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A functional melanocortin system may be required for chronic CNS-mediated antidiabetic and cardiovascular actions of leptin.

da Silva AA, do Carmo JM, Freeman JN, Tallam LS, Hall JE - Diabetes (2009)

Bottom Line: Seven days after starting the antagonist, leptin (0.62 microg/h) was added to the intracerebroventricular infusion for 10 days.MTII infusions transiently reduced blood glucose and raised heart rate and MAP, which returned to diabetic values 5-7 days after starting the infusion.Although a functional melanocortin system is necessary for the CNS-mediated antidiabetic and cardiovascular actions of leptin, chronic MC3/4R activation is apparently not sufficient to mimic these actions of leptin that may involve interactions of multiple pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics and Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi, USA. asilva@physiology.umsmed.edu

ABSTRACT

Objective: We recently showed that leptin has powerful central nervous system (CNS)-mediated antidiabetic and cardiovascular actions. This study tested whether the CNS melanocortin system mediates these actions of leptin in diabetic rats.

Research design and methods: A cannula was placed in the lateral ventricle of Sprague-Dawley rats for intracerebroventricular infusions, and arterial and venous catheters were implanted to measure mean arterial pressure (MAP) and heart rate 24 h/day and for intravenous infusions. After recovery from surgery for 8 days, rats were injected with streptozotocin (STZ), and 5 days later, either saline or the melanocortin 3 and 4 receptor (MC3/4R) antagonist SHU-9119 (1 nmol/h) was infused intracerebroventricularly for 17 days. Seven days after starting the antagonist, leptin (0.62 microg/h) was added to the intracerebroventricular infusion for 10 days. Another group of diabetic rats was infused with the MC3/4R agonist MTII (10 ng/h i.c.v.) for 12 days, followed by 7 days at 50 ng/h.

Results: Induction of diabetes caused hyperphagia, hyperglycemia, and decreases in heart rate (-76 bpm) and MAP (-7 mmHg). Leptin restored appetite, blood glucose, heart rate, and MAP back to pre-diabetic values in vehicle-treated rats, whereas it had no effect in SHU-9119-treated rats. MTII infusions transiently reduced blood glucose and raised heart rate and MAP, which returned to diabetic values 5-7 days after starting the infusion.

Conclusions: Although a functional melanocortin system is necessary for the CNS-mediated antidiabetic and cardiovascular actions of leptin, chronic MC3/4R activation is apparently not sufficient to mimic these actions of leptin that may involve interactions of multiple pathways.

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Related in: MedlinePlus

Heart rate (A) and MAP (B) responses to chronic intracerebroventricular infusion of leptin (●, n = 5) or the MC3/4R agonist MTII in ad libitum–fed (□, n = 5) and pair-fed (▲, n = 5) STZ-diabetic rats. Baseline heart rate and MAP values for leptin, MTII ad libitum–fed, and MTII pair-fed groups were 378 ± 5 bpm and 100 ± 3 mmHg, 366 ± 11 bpm and 90 ± 1 mmHg, and 398 ± 8 bpm and 101 ± 4 mmHg, respectively. Data are means ± SE.
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Figure 2: Heart rate (A) and MAP (B) responses to chronic intracerebroventricular infusion of leptin (●, n = 5) or the MC3/4R agonist MTII in ad libitum–fed (□, n = 5) and pair-fed (▲, n = 5) STZ-diabetic rats. Baseline heart rate and MAP values for leptin, MTII ad libitum–fed, and MTII pair-fed groups were 378 ± 5 bpm and 100 ± 3 mmHg, 366 ± 11 bpm and 90 ± 1 mmHg, and 398 ± 8 bpm and 101 ± 4 mmHg, respectively. Data are means ± SE.

Mentions: Induction of STZ-diabetes also caused marked bradycardia with heart rate rapidly falling by as much as −77 bpm 5 days after STZ injection (Fig. 2A). MAP responses after the induction of diabetes were variable among the groups but remained unchanged on average during the first 5 days after induction of diabetes (Fig. 2B). We previously showed that it takes ∼10–15 days after the STZ injection for a significant reduction in MAP (11).


