Michael L. Mathai

The brain renin-angiotensin system: location and physiological roles

Angiotensinogen, the precursor molecule for angiotensins I, II and III, and the enzymes renin, angiotensin-converting enzyme (ACE), and aminopeptidases A and N may all be synthesised within the brain. Angiotensin (Ang) AT(1), AT(2) and AT(4) receptors are also plentiful in the brain. AT(1) receptors are found in several brain regions, such as the hypothalamic paraventricular and supraoptic nuclei, the lamina terminalis, lateral parabrachial nucleus, ventrolateral medulla and nucleus of the solitary tract (NTS), which are known to have roles in the regulation of the cardiovascular system and/or body fluid and electrolyte balance. Immunohistochemical and neuropharmacological studies suggest that angiotensinergic neural pathways utilise Ang II and/or Ang III as a neurotransmitter or neuromodulator in the aforementioned brain regions. Angiotensinogen is synthesised predominantly in astrocytes, but the processes by which Ang II is generated or incorporated in neurons for utilisation as a neurotransmitter is unknown. Centrally administered AT(1) receptor antagonists or angiotensinogen antisense oligonucleotides inhibit sympathetic activity and reduce arterial blood pressure in certain physiological or pathophysiological conditions, as well as disrupting water drinking and sodium appetite, vasopressin secretion, sodium excretion, renin release and thermoregulation. The AT(4) receptor is identical to insulin-regulated aminopeptidase (IRAP) and plays a role in memory mechanisms. In conclusion, angiotensinergic neural pathways and angiotensin peptides are important in neural function and may have important homeostatic roles, particularly related to cardiovascular function, osmoregulation and thermoregulation.

Vasopressin secretion: osmotic and hormonal regulation by the lamina terminalis.

The lamina terminalis, located in the anterior wall of the third ventricle, is comprised of the subfornical organ, median preoptic nucleus (MnPO) and organum vasculosum of the lamina terminalis (OVLT). The subfornical organ and OVLT are two of the brains circumventricular organs that lack the blood–brain barrier, and are therefore exposed to the ionic and hormonal environment of the systemic circulation. Previous investigations in sheep and rats show that this region of the brain has a crucial role in osmoregulatory vasopressin secretion and thirst. The effects of lesions of the lamina terminalis, studies of immediate–early gene expression and electrophysiological data show that all three regions of the lamina terminalis are involved in osmoregulation. There is considerable evidence that physiological osmoreceptors subserving vasopressin release are located in the dorsal cap region of the OVLT and possibly also around the periphery of the subfornical organ and in the MnPO. The circulating peptide hormones angiotensin II and relaxin also have access to peptide specific receptors (AT1 and LGR7 receptors, respectively) in the subfornical organ and OVLT, and both angiotensin II and relaxin act on the subfornical organ to stimulate water drinking in the rat. Studies that combined neuroanatomical tracing and detection of c‐fos expression in response to angiotensin II or relaxin suggest that both of these circulating peptides act on neurones within the dorsal cap of the OVLT and the periphery of the subfornical organ to stimulate vasopressin release.

Green tea, black tea, and epigallocatechin modify body composition, improve glucose tolerance, and differentially alter metabolic gene expression in rats fed a high-fat diet

The mechanisms of how tea and epigallocatechin-3-gallate (EGCG) lower body fat are not completely understood. This study investigated long-term administration of green tea (GT), black tea (BT), or isolated EGCG (1 mg/kg per day) on body composition, glucose tolerance, and gene expression related to energy metabolism and lipid homeostasis; it was hypothesized that all treatments would improve the indicators of metabolic syndrome. Rats were fed a 15% fat diet for 6 months from 4 weeks of age and were supplied GT, BT, EGCG, or water. GT and BT reduced body fat, whereas GT and EGCG increased lean mass. At 16 weeks GT, BT, and EGCG improved glucose tolerance. In the liver, GT and BT increased the expression of genes involved in fatty acid synthesis (SREBP-1c, FAS, MCD, ACC) and oxidation (PPAR-alpha, CPT-1, ACO); however, EGCG had no effect. In perirenal fat, genes that mediate adipocyte differentiation were suppressed by GT (Pref-1, C/EBP-beta, and PPAR-gamma) and BT (C/EBP-beta), while decreasing LPL, HSL, and UCP-2 expression; EGCG increased expression of UCP-2 and PPAR-gamma genes. Liver triacylglycerol content was unchanged. The results suggest that GT and BT suppressed adipocyte differentiation and fatty acid uptake into adipose tissue, while increasing fat synthesis and oxidation by the liver, without inducing hepatic fat accumulation. In contrast, EGCG increased markers of thermogenesis and differentiation in adipose tissue, while having no effect on liver or muscle tissues at this dose. These results show novel and separate mechanisms by which tea and EGCG may improve glucose tolerance and support a role for these compounds in obesity prevention.

