and severe inflammation. Moreover, the adipose inflammation and pyroptosis in Nfe2l1(f)-KO mice could be mitigated by cold exposure or β3-agonist treatment. These findings provided a deeper insight into the function of NFE2L1 in the metabolic programming of brown adipocytes.

ORGANISM(S): Mus musculus

PROVIDER: GSE225279 | GEO | 2023/09/20

REPOSITORIES: GEO

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Project description:Brown adipose tissue (BAT) is a major site of nonshivering thermogenesis (NST) in mammals and might play an important role in human obesity and energy homeostasis. Recent single-cell/nucleus RNA-sequencing studies have revealed heterogeneity in thermogenesis among brown adipocytes, such as the findings of low thermogenesis and regulated thermogenesis in brown adipocytes. Activating and enhancing function adipocytes (BAC) has acquired attention as a possible therapeutic intervention for metabolic diseases. Nuclear factor-erythroid 2-related factor 1 (NFE2L1, also known as Nrf1), a CNC-bZIP protein, is a master regulator of multiple cellular functions and responds to various stress in many cells and tissues. NFE2L1 acts as a guardian role in BAC function providing increased proteometabolic quality control for adapting to cold or obesity. Our previous studies demonstrated that NFE2L1-dependent lipolytic activity is crucial for white adipose tissue (WAT) plasticity and lipid homeostasis. To further clarify the role of NFE2L1 in adipocytes, we focused on the phenotype and gene expression profiling of BAT in adipocyte-specific Nfe2l1-knockout [Nfe2l1(f)-KO] mice. We found that deletion of Nfe2l1 decreased core body temperature and cold intolerance under cold exposure. Compared with floxed mice, the BAT of Nfe2l1(f)-KO mice expressed substantially lower levels of many genes related to lipolysis, thermogenesis, oxidative capacity of mitochondria, cellular respiration while higher genes related to inflammation, pyroptosis. By snRNA-seq, we found that Nfe2l1-knockout resulted in increased antigen processing and presentation (APP), necroptosis and NOD-like receptor signal pathway (NOD) signaling pathways in most subpopulations of BAC, with devastating effects on a normal subpopulation of BAC with low thermogenesis and high necroptosis genes expression. Absent of Nfe2l1 impairs the function of BAC, causing a morphological “whitening” phenotype with adipocyte hypertrophy and severe inflammation. Moreover, the adipose inflammation and pyroptosis in Nfe2l1(f)-KO mice could be mitigated by cold exposure or β3-agonist treatment. These findings provided a deeper insight into the function of NFE2L1 in the metabolic programming of brown adipocytes.

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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Single-nucleus RNA-sequencing reveals NRF1/NFE2L1 as a key determining metabolic state and fate decision of brown adipocytes in mice [bulk RNA-seq]

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