T. D. Williams

Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons

Glucagon-like peptide-1 (GLP-1) released from the gut functions as an incretin that stimulates insulin secretion. GLP-1 is also a brain neuropeptide that controls feeding and drinking behavior and gastric emptying and elicits neuroendocrine responses including development of conditioned taste aversion. Although GLP-1 receptor (GLP-1R) agonists are under development for the treatment of diabetes, GLP-1 administration may increase blood pressure and heart rate in vivo. We report here that centrally and peripherally administered GLP-1R agonists dose-dependently increased blood pressure and heart rate. GLP-1R activation induced c-fos expression in the adrenal medulla and neurons in autonomic control sites in the rat brain, including medullary catecholamine neurons providing input to sympathetic preganglionic neurons. Furthermore, GLP-1R agonists rapidly activated tyrosine hydroxylase transcription in brainstem catecholamine neurons. These findings suggest that the central GLP-1 system represents a regulator of sympathetic outflow leading to downstream activation of cardiovascular responses in vivo.

Diet-induced obesity and cardiovascular regulation in C57BL/6J mice.

1. In the present study, we determined the effect of diet‐induced obesity on cardiovascular and metabolic regulation in mice at standard laboratory temperatures (ambient temperature (Ta) = 22°C) and during exposure to thermoneutrality (Ta = 30°C).

Central Leptin Infusion Attenuates the Cardiovascular and Metabolic Effects of Fasting in Rats

The role of reduced leptin signaling in the regulation of cardiovascular responses to negative energy balance is not known. We tested the hypothesis that central infusion of leptin would attenuate the cardiovascular and metabolic responses to fasting. Male Sprague-Dawley rats, instrumented with telemetry devices and intracerebroventricular cannulas, were housed in metabolic chambers for continuous (24 hours) measurement of dark-phase (active) and light-phase (inactive) mean arterial pressure, heart rate, oxygen consumption, and respiratory quotient. Rats received central infusions of either saline (0.5 &mgr;L/h) or leptin (42 ng/h) for 6 days through osmotic pumps and were either fed ad libitum or were fasted for 48 hours followed by refeeding for 4 days. In ad lib animals, continuous intracerebroventricular leptin infusion significantly reduced caloric intake, body weight, and respiratory quotient compared with saline controls while having no effect on mean arterial pressure or heart rate. Fasting reduced mean arterial pressure, heart rate, oxygen consumption, and respiratory quotient in rats receiving saline infusions. Fasting-induced reductions in mean arterial pressure were specific to the active phase and were not attenuated by central leptin infusion. In contrast, intracerebroventricular leptin, at a dose that had no cardiovascular effects in ad lib control animals, completely prevented fasting-induced decreases in light-phase heart rate and oxygen consumption and blunted fasting-induced reductions in dark-phase heart rate and oxygen consumption. The results are consistent with the hypothesis that reductions in central leptin signaling contribute to the integrated cardiovascular and metabolic responses to acute caloric deprivation.

Cardiovascular and metabolic responses to fasting and thermoneutrality in Ay mice.

Several lines of evidence support a role for reduced melanocortin signaling in the regulation of metabolic rate and cardiovascular function during negative energy balance. We tested the hypothesis that agouti yellow (B6.Cg-A(y)) mice would exhibit blunted physiologic responses to fasting and thermoneutrality. Male B6.Cg-A(y) mice (A(y); n=11, 34+/-2 g) and lean B6 littermates (B6; n=7, 26+/-2 g) were implanted with telemetry devices and housed in metabolic chambers (T(a)=23 degrees C) to determine the effects of a 24-h fasting and exposure to thermoneutrality (T(a)=30 degrees C) on mean arterial pressure (MAP), heart rate (HR), AP and HR variability (time and frequency domain), oxygen consumption (VO(2)), and locomotor activity. A(y) mice exhibited elevated baseline light-period MAP (A(y): 113+/-4; B6: 99+/-3 mm Hg) and VO(2) (A(y): 1.82+/-0.08 vs. B6: 1.45+/-0.13 ml/min) with no difference in HR (A(y): 530+/-12 vs. B6: 548+/-19 bpm). At 12-24 h after food removal, A(y) mice displayed normal fasting-induced bradycardia (A(y): -106+/-12; B6: -117+/-19 bpm) and reduction in VO(2) (A(y): -0.19+/-0.04 vs. B6: -0.28+/-0.05 ml/min), but with augmented hypotension (A(y): -9+/-2 vs. B6: -0.5+/-2 mm Hg) and blunted hyperactivity (A(y): 27+/-23 vs. B6: 122+/-42 m/11 h). Fasting was associated with increased HR variability in both time and frequency domain in B6 but not A(y) mice. Exposure to thermoneutrality produced comparable reductions in MAP, HR, and VO(2) in both strains. We conclude that inhibition of melanocortin signaling is not requisite for, but participates in, the metabolic and cardiovascular responses to negative energy balance.