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Heat production from adipose-tissue macrophages regulates lipolysis and diet-induced obesity

ABSTRACT: Recently white adipose tissues (WAT) have been shown to be able to generate heat upon cold exposure through the expression of uncoupling protein-1 (UCP1), a molecule regulating mitochondrial proton gradient. Although the role of UCP1 has been extensively investigated in adipocytes, it is currently unknown whether UCP1 in the microenvironment of WAT such as adipose-tissue macrophages (ATM) could play a role in thermogenesis. Given the critical role of hypoxia in regulating obesity and insulin resistance, we challenged our myeloid-specific hypoxia-inducible factor-1α (Hif-1α) knockout (KO) mice to high fat diet and observed that these mice were not only protected from diet-induced obesity but also resistant to the body temperature changes upon cold exposure, the latter effect being completely lost upon surgical removal of WAT. Mechanistically, ATM deficient for HIF-1α generated heat production through increased expression of UCP1 and increased mitochondrial functions, all of which lead to an enhanced lipolysis in neighboring adipocytes. Lastly, we observed a number of co-localized areas between UCP-1 and CD68 in WAT of lean mice as well as individuals whereas such areas were not observed in an obese mice or human subjects. In conclusion, we demonstrate a novel mechanism by which ATM regulate obesity through UCP1-mediated heat generation.

ORGANISM(S): Mus musculus

PROVIDER: GSE143298 | GEO | 2024/12/17

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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Heat production from adipose-tissue macrophages regulates lipolysis and diet-induced obesity

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