A potent CB1 receptor blocker stimulated glucose production in the liver through sympathetic nerve signaling, revealing that strong CB1 inverse agonism could raise fasting blood sugar and should be avoided in weight-loss drugs.
Read this if you're interested in the metabolic complexities of targeting the cannabinoid system for obesity.
Strong CB1 inverse agonism raised liver glucose production through sympathetic nerve activation
What the researchers found
MJ08, a CB1 receptor antagonist/inverse agonist more potent than rimonabant, was found to stimulate hepatic glucose production (HGP) in a dose-dependent manner in perfused rat livers. It also promoted expression of gluconeogenic genes.
The mechanism involved the liver's sympathetic nervous system. MJ08 triggered noradrenaline release from hepatic nerves and increased cAMP content in the liver. These effects were blocked by propranolol (a beta-blocker) and reserpine (which depletes noradrenaline), confirming the sympathetic pathway.
Importantly, when tested on isolated hepatocytes (liver cells without nerve connections), only slight increases were seen, confirming that the main effect requires intact nerve connections to the liver.
Why it matters
This finding has direct implications for the development of peripheral CB1 blockers for obesity. Strong inverse agonist activity at liver CB1 receptors can raise blood sugar through sympathetic nerve activation, potentially worsening metabolic disease rather than treating it. This means CB1 weight-loss drugs must be carefully designed to avoid high inverse agonistic activity.
The numbers in context
MJ08 showed superior inverse agonism compared to rimonabant. Dose-dependent increase in hepatic glucose production. Effects blocked by propranolol (beta-blocker), reserpine (sympathetic inhibitor), NF449 and H89 (cAMP pathway inhibitors), and WIN 55,212-2 (CB1 agonist).
How the study worked
Perfused rat liver preparations to study glucose production. Primary cultured hepatocytes for comparison. Pharmacological blocking experiments using CB1 agonist, cAMP pathway inhibitors, beta-blocker, and sympathetic inhibitor to dissect the mechanism. Monoamine neurotransmitter and cAMP measurements.
What this study cannot tell us
Animal study using perfused liver preparations, which may not fully replicate intact organism physiology. Only acute effects were studied. The relevance of this mechanism to human liver physiology is assumed but not confirmed. MJ08 is a research tool compound, not a drug candidate.
How to read the evidence
Animal pharmacology study using perfused liver preparations. Provides important mechanistic insights for drug development but is far from clinical application.
When this study was published
Published in 2017. The distinction between CB1 antagonism and inverse agonism continues to guide metabolic drug design.
The bigger picture
Not all CB1 blockers are equal. The distinction between antagonism (simply blocking the receptor) and inverse agonism (actively suppressing baseline receptor activity) has real metabolic consequences. This study shows that inverse agonism specifically activates hepatic sympathetic nerves, which could explain some of the metabolic side effects seen with rimonabant and guide development of safer compounds.
Questions still open
- Can CB1 antagonists be designed with minimal inverse agonism to avoid the glucose production problem? Did rimonabant's metabolic effects in humans partly reflect this hepatic sympathetic mechanism? Would peripheral CB1 blockers with neutral antagonism avoid blood sugar elevation?
Common questions
What is the difference between an antagonist and an inverse agonist?
Could this affect people taking weight-loss drugs?
Read the original research
Cannabinoid CB1 receptor inverse agonist MJ08 stimulates glucose production via hepatic sympathetic innervation in rats.
European journal of pharmacology, 814, 232-239
Citation
Chen, Wei; Liu, Hongying; Guan, Hua; Xue, Nina; Wang, Lili. (2017). Cannabinoid CB1 receptor inverse agonist MJ08 stimulates glucose production via hepatic sympathetic innervation in rats.. European journal of pharmacology, 814, 232-239. https://doi.org/10.1016/j.ejphar.2017.08.030
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