The lamina terminalis and its role in fluid and electrolyte homeostasis.

The lamina terminalis, which forms most of the anterior wall of the third ventricle, consists of the median preoptic nucleus and two circumventricular organs (CVOs), the subfornical organ and organum vasculosum of the lamina terminalis. These latter two regions lack a blood-brain barrier and, unlike other regions of the brain, are influenced by the hormonal and ionic composition of the blood. The CVOs of the lamina terminalis are rich in receptors for a number of circulating peptides and the subfornical organ and the OVLT are clearly established as the prime cerebral targets for circulating angiotensin II, atrial natriuretic peptide (AVP) and relaxin to influence central nervous system pathways regulating body fluid homeostasis. Together with the median preoptic nucleus, these two CVOs also detect changes and relay neural signals relating to the tonicity of body fluids and play important roles in osmoregulatory fluid intake and excretion. The neural circuitry of the lamina terminalis involves both afferent and efferent connections to several other regions of the brain, and neurons within the individual components of lamina terminalis are reciprocally connected with each other. This neural circuitry subserves the influence that the lamina terminalis exerts on vasopressin secretion, thirst, the appetite for salt, renal sodium excretion and renin secretion by the kidney. Copyright 1999 Harcourt Publishers Ltd.

Physiological and pathophysiological influences on thirst.

Thirst motivates animals to seek fluid and drink it. It is regulated by the central nervous system and arises from neural and chemical signals from the periphery interacting in the brain to stimulate a drive to drink. Our research has focussed on the lamina terminalis and the manner in which osmotic and hormonal stimuli from the circulation are detected by neurons in this region and how that information is integrated with other neural signals to generate thirst. Our studies of osmoregulatory drinking in the sheep and rat have produced evidence that osmoreceptors for thirst exist in the dorsal cap of the organum vasculosum of the lamina terminalis (OVLT) and in the periphery of the subfornical organ, and possibly also in the median preoptic nucleus. In the rat, the hormones angiotensin II and relaxin act on neurons in the periphery of the subfornical organ to stimulate drinking. Studies of human thirst using functional magnetic resonance imaging (fMRI) techniques show that systemic hypertonicity activates the lamina terminalis and the anterior cingulate cortex, but the neural circuitry that connects sensors in the lamina terminalis to cortical regions subserving thirst remains to be determined. Regarding pathophysiological influences on thirst mechanisms, both excessive (polydipsia) and inadequate (hypodisia) water intake may have dire consequences. One of the most common primary polydipsias is that observed in some cases of schizophrenia. The neural mechanisms causing the excessive water intake in this disorder are unknown, so too are the factors that result in impaired thirst and inadequate fluid intake in some elderly humans.

Effect of individual or combined ablation of the nuclear groups of the lamina terminalis on water drinking in sheep

The subfornical organ (SFO), organum vasculosum of the lamina terminalis (OVLT), and median preoptic nucleus (MnPO) were ablated either individually or in various combinations, and the effects on drinking induced by either intravenous infusion of hypertonic 4 M NaCl (1.3 ml/min for 30 min) or water deprivation for 48 h were studied. Ablation of either the OVLT or SFO alone did not affect drinking in response to intravenous 4 M NaCl, although combined ablation of these two circumventricular organs substantially reduced but did not abolish such drinking. Ablation of the MnPO or MnPO and SFO together also substantially reduced, but did not abolish, drinking in response to intravenous hypertonic NaCl. Only near-total destruction of the lamina terminalis (OVLT, MnPO, and part or all of the SFO) abolished acute osmotically induced drinking. The large lesions also reduced drinking after water deprivation, whereas none of the other lesions significantly affected such drinking. None of these lesions altered feeding. The results show that all parts of the lamina terminalis play a role in the drinking induced by acute increases in plasma tonicity. The lamina terminalis appears to play a less crucial role in the drinking response after water deprivation than for the drinking response to acute intravenous infusion of hypertonic saline.The subfornical organ (SFO), organum vasculosum of the lamina terminalis (OVLT), and median preoptic nucleus (MnPO) were ablated either individually or in various combinations, and the effects on drinking induced by either intravenous infusion of hypertonic 4 M NaCl (1.3 ml/min for 30 min) or water deprivation for 48 h were studied. Ablation of either the OVLT or SFO alone did not affect drinking in response to intravenous 4 M NaCl, although combined ablation of these two circumventricular organs substantially reduced but did not abolish such drinking. Ablation of the MnPO or MnPO and SFO together also substantially reduced, but did not abolish, drinking in response to intravenous hypertonic NaCl. Only near-total destruction of the lamina terminalis (OVLT, MnPO, and part or all of the SFO) abolished acute osmotically induced drinking. The large lesions also reduced drinking after water deprivation, whereas none of the other lesions significantly affected such drinking. None of these lesions altered feeding. The results show that all parts of the lamina terminalis play a role in the drinking induced by acute increases in plasma tonicity. The lamina terminalis appears to play a less crucial role in the drinking response after water deprivation than for the drinking response to acute intravenous infusion of hypertonic saline.

