Leptin receptor deficiency is associated with upregulation of cannabinoid 1 receptors in limbic brain regions

Behavioral Neuropharmacology and Neuroimaging Lab, Department of Medicine, Brookhaven National Lab, Upton, NY 11973, USA.
Synapse (Impact Factor: 2.13). 09/2008; 62(9):637-42. DOI: 10.1002/syn.20531
Source: PubMed


Leptin receptor dysfunction results in overeating and obesity. Leptin regulates hypothalamic signaling that underlies the motivation to hyperphagia, but the interaction between leptin and cannabinoid signaling is poorly understood. We evaluated the role of cannabinoid 1 receptors (CB(1)R) in overeating and the effects of food deprivation on CB(1)R in the brain. One-month-old Zucker rats were divided into unrestricted and restricted (fed 70% of unrestricted rats) diet groups and maintained until adulthood (4 months). Levels of relative binding sites of CB(1)R (CB(1)R binding levels) were assessed using [(3)H] SR141716A in vitro autoradiography. These levels were higher (except cerebellum and hypothalamus) at 4 months than at 1 month of age. One month CB(1)R binding levels for most brain regions did not differ between Ob and Lean (Le) rats (except in frontal and cingulate cortices in Le and in the hypothalamus in Ob). Four month Ob rats had higher CB(1)R binding levels than Le in most brain regions and food restriction was associated with higher CB(1)R levels in all brain regions in Ob, but not in Le rats. CB(1)R binding levels increased between adolescence and young adulthood which we believe was influenced by leptin and food availability. The high levels of CB(1)R in Ob rats suggest that leptin's inhibition of food-intake is in part mediated by downregulation of CB(1)R and that leptin interferes with CB(1)R upregulation under food-deprivation conditions. These results are consistent with prior findings showing increased levels of endogenous cannabinoids in the Ob rats corroborating the regulation of cannabinoid signaling by leptin.

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Available from: Panayotis Thanos
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    • "Hence, an increase in STAT signaling may represent the primary intracellular cascade triggered by leptin receptor activation in astrocytes. Corroborating evidence in rats demonstrates that downregulation of CB 1 receptors leads to leptin's inhibition of food intake [82], indicating that endocannabinoid signaling may influence reward processing and motivational signals via its actions on leptin receptors. Hormonal signals produced from periphery, such as from adipose or gut tissue, are also known to modify central leptin activity. "
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    ABSTRACT: Receptors of leptin, the prototypical adipokine, are expressed throughout the cortex and several other areas of the brain. Although typically studied for its role in energy intake and expenditure, leptin plays a critical role in many other neurocognitive processes and interacts with various other hormones and neurotransmitters to perform these functions. Here, we review the literature on how leptin influences brain development, neural degradation, Alzheimer’s disease, psychiatric disorders, and more complicated cognitive functioning and feeding behaviors. We also discuss modulators of leptin and the leptin receptor as they relate to normal cognitive functioning and may mediate some of the actions of leptin in the brain. Although we are beginning to better understand the critical role leptin plays in normal cognitive functioning, there is much to be discovered.
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    • "One of the mechanisms that contributes to these differences is defective leptin signaling (Haynes et al. 1997), which is also linked to higher endocannabinoid levels in the hypothalamus (Di Marzo et al. 2001) and more CB 1 receptor binding sites in the limbic regions of the brain (Thanos et al. 2008). These differences likely contribute to altered sensitivity to cannabinoid compounds (Smith and Rasmussen 2010), including rimonabant (Rasmussen and Huskinson 2008; Thanos et al. 2008; Vickers et al. 2003). We hypothesized that obese Zucker rats may be more sensitive to the effects of rimonabant, as they have been shown to be more sensitive to cannabinoid drugs. "
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    ABSTRACT: Cannabinoid antagonists purportedly have greater effects in reducing the intake of highly palatable food compared to less palatable food. However, this assertion is based on free-feeding studies in which the amount of palatable food eaten under baseline conditions is often confounded with other variables, such as unequal access to both food options and differences in qualitative features of the foods. We attempted to reduce these confounds by using a model of choice that programmed the delivery rates of sucrose and carrot-flavored pellets. Lever pressing of ten lean (Fa/Fa or Fa/fa) and ten obese (fa/fa) Zucker rats was placed under three conditions in which programmed ratios for food pellets on two levers were 5:1, 1:1, and 1:5. In phase 1, responses on the two levers produced one type of pellet (sucrose or carrot); in phase 2, responses on one lever produced sucrose pellets and on the other lever produced carrot pellets. After responses stabilized under each food ratio, acute doses of rimonabant (0, 3, and 10 mg/kg) were administered before experimental sessions. The number of reinforcers and responses earned per session under each ratio and from each lever was compared. Rimonabant reduced reinforcers in 1:5 and 5:1 food ratios in phase 1, and across all ratios in phase 2. Rimonabant reduced sucrose and carrot-flavored pellet consumption similarly; rimonabant did not affect bias toward sucrose, but increased sensitivity to amount differences in lean rats. This suggests that relative amount of food, not palatability, may be an important behavioral mechanism in the effects of rimonabant.
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    • "However, leptin is known to inhibit the mesolimbic dopamine system by acting on the lateral hypothalamus (LH) [17]. Furthermore, obese rats with defective leptin signalling present increased CB1 expression and binding in brain reward structures, which implies that the increased motivation to eat, which characterizes this animal model, might be due to a higher endocannabinoid tone in reward-related areas of the brain [18]. The aim of this study was to investigate the effect of the inverse agonist AM 251 on food intake, body weight gain, energy expenditure and other parameters related to the metabolic syndrome, including lipid profile, plasma hepatic metabolic markers and plasma levels of leptin and insulin in Zucker rats. "
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    ABSTRACT: Recent research suggests that cannabinoid receptor CB1 antagonists can affect appetite and body weight gain, although their influence on other parameters related to metabolic syndrome is not well documented. The present study was designed to assess the effects of chronic treatment with the CB1 receptor inverse agonist AM 251 (3mg/kg for 3weeks) in obese and lean Zucker rats on parameters related to metabolic syndrome. Four groups of rats were used: lean Zucker rats, untreated obese Zucker rats, AM 251-treated obese Zucker rats and a pair-fed obese Zucker rat experimental group which received the same amount of food as that consumed by the animals treated with AM251. Food intake, body weight gain, energy expenditure, plasma biochemical parameters, leptin, insulin and hepatic status markers were analysed. Daily injection of AM 251 in obese Zucker rats produced a marked and sustained decrease in daily food intake and body weight and a considerable increase in energy expenditure in comparison with untreated obese Zucker rats. AM 251 administration to obese rats significantly reduced plasma levels of glucose, leptin, AST, ALT, Gamma GT, total bilirubin and LDL cholesterol whereas HDL cholesterol plasma levels increased. The results also showed a decrease in liver/weight body ratio and total fat content in the liver. The main effects of AM251 (3mg/kg) found in this study were not observed in pair-fed obese animals, highlighting the additional beneficial effects of treatment with AM 251. The results obtained in obese rats can be interpreted as a decrease in leptin and insulin resistance, thereby improving glucose and lipid metabolism, alleviating the steatosis present in the metabolic syndrome and thus favourably modifying plasma levels of hepatic biomarkers. Our results indicate that the cannabinoid CB1 inverse agonist AM 251 represents a promising therapeutic strategy for the treatment of obesity and metabolic syndrome.
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