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Canna~Fangled Abstracts

The hepatic cannabinoid 1 receptor as a modulator of hepatic energy state and food intake.

By April 17, 2013No Comments

Pub Med

The hepatic cannabinoid 1 receptor as a modulator of hepatic energy state and food intake.

 

[Epub ahead of print]

The hepatic cannabinoid 1 receptor as a modulator of hepatic energy state and food intake.

Source

Senior Research Scientist at AstraZeneca R&D Mölndal, Pepparedsleden 1, SE-431 83, Mölndal, Sweden.

Abstract

Cannabinoid 1 receptor (CB1R) has a well-established role in appetite regulation. Central CB1R antagonists, notably rimonabant, induced weight loss and improved the metabolic profile in obese individuals, but were discontinued due to psychiatric side-effects. CB1R is also expressed peripherally, where its effects include promoting liver fat accumulation, consuming ATP. Type 2 diabetes in obese subjects is linked to excess liver fat, whilst there is a negative correlation between hepatic ATP content and insulin resistance. A decreased hepatic ATP/AMP ratio increases food intake by signals via the vagus nerve to the brain. The hepatic cannabinoid system is highly upregulated in obesity, and the effects of hepatic CB1R activation include increased activity of lipogenic and gluconeogenic transcription factors. Thus, blocking hepatic CB1Rs could contribute significantly to the weight-reducing and insulin-sensitising effects of CB1R antagonists. Additionally, upregulation of the hepatic CB1R may contribute to chronic liver inflammation, fibrosis and cirrhosis from causes including obesity, alcoholism and viral hepatitis. Peripheral CB1R antagonists induce weight loss and metabolic improvements in obese rodents; however, as there is evidence that hepatic CB1Rs are predominately intracellular, due to high intrinsic clearance, many drugs may not effectively block these receptors and therefore have limited efficacy. Hepatoselective CB1R antagonists may be effective at reducing hepatic steatosis, insulin resistance and body weight in obese, diabetic patients, with far fewer side-effects than first-generation CB1R antagonists. Additionally, such compounds may effective in treating inflammatory liver disease, e.g. non-alcoholic steatohepatitis (NASH), reducing the likelihood of disease progression to cirrhosis or cancer.

© 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.

PMID:

23452341
 
[PubMed – as supplied by publisher] Prisoner of the system
http://www.ncbi.nlm.nih.gov/pubmed/23452341