How many sites of action for endocannabinoids to control energy metabolism?

Pagotto, Uberto; Cervino, Cristina; Vicennati, Valentina; Marsicano, Giovanni; Lutz, Beat; Pasquali, Renato

doi:10.1038/sj.ijo.0803277

Cited by 39 publications

(29 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The origin of these differences between rat strains is not clear, but may be related to the more severe insulin resistance and hyperinsulinemia of the cp/cp rat and polygenetic differences between strains carrying the fa and cp mutations (52). While data on humans are inconsistent, two recently published large clinical trials show a similar lag in reduction of body weight and waist circumference following initiation of rimonabant treatment (30,32). In these clinical studies, reduction in body weight was not accompanied by long-term reduction in food intake, suggesting a fundamental change in metabolism, unrelated to food intake and possibly reflected in increased oxidative activity.…”

mentioning

confidence: 78%

“…Basic research has been dependent on the use of animal models that mimic the metabolic and pathophysiological aspects of the metabolic syndrome (35). Desirable effects of putative pharmaceutical agents have been reduction of food intake with associated weight loss, improvement in insulin sensitivity, reduction in plasma lipid concentrations, improved vascular function, and anti-atherosclerotic/cardioprotective activity.Rimonabant (SR141716, Acomplia) is a highly selective antagonist of the cannabinoid-1 (CB 1 ) receptor and has been shown to have pleitropic effects on metabolism, obesity, and behavioral endpoints, such as addictions (5,12,24,30,32,33). Thus rimonabant (and related compounds) offers a possible approach to prevention or treatment of the metabolic syndrome, prediabetic status, and associated micro-and macrovascular sequelae (3).…”

mentioning

confidence: 99%

“…Rimonabant (SR141716, Acomplia) is a highly selective antagonist of the cannabinoid-1 (CB 1 ) receptor and has been shown to have pleitropic effects on metabolism, obesity, and behavioral endpoints, such as addictions (5,12,24,30,32,33). Thus rimonabant (and related compounds) offers a possible approach to prevention or treatment of the metabolic syndrome, prediabetic status, and associated micro-and macrovascular sequelae (3).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR:LA-cprat model of prediabetic metabolic syndrome

Russell

Kelly

Diané

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

Vine DF, Proctor SD. Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR:LA-cp rat model of prediabetic metabolic syndrome. Am J Physiol Gastrointest Liver Physiol 299: G507-G516, 2010. First published May 27, 2010 doi:10.1152/ajpgi.00173.2010 is a specific antagonist of the cannabinoid-1 receptor. Activation of the receptor initiates multiple effects on central nervous system function, metabolism, and body weight. The hypothesis that rimonabant has protective effects against vascular disease associated with the metabolic syndrome was tested using JCR:LA-cp rats. JCR:LA-cp rats are obese if they are cp/cp, insulin resistant, and exhibit associated micro-and macrovascular disease with end-stage myocardial and renal disease. Treatment of obese rats with rimonabant (10 mg·kg Ϫ1 ·day Ϫ1 , 12-24 wk of age) caused transient reduction in food intake for 2 wk, without reduction in body weight. However, by 4 wk, there was a modest, sustained reduction in weight gain. Glycemic control improved marginally compared with controls, but at the expense of increased insulin concentration. In contrast, rimonabant normalized fasting plasma triglyceride and reduced plasma plasminogen activator inhibitor-1 and acute phase protein haptoglobin in cp/cp rats. Furthermore, these changes were accompanied by reduced postprandial intestinal lymphatic secretion of apolipoprotein B48, cholesterol, and haptoglobin. While macrovascular dysfunction and ischemic myocardial lesion frequency were unaffected by rimonabant treatment, both microalbuminuria and glomerular sclerosis were substantially reduced. In summary, rimonabant has a modest effect on body weight in freely eating obese rats and markedly reduces plasma triglyceride levels and microvascular disease, in part due to changes in intestinal metabolism, including lymphatic secretion of apolipoprotein B48 and haptoglobin. We conclude that rimonabant improves renal disease and intestinal lipid oversecretion associated with an animal model of the metabolic syndrome that appears to be independent of hyperinsulinemia or macrovascular dysfunction. metabolic syndrome; chylomicron overproduction; inflammation; microalbuminuria; glomerular sclerosis; plasminogen activator inhibitor-1; apolipoprotein B48 EXCESSIVE WEIGHT GAIN, PARTICULARLY in the form of abdominal (visceral) adipose tissue, is a major public health problem in prosperous societies worldwide (16,65). The resultant abdominal obesity has driven a developing epidemic of prediabetic insulin resistance and cluster of associated metabolic abnormalities that are termed the metabolic syndrome (9, 35). Insulin resistance leads to chronic hyperinsulinemia and has been implicated as a major determinant of early development of macro-and microvasculopathy, including atherosclerosis, ischemic cardiovascular disease (CVD), and renal damage, which are strongly associated with the metabolic syndrome (9, 26). The contribution of the metabolic syndrome to the development of cardiovascular and re...

