SLC6A2 /MAOA inhibitors improve the glycolipid metabolism by regulating norepinephrine in sympathetic neuron–associated macrophages

Abstract Background: The infiltration of macrophages in white adipose tissue (WAT) is associated with the development of obesity. A recent study reported that sympathetic neuron–associated macrophages (SAMs) had a pro-inflammatory effect by regulating the metabolism of norepinephrine (NE) in obesity. SAMs transport and degrade NE via solute carrier family 6 member 2（SLC6A2）and monoamine oxidase A（MAOA）respectively. NE has a well-established role in promoting lipolysis in adipocytes. Furthermore, SAMs are recruited and activated in obesity, but the exact molecular mechanism is still unclear. The aim of this study is to explore whether the restraint of SLC6A2 or MAOA by SLC6A2 inhibitor (SLC6A2i) or MAOA inhibitor (MAOAi) would rescured metabolic disorders by modulating NE level in high fat diet (HFD) induced obesity mice model. We thus unveiled the effect of NE on glycolipid metabolism, focusing on the contribution of SAMs .Methods: 24 male C57BL/6J mice (5 weeks old) were randomly fed with normal chow diet (NCD, n=6) or HFD (n=18) respectively for 16 weeks. 18 mice fed with HFD were randomly categorized into 3 groups as follows: HFD+NaCl (n=6), HFD+SLC6A2i (n=6) and HFD+MAOAi (n=6). The body weight, length and serum analysis (glucose, lipidprofile, and insulin) were obtained before and after 3 weeks of NE intervention. Then, superior cervical ganglia(SCG), visceral white adipose tissue (vWAT) and subcutaneous white adipose tissue (sWAT) were extracted for further analysis. Results: After 3 weeks NE intervention, Lee’s index, FBG, P2hBG, TG, TC, LDL-C, and insulin showed lower in HFD+SLC6A2i and HFD+MAOAi group, and HDL-C showed higher than those in HFD+NaCl group (p<0.05)，although the weight and length had no significant change. The adiposytes in the HFD+NaCl group were obivously bigger and more inconsistent in size, while HFD+SLC6A2i group and HFD+MAOAi group showed intact morphology similar with NCD group. Compared with HFD+NaCl group, SAMs proportion, expression of SLC6A2, MAOA, TLR4, MYD88, NF-κB, TNF-α and IL-1α were significantly lower in HFD+SLC6A2i and HFD+MAOAi group (p<0.05), while the concentration of NE and expression of IL-10 were significantly higher in HFD+SLC6A2i and HFD+MAOAi group (p<0.05).Conclusion: Our results indicated restraint the function of SLC6A2 or MAOA would rescued metabolic disorders and obesity by modulating NE level. Recruited SAMs in obesity might be derived from the chronic low grade inflammation via TLR4/NF-κB signaling pathway. These findings provide new target for therapeutic potential of glycolipid metabolism and obesity.