A peripherally acting cannabinoid-1 receptor (CB1R) inverse agonist has antiobesity effects and improves metabolic abnormalities in mice with diet-induced obesity, new data reveal. These effects are achieved by reversing leptin resistance.
The endocannabinoid system is overactive in obesity and CB1R inverse agonists, such as rimonabant, showed promise for the treatment of obesity, especially as these agents also reduced associated metabolic complications. However, therapeutic development of this class of drugs was halted owing to neuropsychiatric adverse effects, including anxiety and depression.
Tam et al. synthesized a peripherally acting CB1R inverse agonist, JD5037, by altering the structure of the CB1R inverse agonist SLV319 to reduce its brain penetrance but retain its high affinity for CB1R. The researchers compared the antiobesity effects of JD5037 with those of SLV319 in mice with diet-induced obesity.
JD5037 was as effective as SLV319 in reducing body weight, appetite, insulin resistance and hepatic steatosis, and did not have negative behavioural effects in the mice.
“One can retain all of the metabolic benefits of globally acting CB1R reverse agonists by limiting their brain penetrance, and at the same time minimize or even eliminate their potential to cause adverse effects produced by blocking CB1R in the brain,” says senior author George Kunos of the NIH, Bethesda, USA.
“Leptin resistance in obesity is known to be maintained by elevated plasma levels of leptin,” adds Kunos. “JD5037 reversed leptin resistance by rapidly normalizing plasma leptin levels, by reducing the secretion of leptin from adipocytes and increasing its clearance via the kidney. The ability of JD5037 to reduce appetite and body weight was due to this rapid reversal of leptin resistance in obese animals.”
The team now hope to test whether the novel compound also works in humans. As Kunos stresses, the need is great. “Despite the enormous public health problem posed by obesity and its metabolic complications, there is a shortage of available treatment. Furthermore, CB1R inverse agonists are the only known class of compounds that not only reduce body weight in obesity but also improve all of its metabolic complications.”
ORIGINAL RESEARCH PAPER
Tam, J. et al. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metabolism doi:10.1016/j.cmet.2012.07.002
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Wilson, C. CB1R inverse agonists—antiobesity effects without the neuropsychiatric adverse effects?. Nat Rev Endocrinol 8, 564 (2012). https://doi.org/10.1038/nrendo.2012.145