Brain-mediated antidiabetic, anorexic, and cardiovascular actions of leptin require melanocortin-4 receptor signaling

J Neurophysiol. 2015 Apr 1;113(7):2786-91. doi: 10.1152/jn.00911.2014. Epub 2015 Feb 25.

Abstract

We previously demonstrated that leptin has powerful central nervous system (CNS)-mediated antidiabetic actions. In this study we tested the importance of melanocortin-4 receptors (MC4Rs) for leptin's ability to suppress food intake, increase blood pressure (BP) and heart rate (HR), and normalize glucose levels in insulin-dependent diabetes. MC4R knockout (MC4R-KO) and control wild-type (WT) rats were implanted with intracerebroventricular (ICV) cannula and BP and HR were measured 24 h/day by telemetry. After 5-day control period, an injection of streptozotocin (50 mg/kg, ip) was used to induce diabetes. Eight days after injection, an osmotic pump was implanted subcutaneously and connected to the ICV cannula to deliver leptin (15 μg/day) for 7 days. At baseline, MC4R-KO rats were hyperphagic and 40% heavier than WT rats. Despite obesity, BP was similar (112 ± 2 vs. 111 ± 2 mmHg) and HR was lower in MC4R-KO rats (320 ± 6 vs. 347 ± 5 beats/min). Induction of diabetes increased food intake (30%) and reduced BP (∼17 mmHg) and HR (∼61 beats/min) in WT rats, while food intake, BP, and HR were reduced by ∼10%, 7 mmHg, and 33 beats/min, respectively, in MC4R-KO rats. Leptin treatment normalized blood glucose (437 ± 10 to 136 ± 18 mg/dl), reduced food intake (40%), and increased HR (+60 beats/min) and BP (+9 mmHg) in WT rats. Only modest changes in blood glucose (367 ± 16 to 326 ± 23 mg/dl), food intake (5%), HR (+16 beats/min) and BP (+4 mmHg) were observed in MC4R-KO rats. These results indicate that intact CNS MC4R signaling is necessary for leptin to exert its chronic antidiabetic, anorexic, and cardiovascular actions.

Keywords: blood pressure; food intake; heart rate; insulin; leptin; melanocortin; streptozotocin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anorexia / metabolism*
  • Anorexia / prevention & control
  • Blood Pressure / drug effects
  • Brain / drug effects
  • Brain / metabolism*
  • Diabetes Mellitus / metabolism*
  • Diabetes Mellitus / prevention & control
  • Eating / drug effects
  • Glucose / metabolism
  • Heart Rate / drug effects*
  • Leptin / administration & dosage*
  • Leptin / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Rats, Wistar
  • Receptor, Melanocortin, Type 4 / metabolism*

Substances

  • Leptin
  • MC4R protein, mouse
  • Receptor, Melanocortin, Type 4
  • Glucose