CXCL12-CXCR4 pathway activates brown adipocytes and induces insulin resistance in CXCR4-deficient mice under high-fat diet.

Brown adipose tissue (BAT) plays a role in energy expenditure and is involved in nutrient metabolism. C-X-C chemokine ligand 12 (CXCL12)-CXCR4 pathway regulates the immune, nervous, and cardiovascular systems and affects the adipose tissue. Here, we investigated the role of this pathway as an activator of BAT. Uncoupling protein 1 mRNA and protein levels and oxygen consumption increased in the brown adipocytes treated with 100 nM CXCL12 peptide. CXCL12-mediated upregulation in P38 and extracellular signal-regulated kinase (ERK) levels was reduced by each inhibitor. Thus, the CXCL12-CXCR4 pathway activated the brown adipocytes through P38 and ERK that acted downstream of this pathway. Mice with CXCR4 defects only in the brown adipocytes were generated and fed with high-fat diet (HFD). Body weight and blood glucose after glucose injection increased in these mice. Long-term exposure to HFD deteriorated blood glucose level after glucose injection. Insulin sensitivity was exacerbated in the knockout mice fed with HFD. Serum lipid parameters and CXCL12 level in knockout mice were similar to those in control mice. These results suggest that the CXCL12-CXCR4 pathway induces brown adipocyte activity and affects nutrient metabolism under HFD load.