show abstract

mentioning

confidence: 78%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR:LA-cprat model of prediabetic metabolic syndrome

Russell

Kelly

Diané

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

show abstract

“…There are two primary cannabinoid receptors, CB1 and CB2. The CB1 receptor is the most abundant G protein-coupled receptor expressed in the brain (Pagotto et al, 2006), with particularly dense expression in the hypothalamus, pituitary, cerebellum and mesolimbic dopaminergic reward pathways (Herkenham et al, 1990;Matsuda et al, 1990;Demuth and Molleman, 2006). Endocannabinoid signaling via the CB1 receptor is thought to play an important role in incentive stimuli, in part because of the close involvement of endocannabinoid signaling with the dopaminergic system (Lupica and Riegel, 2005;Laviolette and Grace, 2006;Maldonado et al, 2006;Pillolla et al, 2007).…”

Section: Neurobiology Of Voluntary Exercisementioning

confidence: 99%

The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives

Garland

Schutz

Chappell

et al. 2011

Journal of Experimental Biology

381

434

View full text Add to dashboard Cite

Summary Mammals expend energy in many ways, including basic cellular maintenance and repair, digestion, thermoregulation, locomotion, growth and reproduction. These processes can vary tremendously among species and individuals, potentially leading to large variation in daily energy expenditure (DEE). Locomotor energy costs can be substantial for large-bodied species and those with high-activity lifestyles. For humans in industrialized societies, locomotion necessary for daily activities is often relatively low, so it has been presumed that activity energy expenditure and DEE are lower than in our ancestors. Whether this is true and has contributed to a rise in obesity is controversial. In humans, much attention has centered on spontaneous physical activity (SPA) or non-exercise activity thermogenesis (NEAT), the latter sometimes defined so broadly as to include all energy expended due to activity, exclusive of volitional exercise. Given that most people in Western societies engage in little voluntary exercise, increasing NEAT may be an effective way to maintain DEE and combat overweight and obesity. One way to promote NEAT is to decrease the amount of time spent on sedentary behaviours (e.g. watching television). The effects of voluntary exercise on other components of physical activity are highly variable in humans, partly as a function of age, and have rarely been studied in rodents. However, most rodent studies indicate that food consumption increases in the presence of wheels; therefore, other aspects of physical activity are not reduced enough to compensate for the energetic cost of wheel running. Most rodent studies also show negative effects of wheel access on body fat, especially in males. Sedentary behaviours per se have not been studied in rodents in relation to obesity. Several lines of evidence demonstrate the important role of dopamine, in addition to other neural signaling networks (e.g. the endocannabinoid system), in the control of voluntary exercise. A largely separate literature points to a key role for orexins in SPA and NEAT. Brain reward centers are involved in both types of physical activities and eating behaviours, likely leading to complex interactions. Moreover, voluntary exercise and, possibly, eating can be addictive. A growing body of research considers the relationships between personality traits and physical activity, appetite, obesity and other aspects of physical and mental health. Future studies should explore the neurobiology, endocrinology and genetics of physical activity and sedentary behaviour by examining key brain areas, neurotransmitters and hormones involved in motivation, reward and/or the regulation of energy balance.

