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

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

Alexandre A da Silva  1 , Frank T Spradley  2 , Joey P Granger  2 , John E Hall  2 , Jussara M do Carmo  2
Affiliations

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

Alexandre A da Silva et al. J Neurophysiol. .

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.

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Figures

Fig. 1.
Fig. 1.
Schematic representation of the experimental protocol used in the study. STZ, streptozotocin; MC4R-KO, melanocortin-4 receptor knockout rats; WT, control Wistar Hannover rats; ICV, intracerebroventricular; ip, intraperitoneal.
Fig. 2.
Fig. 2.
Baseline characteristics of melanocortin-4 receptor-deficient (MC4R-KO) and Wistar Hannover control rats (WT). A: body weight. B: food intake. C: mean arterial pressure (MAP). D: heart rate. Data are expressed as means ± SE. #P < 0.05 vs. MC4R-KO rats.
Fig. 3.
Fig. 3.
A–C: blood glucose concentration (A), body weight (B), and change in food intake (C) responses to induction of insulin-dependent diabetes and chronic ICV leptin treatment in melanocortin-4 receptor-deficient (MC4R-KO) and Wistar Hannover control rats (WT). Data are expressed as means ± SE. Results represent the average of the last 3 days of the control period, days 7 and 8 post streptozotocin injection, days 6 and 7 of leptin ICV treatment, and days 4 and 5 of the recovery period. Diab, diabetes. #P < 0.05 vs. MC4R-KO rats; *P < 0.05 vs. Control baseline values; &P < 0.05 vs. Diabetes.
Fig. 4.
Fig. 4.
A and B: mean arterial pressure (A) and heart rate (B) responses to induction of insulin-dependent diabetes and chronic ICV leptin treatment in melanocortin-4 receptor-deficient (MC4R-KO) and Wistar Hannover control rats (WT). Data are expressed as means ± SE. Results represent the average of the last 3 days of the control period, days 7 and 8 post streptozotocin injection, days 6 and 7 of leptin ICV treatment, and days 4 and 5 of the recovery period. #P < 0.05 vs. MC4R-KO rats; *P < 0.05 vs. Control baseline values; &P < 0.05 vs. Diabetes.
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