Review details how CB1 receptors drive insulin resistance and obesity, and the promise and pitfalls of blocking them

CB1 receptor activation in the liver promotes insulin resistance via increased energy intake/storage, impaired glucose and lipid metabolism, enhanced oxidative stress, and inflammatory responses. Peripheral CB1 blockade improved insulin sensitivity, glucose metabolism, reduced hepatic steatosis and body weight in obese mice. Central CB1 antagonists were suspended due to psychiatric adverse effects.

Comprehensive review of CB1 receptor role in hepatic insulin resistance, covering molecular mechanisms, animal models, and therapeutic strategies including peripheral-only CB1 antagonists.

With the failure of rimonabant, the field needs alternative approaches. This review maps exactly how CB1 drives metabolic disease and points to peripheral-only CB1 blockade as a viable path forward.

The endocannabinoid system is overactive in obesity, creating a vicious cycle: overeating elevates endocannabinoids, which activate CB1 receptors that promote more fat storage and insulin resistance. Breaking this cycle at the periphery, without touching the brain, is the therapeutic goal.

Review draws heavily on animal data. Peripheral CB1 antagonists have not yet been validated in large human trials. The distinction between central and peripheral effects may not be absolute at therapeutic doses.