CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity

Abstract

OBJECTIVE: There is growing evidence for an implication of the CB1 receptor subtype of the endocannabinoid system in the regulation of eating and fat deposition. To further define the physiological role of these receptors in the control of energy balance, we characterized the phenotype of CB1 receptor knockout (CB1 À/À ) mice maintained on an obesity-prone regimen or on a standard chow. DESIGN: CB1À/À male mice were compared to wild-type animals (CB1 þ / þ male mice) in two feeding paradigms:(1) with a standard laboratory regimen (3.5 kcal/g, 14.5% of energy as fat) and (2) on a free-choice paradigm consisting of offering both the standard laboratory chow and a high-fat diet (HFD) (4.9 kcal/g, 49% of energy as fat). RESULTS: When maintained on the standard diet, CB1À/À mice are lean. At the age of 20 weeks, their body weight and adiposity are, respectively, 24 and 60% lower than that of CB1 þ / þ mice. They are slightly hypophagic, but when expressed as percent of body weight, their relative energy intake is similar to that of the wild-type animals. Furthermore, inactivation of CB1 receptors reduces plasma insulin and leptin levels, and enhances the response to intracerebroventricular leptin injection. The free-choice paradigm shows that the preference for a high-fat highly palatable chow is slightly delayed in onset but maintained in CB1À/À mice. However, loading CB1 À/À mice with this obesity-prone diet does not result in development of obesity. Knockout mice do not display hyperphagia or reduction of their relative energy intake in contrast to CB1 þ / þ mice, and their feeding efficiency remains low. These data suggest an improved energetic metabolism with the high-fat regimen. Furthermore, the insulin resistance normally occurring in HFD-fed mice is not present in CB1 À/À mice. CONCLUSION: These results provide evidence that the stimulation of CB1 receptors is a key component in the development of diet-induced obesity, and that these receptors and their endogenous ligands are implicated not only in feeding control but also in peripheral metabolic regulations. The lack of effect of SR141716, a selective CB1 receptor antagonist, in CB1 À/À mice further supports this hypothesis, as this compound was previously shown to display potent anti-obesity properties in diet-induced obese C57BL/6 mice.

Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice

“…When maintained on a high-fat diet for 14 weeks, LCB1 -/-mice developed obesity similar to their CB 1 floxed/floxed control littermates, whereas mice with global CB 1 receptor knockout (CB1 -/-mice) were resistant to obesity when exposed to the same diet (Figure 2), in agreement with previous reports (8,9). Total caloric intake over the 14-week period was not different among the 3 groups.…”

“…Again, TEE increased in CB1 -/-mice versus wild-type and LCB1 -/-mice, whereas the high-fat diet-induced suppression of TEE observed in wild-type mice was absent in both CB1 -/-and LCB1 -/-mice. This pattern of responses is compatible with the possibility that under control conditions, fatty acid oxidation and TEE are tonically suppressed by activation of mostly extrahepatic CB 1 receptors and that the absence of this mechanism in CB1 -/-mice accounts for their lean phenotype (7) as well as their resistance to diet-induced obesity (8,9). On the other hand, activation of hepatic CB 1 receptors substantially contributed to the ectopic accumulation of fat in the liver, which manifested in the diet-induced suppression of hepatic CPT1 activity and contributed to the decline in TEE in wild-type mice.…”

“…Mice exposed to high-fat diets develop obesity, steatosis, and insulin and leptin resistance as well as plasma lipid changes similar to those associated with the metabolic syndrome (6). Mice deficient in CB 1 receptors have a lean phenotype (7) and are resistant to these diet-induced changes, even though their total caloric intake is not different from that of wild-type mice fed the same diet (8,9). Similarly, chronic treatment of obese mice or rats with a CB 1 antagonist induces sustained weight loss and protects rodents from this detrimental metabolic phenotype, even though it causes only a transient reduction in food intake (10)(11)(12)(13).…”

Effects of CB1 cannabinoid receptor activation in the nucleos accumbens shell on feeding behavior.

“…Supporting this notion, it was demonstrated that the deletion of CB1R decreased operant behavior and the motivation to obtain highly palatable food in CB1 KO mice (Guegan, et al, 2013). Furthermore, the findings that CB1R KO rodents are resistant to diet-induced obesity (Ravinet-Trillou, Delgorge, Menet, Arnone & Soubrié, 2004), and that over-activity of the endocannabinoid system promotes an obese phenotype (Maccarrone, et al, 2010), in conjunction with the cannabinoid-induced increase of activity observed in this study, suggest a functional connection between the endocannabinoid system, ineffective inhibition of responses and obesity. Accordingly, chronic exposure to cannabinoid agonists should be studied in order to determine if the cannabinoid-induced increase of activity is related to the impulsivity observed in obesity (Nederkoorn, Braet, Van Eijs, Tanghe & Jansen, 2006).…”

CB1 receptor blockade counters age‐induced insulin resistance and metabolic dysfunction

“…Conversely, genetic or pharmacological CB1R blockade improves metabolic status, for example by promoting reductions in body weight and fat mass, as well as enhancing insulin sensitivity and glucose tolerance. Indeed, these beneficial responses may be mediated through central appetite suppression and/or through direct modulation of peripheral energy metabolism (Bensaid et al ., 2003; Ravinet Trillou et al ., 2003, 2004; Jbilo et al ., 2005; Pagotto et al ., 2006; Osei‐Hyiaman et al ., 2008; Jourdan et al ., 2010). …”