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Abstract P213: Metabolic and Cardiovascular Effects of Melanocortin-4 Receptors in Leptin Receptor-expressing Neurons

Studies in both humans and rodents have clearly established a role for melanocortin-4 receptor (MC4R) in energy homeostasis, sympathetic and cardiovascular function. Both MC4R-deficient humans and rodents develop severe obesity while keeping the sympathetic tone and blood pressure below or within the normal range, indicating that MC4R is required for obesity-associated sympathetic overdrive and hypertension. Indeed, sympathetic overdrive and cardiovascular side effect have been a major problem in developing anti-obesity drugs that target MC4R. Thus, better understanding the neural substrates that mediate distinct metabolic and sympathetic actions of MC4R is needed to provide a more specific target to treat obesity and associated hypertension. We have recently mapped the pattern of co-expression of MC4R and leptin receptor (LepR) and found that, throughout entire mouse brain, these two metabolically important receptors are uniquely co-expressed only in neurons of two brain regions, including the lateral hypothalamic area (LHA) and the periaqueductal gray (PAG). To specifically test the role of MC4R in LepR-expressing neurons, we generated mice with MC4R expression only in LepR-positive neurons by breeding Cre-dependently “reactivatable” MC4R-null mice (MC4R-TB) to LepR-Cre mice. We found that specific re-expression of MC4Rs only in LepR-positive neurons partially suppresses body weight gain especially in female mice (MC4R-TB 31.73 ± 2.2g vs. MC4R-TB::LepR-Cre 27.97 ± 1.8 g, p=0.0013). Direct multi-fiber recording of renal nerve activity (RSNA), however, revealed that neither baseline activity nor MC4R agonist-induced RSNA is significantly altered by restoration of MC4R signaling in LepR-positive neurons (change of RSNA in MC4R-TB 8.844 ± 3.05 vs. MC4R-TB::LepR-Cre 11.95 ± 2.7, p>0.05). Our results suggest that MC4R signaling in leptin-responsive neurons is sufficient to suppress body weight in female mice, but seemingly has no effect on sympathetic traffic to the kidney. Further investigation of the effect of MC4Rs in LepR-positive neurons on blood pressure regulation is underway.