Endocannabinoids and the renal proximal tubule: an emerging role in diabetic nephropathy.

Diabetic nephropathy is a leading cause for the development of end-stage renal disease. In diabetes mellitus, a number of structural changes occur within the kidney which leads to a decline in renal function. Damage to the renal proximal tubule cells (PTCs) in diabetic nephropathy includes thickening of the basement membrane, tubular fibrosis, tubular lesions and hypertrophy. A clearer understanding of the molecular mechanisms involved in the development of diabetic kidney disease is essential for the understanding of the role cellular pathways play in its pathophysiology. The endocannabinoid system is an endogenous lipid signalling system which is involved in lipogenesis, adipogenesis, inflammation and glucose metabolism. Recent studies have demonstrated that in diabetic nephropathy, there is altered expression of the endocannabinoid system. Future investigations should clarify the role of the endocannabinoid system in the development of diabetic nephropathy and within this system, identify potential therapeutics to reduce the burden of this disease.

The cannabinoid receptor agonist THC attenuates weight loss in a rodent model of activity-based anorexia.

Anorexia nervosa (AN) is characterized by anhedonia whereby patients experience little pleasure or reward in many aspects of their lives. Reward pathways and the endocannabionid system have been implicated in the mediation of food intake. The potential to exploit these systems to reverse weight loss is investigated in a rodent model of activity-based anorexia (ABA). The effect of subchronic (6 days) Δ(9)-tetrahydrocannabinol (THC) treatment (0.1, 0.5, or 2.0 mg/kg/day) was assessed on chow and high-fat diet (HFD) intake, body weight, running wheel activity (RWA) as well as thermogenesis in brown adipose tissue (BAT) and lipid metabolism in white adipose tissue (WAT). Limited time availability of food and continuous access to running wheels led to anorexia and significantly reduced body weight. THC treatment (0.5 and 2.0 mg/kg/day) transiently stimulated chow intake with a moderate effect on RWA. THC (2.0 mg/kg/day) significantly reduced body weight loss and shifted markers of thermogenesis in BAT and lipid metabolism in WAT in directions consistent with reduced energy expenditure and lipolysis. THC (2.0 mg/kg/day) combined with HFD, produced a transient increase in food intake, reduction in RWA, attenuation of body weight loss, and changes in markers of thermogensis in BAT and lipolysis in the WAT. These changes were significantly greater than those seen in vehicle (HFD), vehicle (chow), and THC (chow)-treated animals. These data show for the first time the effectiveness of the endocannabinoid system in attenuating the weight loss associated with the development of ABA via a mechanism involving reduced energy expenditure.

The endogenous actions of hypothalamic peptides on brown adipose tissue thermogenesis in the rat.

Although the neuronal pathways within the hypothalamus critical in controlling feeding and energy expenditure and projecting to brown adipose tissue (BAT) have been identified and their peptidergic content characterized, endogenous action of such peptides in the control of BAT activity has not been elucidated. Here male Sprague Dawley rats received infusions of either melanin-concentrating hormone antagonist (SNAP-7941) (1 microg/microl x h), orexin A receptor antagonist (SB-334867-A; 1 microg/microl x h), combined SB-334867-A (1 microg/microl x h), and SNAP-7941 (1 microg/microl x h), or melanocortin-3/4 receptor antagonist (SHU9119) (1 microg/microl x h) via an indwelling cannula in the lateral ventricle attached to s.c. implanted osmotic minipump. BAT temperature, physical activity, body weight, food intake, and changes in uncoupling protein (UCP)-1 were measured. SB-334867-A and SNAP-7941 significantly increased BAT temperature and UCP1 expression and reduced food intake and body weight. Combined infusion of SB-334867-A and SNAP-7941 produced a pronounced response that was greater than the addition of the individual effects in all parameters measured. SHU9119 significantly decreased BAT temperature and UCP1 expression and increased feeding and body weight. In a second series of experiments, the effect of SB-334867-A and SNAP-7941 alone or combination on the expression of the Fos protein was determined. SB-334867-A and SNAP-7941 increased Fos expression in key hypothalamic and brainstem feeding-related regions. In combination, these antagonists produced a greater than additive elevation of Fos expression in most of the regions evaluated. These findings support a role for endogenous orexigenic and anorexigenic hypothalamic peptides acting in concert to create a thermogenic tone via BAT activity.

Involvement of hypothalamic peptides in the anorectic action of the CB receptor antagonist rimonabant (SR 141716).

