Glutamatergic MC4R Neurons Regulating Body Weight In Mice

Melanocortin-4 receptor(MC4R)is a key component in maintaining energy balance.MC4R-expressing neurons are concentrated on the paraventricular nucleus(PVN)of the hypothalamus.PVN also contains a large number of glutamatergic neurons(VGlut2),however,little is known about other sites with the same function.Based on the LC is a potential hinge for homeostasis regulation,We hypothesized that the LC could act as a downstream effector nucleus of PVN feeding and temperature control.First,MC4 R was conditionally knocked out in chimeric mice to confirm the effect of VGlut2.PRV and RV retrograde viruses were injected into the IBAT and LC nuclei of VGlut2 mice to determine the projection relationship between IBAT and the center,PVN and LC,and to expand the distribution of MC4 R neurons.The results showed that knockout MC4 R mice increased body weight,and inactivation of PVN & LC of MC4 R mice by Adeno-associated virus(AAV)had a potential additive effect.Retrograde tracing of IBAT indicated that PVN and LC nuclei had local VGlut2/PRV/MC4 R triple-labeling signals.Retrograde transsynaptic tracing results indicated that LC received direct afferents from PVN,ARC,and LDT.In addition,Amylin significantly increased CART and neuronal expression in the DMH in wild-type and sham mice compared with saline controls group.The expression of n NOS in neurons was unchanged in the denervation group.In conclusion,the PVN&LC glutamatergic MC4 R long-range neural circuit plays a positive role in regulating body weight,which is helpful to improve the targeted therapy for obesity.