The effect of estrogen on brown adipose tissue activity in male rats.

OBJECTIVE: Centrally administered estrogen can increase sympathetic nerve activity to brown adipose tissue, resulting in thermogenesis. The central thermogenic effects of estrogen have not been investigated in males. Therefore, this study sought to investigate the effects of peripherally and centrally administered estrogen on thermogenesis, heart rate and mean arterial pressure in male rats. Thermogenesis was assessed by monitoring brown adipose tissue temperature. RESULTS: Peripherally administered estrogen elicited no significant effect on brown adipose tissue temperature, heart rate or mean arterial pressure. Centrally administered estrogen elicited a coincident increase in both brown adipose tissue and core temperature. Centrally administered estrogen also resulted in a decrease in mean arterial pressure but had no effect on heart rate. With the present data it is not possible to elucidate whether changes in temperature were the result of thermogenic or thermoregulatory mechanisms.

Stimulatory, but not anxiogenic, doses of caffeine act centrally to activate interscapular brown adipose tissue thermogenesis in anesthetized male rats.

The role of central orexin in the sympathetic control of interscapular brown adipose tissue (iBAT) thermogenesis has been established in rodents. Stimulatory doses of caffeine activate orexin positive neurons in the lateral hypothalamus, a region of the brain implicated in stimulating BAT thermogenesis. This study tests the hypothesis that central administration of caffeine is sufficient to activate BAT. Low doses of caffeine administered either systemically (intravenous [IV]; 10 mg/kg) and centrally (intracerebroventricular [ICV]; 5-10 µg) increases BAT thermogenesis, in anaesthetised (1.5 g/kg urethane, IV) free breathing male rats. Cardiovascular function was monitored via an indwelling intra-arterial cannula and exhibited no response to the caffeine. Core temperature did not significantly differ after administration of caffeine via either route of administration. Caffeine administered both IV and ICV increased neuronal activity, as measured by c-Fos-immunoreactivity within subregions of the hypothalamic area, previously implicated in regulating BAT thermogenesis. Significantly, there appears to be no neural anxiety response to the low dose of caffeine as indicated by no change in activity in the basolateral amygdala. Having measured the physiological correlate of thermogenesis (heat production) we have not measured indirect molecular correlates of BAT activation. Nevertheless, our results demonstrate that caffeine, at stimulatory doses, acting via the central nervous system can increase thermogenesis, without adverse cardio-dynamic impact.

Central resistin enhances renal sympathetic nerve activity via phosphatidylinositol 3-kinase but reduces the activity to brown adipose tissue via extracellular signal-regulated kinase 1/2.

Resistin is an adipokine, originally identified in adipose tissue, and its plasma levels are elevated in obesity. Characteristics of obesity include impaired metabolic regulation and cardiovascular dysfunction, such as increased sympathetic nerve activity (SNA) to the kidney and skeletal muscle vasculature. Resistin can affect energy homeostasis through central mechanisms that include reduced food intake and reduced thermogenesis, and can also increase lumbar SNA via a central action. The present study investigated: (i) the effect of centrally-administered resistin on SNA targeting the kidney and (ii) the intracellular signalling pathways mediating the changes in SNA innervating the kidney and brown adipose tissue (BAT) induced by resistin. Intracerebroventricular resistin (7 µg) injected into overnight fasted, anaesthetised rats induced a significant increase in renal SNA by approximately 40%. This response was prevented when phosphatidylinositol 3-kinase (PI3K) was inhibited by i.c.v. administration of LY294002 (5 µg). Resistin reduced BAT SNA and this response was delayed by 150 min when extracellular-regulated kinase (ERK)1/2 was inhibited by i.c.v. administration of U0126. The findings indicate that resistin increases renal SNA via PI3K and reduces BAT SNA via ERK1/2.

Centrally administered resistin enhances sympathetic nerve activity to the hindlimb but attenuates the activity to brown adipose tissue.

Resistin, an adipokine, is believed to act in the brain to influence energy homeostasis. Plasma resistin levels are elevated in obesity and are associated with metabolic and cardiovascular disease. Increased muscle sympathetic nerve activity (SNA) is a characteristic of obesity, a risk factor for diabetes and cardiovascular disease. We hypothesized that resistin affects SNA, which contributes to metabolic and cardiovascular dysfunction. Here we investigated the effects of centrally administered resistin on SNA to muscle (lumbar) and brown adipose tissue (BAT), outputs that influence cardiovascular and energy homeostasis. Overnight-fasted rats were anesthetized, and resistin (7 µg) was administered into the lateral cerebral ventricle (intracerebroventricular). The lumbar sympathetic nerve trunk or sympathetic nerves supplying BAT were dissected free, and nerve activity was recorded. Arterial blood pressure, heart rate, body core temperature, and BAT temperature were also recorded. Responses to resistin or vehicle were monitored for 4 h after intracerebroventricular administration. Acutely administered resistin increased lumbar SNA but decreased BAT SNA. Mean arterial pressure and heart rate, however, were not significantly affected by resistin. BAT temperature was significantly reduced by resistin, and there was a concomitant fall in body temperature. The findings indicate that resistin has differential effects on SNA to tissues involved in metabolic and cardiovascular regulation. The decreased BAT SNA and the increased lumbar SNA elicited by resistin suggest that it may contribute to the increased muscle SNA and reduced energy expenditure observed in obesity and diabetes.