A functional melanocortin system may be required for chronic CNS-mediated antidiabetic and cardiovascular actions of leptin.

da Silva AA, do Carmo JM, Freeman JN, Tallam LS, Hall JE - Diabetes (2009)

Heart rate (A) and MAP (B) responses to chronic intracerebroventricular infusion of leptin (●, n = 5) or the MC3/4R agonist MTII in ad libitum–fed (□, n = 5) and pair-fed (▲, n = 5) STZ-diabetic rats. Baseline heart rate and MAP values for leptin, MTII ad libitum–fed, and MTII pair-fed groups were 378 ± 5 bpm and 100 ± 3 mmHg, 366 ± 11 bpm and 90 ± 1 mmHg, and 398 ± 8 bpm and 101 ± 4 mmHg, respectively. Data are means ± SE.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2712780&req=5

Figure 2: Heart rate (A) and MAP (B) responses to chronic intracerebroventricular infusion of leptin (●, n = 5) or the MC3/4R agonist MTII in ad libitum–fed (□, n = 5) and pair-fed (▲, n = 5) STZ-diabetic rats. Baseline heart rate and MAP values for leptin, MTII ad libitum–fed, and MTII pair-fed groups were 378 ± 5 bpm and 100 ± 3 mmHg, 366 ± 11 bpm and 90 ± 1 mmHg, and 398 ± 8 bpm and 101 ± 4 mmHg, respectively. Data are means ± SE.
Mentions: Induction of STZ-diabetes also caused marked bradycardia with heart rate rapidly falling by as much as −77 bpm 5 days after STZ injection (Fig. 2A). MAP responses after the induction of diabetes were variable among the groups but remained unchanged on average during the first 5 days after induction of diabetes (Fig. 2B). We previously showed that it takes ∼10–15 days after the STZ injection for a significant reduction in MAP (11).

Bottom Line: Seven days after starting the antagonist, leptin (0.62 microg/h) was added to the intracerebroventricular infusion for 10 days.MTII infusions transiently reduced blood glucose and raised heart rate and MAP, which returned to diabetic values 5-7 days after starting the infusion.Although a functional melanocortin system is necessary for the CNS-mediated antidiabetic and cardiovascular actions of leptin, chronic MC3/4R activation is apparently not sufficient to mimic these actions of leptin that may involve interactions of multiple pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics and Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi, USA. asilva@physiology.umsmed.edu

ABSTRACT

Objective: We recently showed that leptin has powerful central nervous system (CNS)-mediated antidiabetic and cardiovascular actions. This study tested whether the CNS melanocortin system mediates these actions of leptin in diabetic rats.

Research design and methods: A cannula was placed in the lateral ventricle of Sprague-Dawley rats for intracerebroventricular infusions, and arterial and venous catheters were implanted to measure mean arterial pressure (MAP) and heart rate 24 h/day and for intravenous infusions. After recovery from surgery for 8 days, rats were injected with streptozotocin (STZ), and 5 days later, either saline or the melanocortin 3 and 4 receptor (MC3/4R) antagonist SHU-9119 (1 nmol/h) was infused intracerebroventricularly for 17 days. Seven days after starting the antagonist, leptin (0.62 microg/h) was added to the intracerebroventricular infusion for 10 days. Another group of diabetic rats was infused with the MC3/4R agonist MTII (10 ng/h i.c.v.) for 12 days, followed by 7 days at 50 ng/h.

Results: Induction of diabetes caused hyperphagia, hyperglycemia, and decreases in heart rate (-76 bpm) and MAP (-7 mmHg). Leptin restored appetite, blood glucose, heart rate, and MAP back to pre-diabetic values in vehicle-treated rats, whereas it had no effect in SHU-9119-treated rats. MTII infusions transiently reduced blood glucose and raised heart rate and MAP, which returned to diabetic values 5-7 days after starting the infusion.

Conclusions: Although a functional melanocortin system is necessary for the CNS-mediated antidiabetic and cardiovascular actions of leptin, chronic MC3/4R activation is apparently not sufficient to mimic these actions of leptin that may involve interactions of multiple pathways.

Show MeSH
Related in: MedlinePlus