Showing papers by "Harvey J. Grill published in 2008"

Caudal brainstem processing is sufficient for behavioral, sympathetic, and parasympathetic responses driven by peripheral and hindbrain glucagon-like-peptide-1 receptor stimulation.

Abstract: The effects of peripheral glucagon like peptide-1 receptor (GLP-1R) stimulation on feeding, gastric emptying, and energetic responses involve vagal transmission and central nervous system processing. Despite a lack of studies aimed at determining which central nervous system regions are critical for the GLP-1R response production, hypothalamic/forebrain processing is regarded as essential for these effects. Here the contribution of the caudal brainstem to the control of food intake, core temperature, heart rate, and gastric emptying responses generated by peripheral delivery of the GLP-1R agonist, exendin-4 (Ex-4), was assessed by comparing responses of chronic supracollicular decerebrate (CD) rats to those of pair-fed intact control rats. Responses driven by hindbrain intracerebroventricular (fourth icv) delivery of Ex-4 were also evaluated. Intraperitoneal Ex-4 (1.2 and 3.0 μg/kg) suppressed glucose intake in both CD rats (5.0 ± 1.2 and 4.4 ± 1.1 ml ingested) and controls (9.4 ± 1.5 and 7.7 ± 0.8 ml ing...

Divergent leptin signaling in proglucagon neurons of the nucleus of the solitary tract in mice and rats.

Abstract: The central targets mediating the anorectic and other actions of leptin have yet to be fully identified. Although previous studies focused on the hypothalamus, leptin also acts on neurons in extrahypothalamic sites, including the nucleus of the solitary tract (NTS). Moreover, injection of leptin into the NTS of rats suppresses food intake. Within the central nervous system, glucagon-like peptide (GLP-1), a product of proglucagon, is synthesized almost exclusively in neurons of the NTS. Intracerebroventricular administration of GLP-1 inhibits energy intake, and GLP-1 receptor antagonists attenuate the anorexic effects of leptin in rats. To examine whether NTS proglucagon neurons are directly regulated by leptin, we performed double GLP-1 and phosphorylation of signal transducer and activator of transcription-3 immunohistochemistry on brain sections from ip leptin-treated mice and rats. Leptin induced phosphorylation of signal transducer and activator of transcription-3 in 100% of GLP-1 cells in the caudal brainstem of mice. In striking contrast, 0% of GLP-1-positive neurons in rats responded to leptin. We then measured regulation of NTS proglucagon mRNA using real-time RT-PCR in mice and rats fed ad libitum, fasted, or fasted and treated ip with leptin. In mice, proglucagon mRNA fell by fasting, and this was prevented by leptin administration. In rats, by contrast, proglucagon mRNA was unaffected by either fasting or leptin. Taken together, our studies reveal direct regulation of proglucagon neurons by leptin in mice but not rats along with corresponding species differences in the regulation of proglucagon mRNA expression. These data, combined with previous results, suggest a different mechanism of interaction between leptin and NTS proglucagon neurons in mice and rats.

Energetic responses are triggered by caudal brainstem melanocortin receptor stimulation and mediated by local sympathetic effector circuits.

Abstract: The central melanocortin system is a critical contributor to energy balance control. Melanocortin receptors (MC-Rs) are widely distributed throughout forebrain and caudal brainstem nuclei. To assess the contribution of hindbrain MC-Rs to the control of energy expenditure, the MC3/4R agonist melanotan II (MTII) was delivered to either the fourth ventricle or medullary raphe of neurologically intact rats and chronic decerebrate (CD) rats, and interscapular brown adipose tissue (IBAT) temperature (T(IBAT)), core temperature (T(C)), heart rate (HR), and spontaneous activity were recorded. Fourth ventricular MTII (0.1, 1.0 nmol) significantly increased T(IBAT), T(C), and HR in intact rats (T(C): +0.33 +/- 0.08, +0.41 +/- 0.09 C; HR: +40.84 +/- 7.29, +69.04 +/- 6.83 beats per minute) and in CDs (T(C): +1.39 +/- 0.67, +1.52 +/- 0.37 C; HR: +83.21 +/- 19.2, +107.38 +/- 17.65 beats per minute). Response magnitude was greater in CD rats than in neurologically intact rats. T(IBAT), T(C), and HR were significantly increased after 10 pmol MTII delivery to the medullary raphe of intact rats, and here too, the response magnitude was greater in decerebrate rats. The hyperthermia, IBAT thermogenesis, and tachycardia observed in CD rats after fourth ventricular and hindbrain parenchymal MTII injections support the hypothesis that hindbrain MC-R stimulation engages endemic circuits that link sympathetic outflows to thermogenic and cardiac effectors, and that forebrain processing and forebrain-caudal brainstem communication are not required for response production.

Energetic responses to cold temperatures in rats lacking forebrain-caudal brain stem connections

Abstract: Hypothalamic neurons are regarded as essential for integrating thermal afferent information from skin and core and issuing commands to autonomic and behavioral effectors that maintain core temperature (Tc) during cold exposure and for the control of energy expenditure more generally. Caudal brain stem neurons are necessary elements of the hypothalamic effector pathway and also are directly driven by skin and brain cooling. To assess whether caudal brain stem processing of thermal afferent signals is sufficient to drive endemic effectors for thermogenesis, heart rate (HR), Tc, and activity responses of chronic decerebrate (CD) and control rats adapted to 23°C were compared during cold exposure (4, 8, or 12°C) for 6 h. Other CDs and controls were exposed to 4 or 23°C for 2 h, and tissues were processed for norepinephrine turnover (NETO), a neurochemical measure of sympathetic drive. Controls maintained Tc for all temperatures. CDs maintained Tc for the 8 and 12°C exposures, but Tc declined 2°C during the 4°C exposure. Cold exposure elevated HR in CDs and controls alike. Tachycardia magnitude correlated with decreases in environmental temperature for controls, but not CDs. Cold increased NETO in brown adipose tissue, heart, and some white adipose tissue pads in CDs and controls compared with their respective room temperature controls. These data demonstrate that, in neural isolation from the hypothalamus, cold exposure drives caudal brain stem neuronal activity and engages local effectors that trigger sympathetic energetic and cardiac responses that are comparable in many, but not in all, respects to those seen in neurologically intact rats.