Surreal illustration of liver cells intertwined with cannabis plant structures

Can a Cannabis Receptor Blockade Help Manage Fatty Liver and Diabetes?

Lena Voss in Health & Wellness December 2025 • 5 min read.

"New research explores how blocking the CB1 receptor could offer a novel approach to tackling hepatic fat infiltration and inflammation in severe diabetes."

Nonalcoholic fatty liver disease (NAFLD) is a growing concern, encompassing conditions from simple steatosis to nonalcoholic steatohepatitis (NASH). NASH can lead to severe complications like cirrhosis and hepatocellular carcinoma. With the rise in type 2 diabetes, the prevalence of advanced fibrosis linked to NAFLD is also increasing, underscoring the urgent need for effective treatments.

The endocannabinoid system, particularly the cannabinoid 1 (CB1) receptor, has emerged as a key player in metabolic regulation. Overactivation of this system is observed in obesity and type 2 diabetes, making it a potential therapeutic target. In the liver, CB1 receptor activation can drive increased lipogenesis and decreased fatty acid oxidation, contributing to hepatic inflammation, fibrosis, and cellular damage.

Recent research has focused on blocking CB1 receptor activity to combat liver fibrosis. A new study investigates the effects of CB1 receptor blockade on hepatic steatosis and inflammation, independent of weight loss and glycemic control, offering insights into novel therapeutic strategies for managing severe diabetes and related liver complications.

How Does Blocking the CB1 Receptor Affect Liver Health in Diabetes?

Surreal illustration of liver cells intertwined with cannabis plant structures

A study published in PLOS ONE explored the impact of CB1 receptor blockade on hepatic fat infiltration and inflammation in a rat model of severely uncontrolled diabetes. Researchers administered rimonabant, a CB1 receptor antagonist, to Otsuka Long-Evans Tokushima Fatty (OLETF) rats for six weeks. These rats, known for developing obesity and diabetes, were used to mimic the conditions of severely uncontrolled diabetes.

Interestingly, the study found that rimonabant did not significantly change body weight, oral glucose tolerance test (OGTT) results, or serum glucose levels, despite decreased food intake. This suggests that the beneficial effects of CB1 receptor blockade may occur independently of traditional weight loss and glycemic control mechanisms. The rats in the OLETF control group experienced a significant decrease in body weight between the start and end of the study, further indicating their severely diabetic state.

Reduced Liver Enzyme Levels: Rimonabant significantly decreased serum levels of liver enzymes such as ALT and AST, indicating reduced liver damage.
Decreased Hepatic Fat Accumulation: The treatment led to a notable reduction in hepatic fat accumulation and lipid peroxidation.
Reduced Cell Death: There was a significant decrease in cell death, demonstrated by fewer TUNEL-positive cells in the liver tissue.
Modulated Inflammatory and Fibrotic Genes: Rimonabant treatment resulted in decreased hepatic gene expression of pro-inflammatory cytokines (CD11b, F4/80, MCP1, and TNFα), negative inflammatory mediators (SOCS1 and SOCS3), and fibrosis-related proteins (TGFβ, collagen 1, and TIMP1).
Upregulated Fatty Acid Oxidation: The administration of rimonabant significantly increased mRNA levels of CPT1a and PPARα, which are related to β-oxidation.

The study also highlighted an increase in the Nrf2 pathway and AMPK phosphorylation. Specifically, there were significant increases in Nrf2 gene expression and its downstream genes (NQO1, GSAT, HO-1, and TXNRD1), along with increased AMPK phosphorylation in the treated diabetic rats. This suggests that the CB1 receptor blockade may exert its protective effects by enhancing the Nrf2-AMPK pathway, which plays a crucial role in reducing oxidative stress and inflammation.

What Does This Mean for Future Diabetes and Liver Disease Treatments?

This research offers a promising avenue for therapeutic interventions targeting both severe diabetes and associated liver complications. The potent inhibitory effects of CB1 receptor blockade on hepatic fat infiltration and cellular death indicate that the CB1 receptor could be a valuable therapeutic target. Furthermore, the activation of the Nrf2-AMPK pathway may be a key mechanism through which rimonabant exerts its action, opening new possibilities for drug development and treatment strategies. While these findings are based on a rat model, they lay the groundwork for future studies exploring the potential of CB1 receptor antagonists in human clinical trials.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1371/journal.pone.0206152, Alternate LINK

Title: Cb1 Receptor Blockade Ameliorates Hepatic Fat Infiltration And Inflammation And Increases Nrf2-Ampk Pathway In A Rat Model Of Severely Uncontrolled Diabetes

Subject: Multidisciplinary

Journal: PLOS ONE

Publisher: Public Library of Science (PLoS)

Authors: Eugene Chang, Dae-Hee Kim, Hyekyung Yang, Da Hyun Lee, Soo Han Bae, Cheol-Young Park

Published: 2018-10-26

Everything You Need To Know

What is the CB1 receptor, and why is it significant in this context?

The CB1 receptor is part of the endocannabinoid system and plays a role in metabolic regulation. Overactivation of the CB1 receptor is associated with obesity and type 2 diabetes. In the liver, activation of the CB1 receptor can lead to increased lipogenesis and decreased fatty acid oxidation, contributing to inflammation, fibrosis, and cellular damage. Blocking the CB1 receptor is important because it could potentially reverse these harmful effects and improve liver health in the context of diabetes.

How does blocking the CB1 receptor affect hepatic fat infiltration and inflammation?

Hepatic fat infiltration refers to the accumulation of fat within the liver cells, a key feature of nonalcoholic fatty liver disease (NAFLD). Inflammation, in this context, refers to the immune response within the liver, which can lead to cell damage and the progression to nonalcoholic steatohepatitis (NASH). Blocking the CB1 receptor using rimonabant has been shown to reduce both hepatic fat accumulation and inflammation, suggesting that it can protect the liver from damage associated with diabetes.

What is the significance of the Nrf2-AMPK pathway in this research?

The Nrf2-AMPK pathway is a cellular signaling pathway involved in reducing oxidative stress and inflammation. Nrf2 is a transcription factor that regulates the expression of antioxidant and detoxification genes, while AMPK is an enzyme that regulates cellular energy homeostasis. The study found that CB1 receptor blockade increased Nrf2 gene expression and AMPK phosphorylation. This suggests that the beneficial effects of CB1 receptor blockade may, in part, be mediated by activating this pathway, which could help protect the liver from damage.

What is rimonabant, and what were the key findings of its use in the study?

Rimonabant is a CB1 receptor antagonist, meaning it blocks the action of the CB1 receptor. The study used rimonabant in a rat model. The results showed that rimonabant treatment led to reduced liver enzyme levels, decreased hepatic fat accumulation, reduced cell death, modulated inflammatory and fibrotic genes, and upregulated fatty acid oxidation. These findings suggest that blocking the CB1 receptor with rimonabant can improve liver health in diabetes.

What are the implications of this research for the treatment of fatty liver and diabetes?

NAFLD encompasses a range of liver conditions from simple steatosis to NASH. NASH can lead to severe complications such as cirrhosis and hepatocellular carcinoma. Diabetes exacerbates the risk of NAFLD, increasing the need for effective treatments. The study offers a novel approach by targeting the CB1 receptor. If proven effective in human trials, CB1 receptor blockade could offer a new therapeutic strategy to combat both diabetes and associated liver complications, potentially preventing severe liver damage in patients.