Numerous studies have demonstrated that administration of rimonabant (SR 141716), a CB(1) receptor antagonist, causes a decrease in energy intake. However, the mechanisms by which rimonabant exerts its anorectic actions are unclear. The main focus of the study reported here was to establish the chemical identity of neurons that may subserve the anorectic effects of rimonabant. As such three approaches were utilised: (i) the identification of rimonabant-activated neurons using Fos as a marker of neuronal activity; (ii) the identification of the chemical phenotype of rimonabant-activated neurons by combining immunocytochemical identification of Fos and feeding-related peptides; and (iii) the evaluation of the effect of rimonabant on messenger RNA (mRNA) and protein for a number of feeding-related peptides. Rimonabant-induced Fos-positive nuclei were localized within a range of discrete hypothalamic regions with a predominance in the parvocellular part of the paraventricular nucleus of the hypothalamus, dorsomedial hypothalamus, arcuate nucleus and lateral hypothalamic area. Furthermore, Fos labelling within these hypothalamic regions was colocalized with anorexigenic and orexigenic peptides including melanin-concentrating hormone (MCH), orexin, cocaine- and amphetamine-regulated transcript (CART) and alpha-melanocyte-stimulating hormone (alpha-MSH). Rimonabant specifically induced a decrease in NPY and an increase in CART and alpha-MSH mRNA and protein, consistent with its effect in reducing food intake and increasing energy expenditure. As such these data provide insights into the mechanisms of action that may underpin rimonabant's effects on energy balance and body weight.

The role of thermogenesis in antipsychotic drug-induced weight gain.

The administration of antipsychotic drugs to human patients or experimental animals leads to significant weight gain, which is widely presumed to be driven by hyperphagia; however, the contribution from energy expenditure remains unclear. These studies aim to examine the contribution of shifts in energy expenditure, particularly those involving centrally mediated changes in thermogenesis, to the body weight gain associated with the administration of olanzapine to female Sprague Dawley rats. Olanzapine (6 mg/kg/day orally) caused a transient increase in food intake but a maintained increase in body weight. When pair-fed rats were treated with olanzapine, body weight continued to rise compared to vehicle-treated rats, consistent with a reduction in energy expenditure. Brown adipose tissue (BAT) temperature, measured using biotelemetry devices, decreased immediately after the onset of olanzapine treatment and remained depressed, as did physical activity. UCP1 expression in interscapular BAT was reduced following chronic olanzapine treatment. An acute injection of olanzapine was preceded by an injection of a retrograde tracer into the spinal cord to evaluate the nature of the olanzapine-activated neural pathway. Levels of Fos protein in a number of spinally projecting neurons within discrete hypothalamic and brainstem sites were elevated in olanzapine-treated rats. Some of these neurons in the perifornical region of the lateral hypothalamus (LHA) were also Orexin A positive. These data collectively show a significant impact of thermogenesis (and physical activity) on the weight gain associated with olanzapine treatment. The anatomical studies provide an insight into the central neuroanatomical substrate that may subserve the altered thermogenic responses brought about by olanzapine.

The effects of rimonabant on brown adipose tissue in rat: implications for energy expenditure.

The cannabinoid CB1 receptor antagonist rimonabant (SR 141716) produces a sustained decrease in body weight on a background of a transient reduction in food intake. An increase in energy expenditure has been implicated, possibly mediated via peripheral endocannabinoid system; however, the role of the central endocannabinoid system is unclear. The present study investigates this role. Rimonabant (10 mg/kg IP) was administered for 21 days to rats surgically implanted with biotelemetry devices to measure temperature in the interscapular brown adipose tissue (BAT). BAT temperature as a putative measure of thermogenesis in the BAT, physical activity, body weight, food intake, as well as changes in UCP1 messenger RNA (mRNA) and protein were measured. In addition, role of the CNS in mediating these actions of rimonabant was determined in rats where the BAT was sympathetically denervated. As expected, chronic administration of rimonabant significantly reduced body weight for the entire treatment period despite only a transient decrease in food intake. There was a profound increase in BAT temperature, particularly during the dark phase of each circadian cycle throughout the treatment period. A corresponding increase in uncoupling protein (UCP1) was also observed following chronic rimonabant treatment. The rimonabant-induced elevation in BAT temperature and decrease in body weight were significantly attenuated following denervation, indicating an involvement of the CNS. These findings suggest that the long-term weight loss associated with rimonabant treatment is due at least in part to an elevation in energy expenditure, represented here by elevated temperature recorded in the BAT, which is mediated primarily by the central endocannabinoid system.

Paraventricular hypothalamic CB(1) cannabinoid receptors are involved in the feeding stimulatory effects of Delta(9)-tetrahydrocannabinol.

