Melanocortin‐4 Receptor (MC4R) Deficiency Promotes Increases in High‐Fat Diet‐Induced Body Weight Gain And Visceral Fat, but Not Hypertension, during Pregnancy

Abstract

Obesity is a major risk factor for preeclampsia but the mechanisms linking obesity with this disease of new-onset hypertension during pregnancy remain unclear. Although MC4R is an important neural mechanism for obesity-induced hypertension, whereby deficiency of MC4R promotes hyperphagia and obesity without hypertension, this mechanism has not been examined during pregnancy. We tested the hypothesis that MC4R mediates high-fat diet (HFD)-induced obesity and hypertension during pregnancy. Female MC4R+/+ and MC4R+/- rats were started on normal fat diet (NFD; 13% kcal fat) or HFD (40% kcal fat) at 6 wks old; pregnant rats generated at 18 wks; then implanted with carotid catheters on gestational day 18 for mean arterial pressure (MAP), plasma and visceral adipose tissue collections on day 19. In MC4R+/+ pregnant rats, gestational body weight gain (79±3 vs. 69±5 g) and adipose tissue mass (5.4±0.4 vs. 6.2±1.1 g) were similar in NFD (N=16) and HFD (N=15) groups, respectively. In contrast, in MC4R+/- pregnant rats, weight gain (84±6 vs. 73±4 g, P<0.05) and adipose tissue mass (9.7±1.1 vs. 7.1±0.8 g, P<0.05) were increased with HFD (N=10) compared to NFD (N=13). Plasma leptin was similar in respective NFD and HFD groups within rat strains: MC4R+/+: 6.5±0.8 vs. 7.8±2.1; MC4R+/-: 12.1±1.4 vs. 10.5±2.0 ng/mL. MAP was not significantly different between NFD and HFD MC4R+/+ (111±2 vs. 116±4 mmHg) or MC4R+/- (120±2 vs. 115±4 mmHg) pregnant rats. Thus, MC4R deficiency promoted increases in HFD-induced body weight gain and visceral fat, but not hypertension, during pregnancy. In conclusion, these data indicate that MC4R signaling is a mechanism linking obesity to preeclampsia. Funding: HL105324, HL51971.