Cold-activated raphé-spinal neurons in rats.

1. In a search for sympathetic premotor neurons subserving thermoregulatory functions, medullary raphé-spinal neurons were studied in urethane-anaesthetized, artificially ventilated, paralysed rats. Extracellular unit recordings were made from a region previously shown to drive the sympathetic supplies to tail vessels and brown adipose tissue. Neurons that were antidromically activated by stimulation across the intermediate region of the upper lumbar cord (the origin of the tail sympathetic outflow) were selected for study. 2. Non-noxious cooling stimuli were delivered to the animal's shaved trunk by circulating cold instead of warm water through a water jacket. Cooling increased the activity of 21 out of 76 raphé-spinal neurons by 1.0 +/- 0.2 spikes x s(-1) degrees C(-1) for falls in skin temperature of 3-5 degrees C below a threshold of 35.0 +/- 0.6 degrees C. Their responses followed skin temperature in a graded manner, and did so whether or not there was any change in core (rectal) temperature. 3. Indirect observations suggested that seven of the neurons that were activated by skin cooling were also activated by falls in core temperature (by 2.1 +/- 0.7 spikes x s(-1) x degrees C(-1) below a threshold of 36.1 +/- 0.7 degrees C), while the remainder were unaffected by core cooling. 4. An additional 7/76 raphé-spinal neurons showed evidence of inhibition (activity reduced by 2.1 +/- 0.5 spikes x s(-1) x degrees C(-1)) when the trunk skin was cooled. 5. Cold-activated raphé-spinal neurons were found in the nuclei raphé magnus and pallidus, centred at the level of the caudal part of the facial nucleus. Their spinal axons conducted at velocities between 3.4 and 29 m x s(-1) (median 6.8). 6. Drug-induced rises in arterial pressure partially inhibited the discharge of 6/14 cold-activated raphé-spinal neurons. Weak-to-moderate cardiac modulation (10-70 %) was present in arterial pulse-triggered histograms of the activity of 11/21 cold-activated raphé-spinal neurons, and 6/6 showed evidence of ventilatory modulation (two strongly, four weakly) in pump-triggered histograms. 7. Raphé-spinal neurons responded to cooling in the absence of any change in the electroencephalogram pattern (6/6 neurons). 8. Most cold-activated raphé-spinal neurons responded to noxious tail pinch (13/21 inhibited, 6/21 excited), as did most thermally unresponsive raphé-spinal cells in the same region (19/41 excited, 9/41 inhibited). 9. It is suggested that these cold-activated raphé-spinal neurons may constitute a premotor pathway that drives sympathetically mediated cold defences, such as cutaneous vasoconstriction or thermogenesis. The data are consistent with the hypothesis that a brainstem reflex, with additional descending input signalling body core temperature, may mediate autonomic responses to environmental cooling.

Differential control of sympathetic drive to the rat tail artery and kidney by medullary premotor cell groups.

Sympathetic activity was recorded from the renal nerve and the ventral tail artery of anesthetized rats while neurons in three sympathetic premotor groups, the rostroventrolateral medulla (RVLM), rostroventromedial medulla (RVMM) and medullary raphe, were activated by microinjections of sodium glutamate (1-15 nl, 50 mM). RVLM activation increased renal nerve activity by 27+/-3% but caused small, inconsistent effects on the tail outflow (+15+/-10%). Raphe neuron stimulation had little effect on the renal nerve (+8+/-3%), but strongly increased tail sympathetic unit activity (+125+/-28%). RVMM neurons had little effect on either outflow. These results indicate that different premotor cell groups have different sympathetic actions.

The lumbar preganglionic sympathetic supply to rat tail and hindpaw.

The segmental origins of the preganglionic sympathetic neurons which control the circulation of the rat tail were investigated and compared with those that supply the hindpaw. The left ventral roots of the first, second and sometimes the third lumbar segments were stimulated with 2-min pulse trains in 10 male Sprague-Dawley rats, which were anaesthetised with urethane (1-1.5 g/kg i.v.) and paralysed with pancuronium. Rats were warmed to increase cutaneous blood flow, and vasoconstrictor responses were detected by thermocouples as stimulus-locked falls in skin temperature. Stimulating the L2 ventral root always vasoconstricted the tail: in 50% of the rats, it also vasoconstricted the ipsilateral hindpaw, while in 50%, it did not. Stimulating the L1 ventral root always vasoconstricted both tail and hindpaw. Stimulating the L3 ventral root caused no measurable effect. Electrodermal potentials were recorded from the ipsilateral hindpaw pad in 7 rats: these accompanied hindpaw vasoconstrictor responses but were not seen otherwise. We conclude that at least in 50% of rats, the preganglionic neurons supplying hindpaw and tail skin are not clearly segregated by spinal segment. Sweat glands and blood vessels in the hindpaw are supplied by the same segments.