Abstract
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.
Highlights
Brown adipose tissue (BAT) dissipates energy in the form of heat to maintain body temperature and energy balance[1]
Uncoupling protein (UCP)-1 is a crucial molecule involved in brown adipocyte activity and acts as a surrogate marker of brown adipocyte activity
Results of the present study indicate that the CXCL12-CXCR4 pathway plays an essential role in the activation of the brown adipocytes through the P38 and extracellular signal-regulated kinase (ERK), but not protein kinase A (PKA), signalling pathways
Summary
Brown adipose tissue (BAT) dissipates energy in the form of heat to maintain body temperature and energy balance[1]. Noradrenaline is a canonical activating factor of brown adipocytes that is released from the sympathetic nerve terminal as a neurotransmitter in response to cold. The CXCL12-CXCR4 pathway plays a pivotal role in cell migration, haematopoiesis, cardiovascular development, lymphoid organ morphogenesis, and neural differentiation during embryonic stage[6,7]. This pathway is involved in various neoplasms such as multiple myeloma, acute myeloid leukaemia, diffuse large B cell lymphoma, adrenocortical cancer, and small lung cancer[8]. Serum levels of CXCL12 were higher in patients with type 2 diabetes than in healthy subjects[10] This pathway deteriorated non-alcoholic steatohepatitis (NASH) through CD4+ T cell recruitment[11]. CXCL12 from white adipocytes directly deteriorate insulin sensitivity of the parent cells[14]
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