Mice lacking the GPR55 receptor showed impaired glucose tolerance regardless of diet, and the weight-reducing effects of both rimonabant and THCV were partly mediated through GPR55.
Metabolic researchers studying cannabinoid receptors, pharmacologists developing anti-obesity drugs, and scientists investigating THCV's metabolic potential.
Impaired glucose tolerance in GPR55 knockouts without weight differences
What the researchers found
GPR55 knockout mice had worse glucose tolerance than wildtype mice on both standard and high-fat diets, despite no differences in body weight, composition, food intake, or energy expenditure. Weight loss from rimonabant and THCV was reduced in knockout mice, suggesting GPR55 partially mediates their anti-obesity effects. Surprisingly, genotype did not affect these drugs' effects on glucose homeostasis.
Why it matters
GPR55 is an emerging cannabinoid receptor target. Understanding its role in metabolism could lead to new treatments for obesity and diabetes that work through the broader endocannabinoid system without the psychiatric side effects of CB1 blockers.
The numbers in context
GPR55 knockouts had impaired glucose tolerance in both experiments. No genotype effect on body weight, composition, food intake, or energy expenditure. THCV (15 mg/kg) and rimonabant (10 mg/kg) produced less weight loss in knockouts. No genotype effect on drugs' glucose homeostasis effects.
How the study worked
GPR55 knockout and wildtype mice studied on standard chow and high-fat diets. Body weight, composition (DEXA and NMR), food intake, energy expenditure, locomotor activity, and glucose/insulin tolerance were measured. THCV (15 mg/kg) and rimonabant (10 mg/kg) were administered daily to both genotypes.
What this study cannot tell us
Knockout mice may have developmental compensatory mechanisms. Only male mice appear to have been studied. The disconnect between glucose tolerance and insulin tolerance findings is unexplained. Drug effects on glucose were not genotype-dependent despite effects on weight.
How to read the evidence
Well-designed preclinical study with multiple metabolic endpoints, but knockout model limitations and unexplained disconnect between weight and glucose findings.
When this study was published
2020 animal study. Adds to understanding of GPR55's metabolic role and its interaction with cannabinoid drugs.
The bigger picture
After rimonabant was withdrawn due to psychiatric side effects, the search for metabolically active cannabinoid targets continued. GPR55 may offer a way to influence metabolism without the mood-related risks of CB1 antagonism.
Questions still open
- Does GPR55 directly regulate insulin secretion? Could selective GPR55 agonists improve glucose tolerance without weight effects? Why did GPR55 genotype affect weight but not glucose responses to these drugs?
Common questions
What is THCV?
Why was rimonabant withdrawn?
Read the original research
High fat-fed GPR55 null mice display impaired glucose tolerance without concomitant changes in energy balance or insulin sensitivity but are less responsive to the effects of the cannabinoids rimonabant or Δ(9)-tetrahydrocannabivarin on weight gain.
PeerJ, 8, e9811
Citation
Wargent, Edward T; Kepczynska, Malgorzata; Zaibi, Mohamed Sghaier; Hislop, David C; Arch, Jonathan R S; Stocker, Claire J. (2020). High fat-fed GPR55 null mice display impaired glucose tolerance without concomitant changes in energy balance or insulin sensitivity but are less responsive to the effects of the cannabinoids rimonabant or Δ(9)-tetrahydrocannabivarin on weight gain.. PeerJ, 8, e9811. https://doi.org/10.7717/peerj.9811
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