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CXCL5 secreted from macrophages during cold exposure mediates white adipose tissue browning

ABSTRACT: Adipose tissue affects metabolic-related diseases as it consists of various types of cells that are involved in fat metabolism and adipokine release. CXC ligand 5 (CXCL5) is a member of the CXC chemokine family and is highly expressed by macrophages in white adipose tissue (WAT). In this study, we generated and investigated the function of Cxcl5 in knockout (KO) mouse. Cxcl5 KO mouse was generated using CRISPR/Cas9. The KO male mice didn’t show significant phenotype difference in normal condition. However, proteomic analysis revealed that many proteins are enriched in the process of fatty acid beta-oxidation and mitochondrial localization in iWAT of Cxcl5 KO mice. Cxcl5 KO mouse showed rather decreased proteins and transcripts expression associated with thermogenesis including uncoupled protein 1 (UCP1), a well-known thermogenic gene, and increased expressions associated with inflammation. The increase of Ucp1 expression in cold conditions was significantly retarded in Cxcl5 KO mice. The expression of transcription factors involved in thermogenesis including peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1α) was not properly increased in Cxcl5 KO under cold challenge and its mimic conditions. CXCL5 treatment increased the expression of transcription factors for Ucp1 and Ucp1 itself. Collectively, our data shows that Ucp1 expression is induced in adipocyte by CXCL5 secreted by β-Adrenergic stimulation in M1 macrophages. Our data indicates that CXCL5 has a crucial role in regulating energy metabolism, particularly in cold exposure. These results strongly suggest that targeting CXCL5 could be a therapeutic aim for people with a disorder of energy metabolism.

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Dabin Lee

PROVIDER: PXD027291 | JPOST Repository | Thu Jul 14 00:00:00 BST 2022

REPOSITORIES: jPOST

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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.

			Action	DRS
	Cxcl5_iWAT_set1_Bx.raw	Raw
	Cxcl5_iWAT_set1_X1.raw	Raw
	Cxcl5_iWAT_set1_X2.raw	Raw
	Result.txt	Txt

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CXCL5 secreted from macrophages during cold exposure mediates white adipose tissue browning

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