show abstract

“…The important point is that CB1 activation has multiple direct metabolic actions on tissues that are consistent with storing more fat, and these appear to occur independently of any transient change of energy intake. So whereas the CB1 receptor subtype mediates both central and peripheral actions of endocannabinoids on energy balance, it is often unclear if endocannabinoidmediated changes of lipid and glucose metabolism depend on central and/or peripheral CB1 activation (32)(33)(34). In fact, even though chronic CB1 blockade in obese animals and humans improves several symptoms of the metabolic syndrome (35), it still remains to be determined whether beneficial metabolic effects can directly result from CB1 receptor antagonism in the absence of changes in food intake.…”

mentioning

confidence: 99%

Peripheral, but Not Central, CB1 Antagonism Provides Food Intake–Independent Metabolic Benefits in Diet-Induced Obese Rats

et al. 2008

View full text Add to dashboard Cite

OBJECTIVE-Blockade of the CB1 receptor is one of the promising strategies for the treatment of obesity. Although antagonists suppress food intake and reduce body weight, the role of central versus peripheral CB1 activation on weight loss and related metabolic parameters remains to be elucidated. We therefore specifically assessed and compared the respective potential relevance of central nervous system (CNS) versus peripheral CB1 receptors in the regulation of energy homeostasis and lipid and glucose metabolism in diet-induced obese (DIO) rats.RESEARCH DESIGN AND METHODS-Both lean and DIO rats were used for our experiments. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR, and euglycemic-hyperinsulinemic clamps were used for insulin sensitivity and glucose metabolism studies.RESULTS-Specific CNS-CB1 blockade decreased body weight and food intake but, independent of those effects, had no beneficial influence on peripheral lipid and glucose metabolism. Peripheral treatment with CB1 antagonist (Rimonabant) also reduced food intake and body weight but, in addition, independently triggered lipid mobilization pathways in white adipose tissue and cellular glucose uptake. Insulin sensitivity and skeletal muscle glucose uptake were enhanced, while hepatic glucose production was decreased during peripheral infusion of the CB1 antagonist. However, these effects depended on the antagonistelicited reduction of food intake.CONCLUSIONS-Several relevant metabolic processes appear to independently benefit from peripheral blockade of CB1, while CNS-CB1 blockade alone predominantly affects food intake and body weight. Diabetes 57:2977-2991, 2008 T he incidence of obesity and the metabolic syndrome have grown to epidemic proportions, making increased research efforts toward discovery of novel anti-obesity therapies increasingly important. Endocannabinoids are key modulators of feeding behavior through the activation of the CB1 receptor (1,2), which is localized in the periphery as well as in many brain areas involved in the regulation of energy homeostasis and reward processes (3,4). Recent studies (5-11) have demonstrated that blocking the activity of the endogenous cannabinoid system may be a successful strategy for the treatment of obesity and the metabolic syndrome.It is well known that CB1 receptors in the hypothalamus might regulate food intake through the disinhibition of the release of melanin-concentrating hormone from lateral hypothalamic neurons (12) and the inhibition of the release and/or expression of corticotrophin-releasing hormone in the paraventricular nucleus (13). Both these effects are under the negative control of leptin, which is known to negatively control endocannabinoid tone in the hypothalamus (2). On the other hand, the effects of CB1 activation on ␣-melanocyte-stimulating hormone are controversial, since both inhibition and stimulation were reported in the study by Hentges et al. (14), and no downstream effects of ␣-melanocyte-stimulating hormone on endocannabinoi...

show abstract

How many sites of action for endocannabinoids to control energy metabolism?

Cited by 39 publications

References 38 publications

Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR:LA-cprat model of prediabetic metabolic syndrome

Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR:LA-cprat model of prediabetic metabolic syndrome

The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives

Peripheral, but Not Central, CB1 Antagonism Provides Food Intake–Independent Metabolic Benefits in Diet-Induced Obese Rats

Contact Info

Product

Resources

About