JoséA. Menéndez

Metabolic effects of neuropeptide Y injections into the paraventricular nucleus of the hypothalamus

The metabolic effects of single injections of neuropeptide Y (NPY) into the paraventricular hypothalamus were investigated in an open-circuit calorimeter. Wistar rats were tested, with no food available during the tests. Over the dose range of 10-156 pmol NPY had large effects on respiratory quotient (RQ) while having no effect on energy expenditure or locomotor activity. The effects of NPY on RQ were unusual both in respect to their dose-response and time-dose-response characteristics. The lowest dose (10 pmol) produced a very low latency reduction in RQ which indicates a decreased utilization of carbohydrates as an energy substrate. The next higher dose (20 pmol) had no effect, whereas the next three doses (39, 78 and 156 pmol) produced increases in RQ which indicate an increased utilization of carbohydrates as an energy substrate. Surprisingly, the latencies of the increased RQs were dose-dependent over the range of 30 min to 20 h with the highest dose producing the longest latency effect. The finding of a positive relation of dose to response latency over a time range of from a few minutes to 20 h is unprecedented and appears to represent a neuromodulatory effect of NPY that acts in concert with its neurotransmitter effects. These data highlight the central role of NPY in modulating energy substrate utilization and indicate the importance of elucidating time-dose-response relationships when investigating the effects of NPY.

Insulin and the paraventricular hypothalamus: modulation of energy balance

The effects of insulin injections (0.1, 1, 10 and 40 mU) into the paraventricular hypothalamus (PVN) were investigated in an open-circuit calorimeter. Wistar rats were tested, with no food available during the tests. The 0.1 and 1 mU doses had no effects on either respiratory quotient or energy expenditure. The 10 mU dose increased respiratory quotient which indicates increased dependency on carbohydrates as an energy substrate. The same dose had no effects on thermogenesis. In contrast, the 40 mU dose decreased respiratory quotient which indicates increased dependency on fats as an energy substrate. The higher dose also increased thermogenesis. Since neither dose significantly affected locomotor activity, the metabolic data are not confounded with activity effects. These data indicate that insulin in the PVN produces a primary modulation of the metabolic parameters central to maintaining energy balance. In separate experiments, the 4 doses of insulin reduced food intake and body weight over a 24 h period. They also produced a dose-related increase in blood glucose concentration over a one hour period. Taken together, these findings are interpreted in a model in which insulin in the PVN acts as a signal indicating increased body fat. This increases thermogenesis, fat utilization and glycemic levels, and inhibits feeding. The net effect of this integrated metabolic-behavioural response is a regulatory reduction in body fat.

Metabolic effects of galanin injections into the paraventricular nucleus of the hypothalamus

The metabolic effects of single injections of galanin into the paraventricular nucleus of the hypothalamus (PVN) were investigated in an open-circuit calorimeter. Wistar rats were tested, with no food available during the tests. In the dose range of 0.03-0.3 nmol, galanin produced a very short-latency (approximately 2 minutes) and short-lasting (approximately 15 minutes) reduction in energy expenditure. Since the same doses had no effect on respiratory quotient or locomotor activity, the metabolic effect is not secondary to changes in energy substrate utilization or locomotor activity. This antithermogenic effect complements the eating stimulatory action of PVN galanin, and together these phenomena suggest a role for galanin as an anabolic neuropeptide. The similarity of galanins effects to those of norepinephrine, with which it coexists in PVN nerve endings, further suggests the involvement of this amine and the PVN alpha2-noradrenergic system in galanins mechanism of action.

Metabolic effects of neuropeptide Y injected into the sulcal prefrontal cortex

The metabolic effects of 10, 39 and 156 pmol doses of neuropeptide Y (NPY) injected into the sulcal prefrontal cortex (SPC) were investigated in an open-circuit calorimeter. The 39 pmol dose produced a large and long lasting increase in respiratory quotient indicating both increased utilization of carbohydrate as an energy substrate and the synthesis of fat from carbohydrate. The 10 and 39 pmol doses produced an inhibition of energy expenditure that was still evident 24 hours following the 10, but not the 39 pmol, dose. These energy expenditure effects appeared to reflect an inhibition of thermogenesis as they were not systematically related to changes in locomotor activity. In separate tests, 39 pmol NPY reliably enhanced food intake. This combination of effects, namely increased carbohydrate utilization, fat synthesis and food intake with reduced energy expenditure, shows NPY to be a potent anabolic force. In addition, these results indicate both the functional significance of NPY at a cortical level and the important role of the SPC in the control of energy balance.

Insulin increases energy expenditure and respiratory quotient in the rat

The effects of insulin on energy expenditure are a matter of dispute. Various authors have reported increases or decreases. Irrespective of their nature, it is not clear whether the effects of insulin on energy expenditure are secondary to insulin-induced hypoglycemia or changes in motor activity. The present study investigated the acute effects of insulin on energy expenditure, energy substrate utilisation, motor activity and blood glucose levels. Four U/kg of fast acting insulin had no effect on any of the metabolic or motor activity measures in spite of producing a 30% reduction in blood glucose levels. In contrast, 8 U/kg of insulin increased energy expenditure and respiratory quotient, with the latter effect indicating increased reliance on carbohydrates as a source of energy. This dose reduced blood glucose levels by 68%, yet had no significant effect on motor activity. Insulin, therefore, enhances thermogenesis and carbohydrate utilisation in a manner that can be dissociated from any effect on motor activity. These effects occur at a high dose and they are not counteracted by even massive hypoglycemia. It, therefore, appears that in terms of energy expenditure insulin may be characterised as catabolic, whereas in terms of substrate utilisation it may be characterised as anabolic.