Angiotensin converting enzyme inhibition from birth reduces body weight and body fat in Sprague-Dawley rats.

In vitro studies have demonstrated that angiotensin II (ANG II) induces adipocyte hyperplasia and hypertrophy. The aim of the present study was to determine the effect of angiotensin-converting enzyme inhibition on body weight, adiposity and blood pressure in Sprague-Dawley rats. From birth half of the animals (n=15) were given water to drink, while the remainder were administered perindopril in their drinking water (2 mg/kg/day). Food intake, water intake and body weight were measured weekly. Blood pressure was measured by tail cuff plethysmography at 11-weeks. Body fat content and distribution were assessed using dual energy X-ray absorptiometry and Magnetic Resonance Imaging at 12 weeks. Animals administered with perindopril had a body fat proportion that was half that of controls. This was consistent with, but disproportionately greater than the observed differences in food intake and body weight. Perindopril treatment completely removed hypertension. We conclude that the chronic inhibition of ANG II synthesis from birth specifically reduces the development of adiposity in the rat.

The cannabinoid receptor 1 and its role in influencing peripheral metabolism

Evidence from in vitro and in vivo studies has demonstrated the deleterious pathological effects of a dysregulated endocannabinoid system. Increased stimulation of the cannabinoid receptor 1 (CB1) and subsequent downstream cellular signalling are both causative in the deleterious pathological effects observed in a number of diseases. When the CB1 cell signalling cascade is blocked, this results in whole body weight‐loss, leading to a reduction in obesity and associated co‐morbidities. In the central nervous system; however, CB1 antagonism results in adverse psychological side effects. Blockade of CB1 via peripheral acting compounds that do not cross the blood–brain barrier have been determined to have beneficial effects in metabolic tissues such as the liver and skeletal muscle. These results support the notion that peripheral blockade of CB1 using pharmacological antagonists is a viable target for the treatment of the current epidemic of obesity and its associated co‐morbidities.

Neural Mechanisms Subserving Central Angiotensinergic Influences on Plasma Renin in Sheep

Abstract—The mechanisms and brain regions subserving the suppression of plasma renin concentration caused by intracerebroventricular (ICV) infusion of angiotensin II were studied in sodium-depleted sheep. Infusion of angiotensin II (3 &mgr;g/h for 1 hour) into the lateral ventricle reduced plasma renin from 4.3±0.4 to 1.6±0.2 pmol angiotensin I/mL per hour at 1 hour after the commencement of infusion. This change persisted for at least another 90 minutes and was blocked by concomitant ICV infusion of the AT1 antagonist losartan (1 mg/h). Arterial pressure did not change, but plasma vasopressin secretion was increased. ICV infusion of losartan (1 mg/h) significantly increased plasma renin in sodium-depleted sheep. The reduction of plasma renin concentration in response to either ICV angiotensin II or hypertonic NaCl (0.75 mol/L at 1 mL/h) and the increase in response to ICV losartan was prevented in sheep in which the lamina terminalis of the brain had been ablated. Lesions in the median eminence (MEL), which blocked the increased plasma vasopressin levels, did not prevent suppression of plasma renin in response to ICV angiotensin II. However, bilateral renal denervation largely blocked this inhibition of plasma renin concentration but not the increased plasma renin resulting from ICV infusion of losartan in sodium-depleted sheep. The results show that AT1 receptors, probably located in the lamina terminalis, mediate a central inhibitory influence of angiotensin II on renin secretion. This inhibition of renin release is probably due to a reduction in activity of renal sympathetic nerves innervating the juxtaglomerular apparatus of the kidney.

A potential role for GPR55 in the regulation of energy homeostasis

G protein-coupled receptor 55 (GPR55) is a putative cannabinoid receptor that is expressed in several tissues involved in regulating energy homeostasis, including the hypothalamus, gastrointestinal tract, pancreas, liver, white adipose and skeletal muscle. GPR55 has been shown to have a role in cancer and gastrointestinal inflammation, as well as in obesity and type 2 diabetes mellitus (T2DM). Despite this, the (patho)physiological role of GPR55 in cell dysfunction is still poorly understood, largely because of the limited identification of downstream signalling targets. Nonetheless, research has suggested that GPR55 modulation would be a useful pharmacological target in metabolically active tissues to improve treatment of diseases such as obesity and T2DM. Further research is essential to gain a better understanding of the role that this receptor might have in these and other pathophysiological conditions.