BACKGROUND/AIMS: The paraventricular nucleus of the hypothalamus (PVN) is the target of converging orexigenic and anorexigenic pathways originating from various hypothalamic sites and is, therefore, considered to be the chief site mediating hypothalamic regulation of energy homeostasis. Although a large body of evidence suggests that central CB(1) cannabinoid receptors mediate food intake, it is not clear whether PVN CB(1) receptors are involved in the control of feeding behaviour. The present study therefore examined the effects of intra-PVN administration of Delta(9)-tetrahydrocannabinol (THC) and the cannabinoid receptor antagonist SR 141716 on feeding. METHODS: After being habituated to the test environment and injection procedure, sated rats were injected with SR 141716 (0.03-3.0 microg, Experiment 1) alone or in combination with THC (5.0 microg, Experiment 2) into the PVN. Food intake and locomotor activity then were recorded for 120 min. RESULTS: Intra-PVN administration of THC produced a significant increase in food intake that was attenuated by SR 141716. Administration of SR 141716 alone did not affect feeding. Locomotor activity was not significantly affected by any drug treatments, suggesting that effects on feeding were not due to a non-specific reduction in motivated behaviour. These findings suggest an important role for PVN cannabinoid signalling in mediating THC-induced feeding behaviour. These results also demonstrate that the blockade of PVN CB(1) receptors alone is insufficient to reduce baseline feeding behaviour under these conditions.

The dopamine receptor antagonist SCH 23390 attenuates feeding induced by Delta9-tetrahydrocannabinol.

A large body of evidence supports the notion that Delta9-tetrahydrocannabinol (THC) stimulates food intake by its actions on CB1 cannabinoid receptors. Indirect evidence also suggests a role for dopamine (DA) receptors in mediating THC-induced feeding. In the present study, a series of experiments involving intraperitoneal drug administration in rats were conducted to further investigate the interaction between cannabinoid and dopamine receptors in feeding behaviour. Male Wistar rats were habituated to the test environment and injection procedure, and then were injected with vehicle alone, the dopamine D1-like receptor antagonist SCH 23390 (0.005, 0.01, 0.5 or 0.1 mg/kg), THC (0.1, 0.5 or 1.0 mg/kg) or SCH 23390 and THC combined. Food intake and locomotor activity were then measured for 120 min. Results revealed that administration of SCH 23390 dose-dependently decreased food intake while THC dose-dependently increased feeding. Furthermore, SCH 23390 attenuated feeding induced by THC at a dose that did not affect feeding on its own. These findings provide direct evidence for the existence of cannabinoid-dopamine interactions in feeding behaviour and suggest that dopamine D1 signalling is necessary for cannabinoids to stimulate food intake.

Consumption of high carbohydrate, high fat, and normal chow is equally suppressed by a cannabinoid receptor antagonist in non-deprived rats.

Administration of the CB1 receptor antagonist SR 141716 [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] suppresses intake of highly palatable (high carbohydrate) food. However, the effects of SR 141716 on intake of foods with varying macronutrient compositions, and in non-deprived animals have not been well studied. In the present study, non-deprived rats were injected intraperitoneally with SR 141716 (0.03-3.0 mg/kg) and presented with a high carbohydrate, high fat, or normal chow diet. Food intake and locomotor activity were recorded for 120 min. Results showed that SR 141716 significantly suppressed food intake irrespective of the composition of the test food without affecting locomotor activity. These data suggest that food deprivation or high palatability of the ingesta are not necessary to observe the suppressive effects of SR 141716 on food intake.

The cannabinoid receptor antagonist SR 141716 attenuates overfeeding induced by systemic or intracranial morphine.

RATIONALE: Considerable interplay exists between the brain's opioid and cannabinoid systems. These systems are both involved in the control of appetite and research supports the notion that the opioid system modulates the role of the cannabinoid system on appetite. However, the ability of the cannabinoid system to modulate the opioid system's control over appetite has not been well studied. OBJECTIVES: The present study examined the role of cannabinoid CB(1) receptors in the control of opioid-induced feeding, and sought to identify specific brain regions underlying this role. METHODS: After being habituated to the test environment and injection procedure, sated rats were injected with the cannabinoid CB(1) receptor antagonist SR 141716 (0.03-3.0 mg/kg, IP). Thirty minutes later, morphine or its vehicle were administered systemically (2.5 mg/kg SC, experiments 1 and 2) or intracranially into the nucleus accumbens (nAcc, experiment 3) or paraventricular nucleus of the hypothalamus (PVN, experiment 4). Food intake and locomotor activity was then recorded for 120 min. RESULTS: A significant increase in food intake was observed following systemic and intracranial (10 nmol) application of morphine in all experiments. SR 141716 suppressed systemic and intra-PVN morphine induced feeding (experiments 2 and 4), but did not attenuate food intake induced by intra-nAcc application of morphine (experiment 3). CONCLUSIONS: Because SR 141716 had no effect on intra-nAcc morphine-stimulated feeding, it would appear that cannabinoid receptors do not modify opioid-mediated hedonic responses to food. Rather, we conclude that cannabinoid CB(1) receptor blockade may suppress opioid-induced feeding by stimulating the release of satiety-related peptides within the hypothalamus. Further, because SR 141716 did not block morphine induced locomotor activity, the observed effects on feeding do not appear to be due to a non-specific reduction in motivated behaviour.