Metabolic effects obtained from excitatory amino acid stimulation of the sulcal prefrontal cortex

Indirect calorimetry was used to assess metabolic changes in rats following injections of the excitatory amino acid D,L-homocysteic acid (DLH) into the sulcal or medial prefrontal cortex. Injection of 7 nmol of DLH into the sulcal prefrontal cortex (SPC) increased respiratory quotient (RQ), indicating increased utilization of carbohydrate as an energy substrate. This treatment also decreased energy expenditure in the absence of related changes in motor activity, suggesting an inhibition of thermogenesis. A larger dose of DLH (50 nmol) injected into the SPC caused opposite effects, with a significant decrease in RQ and increased energy expenditure and motor activity. Rectal temperature was also increased by 20 or 50 nmol DLH but decreased with 7 nmol DLH. The anatomical specificity of these effects was indicated in that equivalent injections DLH into the medial prefrontal cortex did not affect energy balance. From this and related evidence it is concluded that SPC neurons exert a potent influence upon thermogenesis and metabolic substrate utilization that is bidirectional according to the magnitude of the excitatory stimulation that is applied.

Prefrontal cortex α2 adrenoceptors and energy balance

Abstract The sulcal prefrontal cortex (SPC) influences thermogenesis, energy substrate utilization and feeding behaviour. The present study examined the role of SPC α noradrenergic receptors in these effects. Fifty nmol norepinephrine (NE) injected into the SPC produced a large and long-lasting increase in respiratory quotient (RQ), indicating enhanced carbohydrate utilization and fat synthesis. This dose also reduced energy expenditure without corresponding decreases in locomotor activity, suggesting an inhibition of thermogenesis. Neither a lower dose of NE (25 nmol) injected into the SPC, nor injections of NE (50 nmol) into a variety of sites adjacent to the SPC affected energy balance. The α2 agonist clonidine (20 nmol) injected into the SPC produced similar effects to 50 nmol NE, with a large increase in RQ and a decrease in thermogenesis. Forty nmol clonidine, however, decreased RQ and reduced both energy expenditure and activity. The α1 agonist L-phenylephrine (20 and 40 nmol) injected into the SPC had no clear effect on energy balance. Finally, it was shown that clonidine or NE injected into the SPC promotes food intake. These results implicate α2 adrenoceptors in the sulcal prefrontal cortex in the control of food intake, thermogenesis and metabolic substrate utilization.

Effects of ethanol and tertiary butanol on blood glucose levels and body temperature of rats.

The mechanisms of ethanols hyperglycemic and hypothermic effects were investigated by comparing the effects of ethanol with those of tertiary butanol. Tertiary butanol is an intoxicant like ethanol, but unlike ethanol it is only minimally metabolized. Consequently, tertiary butanol does not produce appreciable amounts of active metabolites or energy. Tertiary butanol exerts its neural effects primarily by directly altering the physico-chemical properties of nerve cell membranes. It was found that ethanol and tertiary butanol produce hyperglycemic and hypothermic effects whose magnitude and time course are nearly identical. These data suggest that the hyperglycemic and hypothermic effects of ethanol represent a primary physico-chemical effect on nerve cell membranes and are not secondary to its energy content or metabolites.

The intrinsic and interactive effects of RO 15-4513 and ethanol on locomotor activity, body temperature, and blood glucose concentration

The ability of the putative ethanol antagonist RO 15-4513 to antagonize ethanol - induced hypoactivity, hypothermia and hyperglycemia was investigated in rats. Although RO 15-4513 produced hypoactivity by itself, it attenuated ethanol - induced hypoactivity. This antagonism suggests that ethanol - induced hypoactivity is mediated by the GABA-benzodiazepine receptor complex which is thought to be the site of action of RO 15-4513. In contrast, although RO 15-4513 produced hypothermia by itself, it had no significant effect on ethanol - induced hypothermia. This suggests that the hypothermic effect of ethanol is not mediated by the GABA-benzodiazepine receptor complex. The fact that RO 15-4513, ethanol and the vehicle all produced hyperglycemia suggests a common stress effect and does not permit any firm conclusions to be drawn as to the interaction between ethanol and RO 15-4513 in modulating glycemic responses. These data indicate that the ethanol antagonism of RO 15-4513 is primarily confined to ethanols behavioural effects and that ethanols behavioural and physiological effects are mediated by neurochemically distinct mechanisms.

Influence of different concentrations of ethanol on energy expenditure, substrate utilisation, and activity in the rat

The acute (one hour) effects of intraperitoneal injections of four concentrations (10%, 30%, 45% and 60%) of a single dose (0.5 g/kg) of ethanol were investigated in unanesthetised rats in an open-circuit calorimeter. Ethanol increased energy expenditure, with the greatest effect being produced by the two lowest concentrations. In contrast, ethanol decreased respiratory quotient, with the greatest effect being produced by the two highest concentrations. The decreased respiratory quotients indicate that ethanol promotes an exclusive reliance on lipids as a source of energy, and further causes lipids to be catabolised for the synthesis of glucose. The peak metabolic effects were produced at a dose that did not significantly affect motor activity, which indicates that the metabolic effects are not secondary to changes in activity. These data support the view that ethanols effects on energy expenditure and substrate utilisation are mediated by distinct mechanisms. Moreover, since the different metabolic effects were produced by the same ethanol dose, they cannot be due to ethanols energy content. Thus, ethanol concentration is a major modulator of its effects on energy expenditure and substrate utilisation quite apart from effects due to dose, motor activity or its energy content. This suggests the need to consider the effects of ethanol concentration when analysing ethanols other pharmacological effects.