Chemokine receptor CCR1 restrains adipose tissue remodelling via cAMP/PKA/CREB signalling and adipocyte‒macrophage crosstalk in mice
Suili Cai, Mengchen Ma, Yuqin Zhu, Mengru Shi, Xiaoyan Dai, Yujie Wang, Mengru Li, Yanwen Yu, Yajiao Wang, Liang XuAbstract
Background
Adipose tissue remodelling, encompassing white adipose tissue (WAT) browning alongside brown adipose tissue (BAT) activation, holds promise for combating obesity, yet the endogenous chemokine receptors that restrain this plasticity remain ill‐defined. Here, we uncover that C‒C chemokine receptor 1 (CCR1) restrains adipocyte remodelling and energy expenditure.
Methods
A high‐fat diet (HFD) was provided to systemic and adipocyte‐specific Ccr1 knockout mice. The CCR1‐selective antagonist BX471 was administered to HFD‐fed wild‐type (WT) mice as a preventive regimen. Energy expenditure was assessed via indirect calorimetry; BAT thermogenic activity and WAT beiging were quantified through histology and gene expressin analyses. Adipose tissue macrophage homeostasis was analysed via flow cytometry. Peritoneal macrophages were differentiated into either the M1 or M2 state, and conditioned media were applied to the adipocytes.
Results
In HFD‐fed mice, Ccr1 ablation conferred resistance to obesity and insulin resistance, coupled with enhanced WAT browning, augmented BAT thermogenesis and elevated energy expenditure. These metabolic benefits were associated with a shift towards M2 macrophage polarisation and reduced adipose tissue inflammation. Adipocyte‐specific Ccr1 knockout recapitulated these phenotypes. BX471 administration in WT mice phenocopied the metabolic effects of Ccr1 deficiency under HFD conditions. Mechanistically, in vitro experiments suggested that Ccr1 loss suppressed Gαi‐dependent signalling, leading to increased intracellular cyclic adenosine monophosphate (cAMP) and subsequent protein kinase A/cAMP‐response element‐binding protein 1 (PKA/CREB) activation, thereby promoting thermogenic gene expression in adipocytes. In addition, conditioned media from M2‐polarised macrophages enhanced thermogenic gene expression in adipocytes, and this effect was further potentiated in Ccr1 ‐deficient adipocytes.
Conclusion
CCR1 regulates adipose tissue remodelling and systemic energy expenditure, at least in part, through cAMP/PKA/CREB signalling and macrophage homeostasis. Pharmacological inhibition of CCR1 attenuates obesity development, suggesting a potential preventive strategy.
Key points
CCR1 expression is significantly elevated in adipose tissue of obese individuals.
Systemic and adipocyte‐specific
Ccr1
deletion promotes fat browning via cAMP/PKA/CREB activation and M2 macrophage polarisation, protecting against obesity.
Pharmacological blockade of CCR1 suppresses obesity progression, highlighting its potential as a novel target for metabolic disorders.