Melanocortin-4 receptor-deficient mice are not hypertensive or salt-sensitive despite obesity, hyperinsulinemia, and hyperleptinemia.
The purpose of this study was to test whether the melanocortin-4 receptor (MC4R) is critical in the development of hypertension associated with obesity and its metabolic disorders. MC4R-deficient homozygous (-/-) and heterozygous (+/-) and wild-type (WT) C57BL/6J mice 17 to 19 weeks old (n=5 to 7 per group) were implanted with telemetry devices for monitoring 24-hour mean arterial pressure (MAP) and heart rate (HR). After 3-day stable control measurements on normal-salt diet (NSD; 0.4% NaCl), mice received a high-salt diet (HSD; 4% NaCl) for 7 days, followed by 3-day recovery on NSD. MC4R (-/-) mice were severely obese compared with MC4R (+/-) and WT mice (body weight 48+/-1.5 versus 31+/-0.6 and 30+/-0.5 g respectively). On NSD, MAP was similar in all groups of mice (MC4R (-/-) 110+/-3 mm Hg; MC4R (+/-) 109+/-2 mm Hg; WT 114+/-2 mm Hg), and HR in MC4R (-/-) was lower than in WT (604+/-5 versus 645+/-9 bpm; P<0.05) but not different from MC4R (+/-) (625+/-13 bpm) mice. HSD did not significantly alter MAP or HR in any of the groups. Epididymal and retroperitoneal fat weights and plasma leptin levels were several-fold greater in MC4R (-/-) compared with MC4R (+/-) and WT mice. Plasma insulin and glucose levels were also significantly greater in MC4R (-/-) than in MC4R (+/-) and WT mice. These data suggest that despite obesity, visceral adiposity, hyperleptinemia, and hyperinsulinemia, MC4R (-/-) mice are neither hypertensive nor salt sensitive, indicating that a functional MC4R may be necessary for the development of hypertension associated with obesity and its metabolic abnormalities.
Tallam
Lakshmi S
LS
Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216-4505, USA. ltallam@physiology.umsmed.edu
Stec
David E
DE
Willis
Mary A
MA
da Silva
Alexandre A
AA
Hall
John E
JE
D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D049628:Body Size; D004305:Dose-Response Relationship, Drug; D004326:Drinking; D004435:Eating; D006339:Heart Rate / Q000187:drug effects; D006728:Hormones / Q000097:blood; D006946:Hyperinsulinism / Q000150:complications*; D006973:Hypertension / Q000209:etiology*; D020738:Leptin / Q000097:blood*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications* / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000172:deficiency / Q000378:metabolism*; D012965:Sodium Chloride / Q000494:pharmacology*; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000494:pharmacology; D014781:Viscera / Q000473:pathology; D015430:Weight Gain
D006728:Hormones; D020738:Leptin; D044105:Receptor, Melanocortin, Type 4; D017673:Sodium Chloride, Dietary; D012965:Sodium Chloride