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The hepatic cannabinoid 1 receptor as a modulator of hepatic energy state and food intake
Author(s) -
Cooper Martin E.,
Regnell Simon E.
Publication year - 2014
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12102
Subject(s) - endocrinology , medicine , insulin resistance , steatosis , rimonabant , weight loss , appetite , cirrhosis , insulin , cannabinoid receptor , receptor , obesity , antagonist
The cannabinoid 1 receptor ( CB 1 R ) has a well‐established role in appetite regulation. Central CB 1 R antagonists, notably rimonabant, induced weight loss and improved the metabolic profile in obese individuals, but were discontinued due to psychiatric side‐effects. The CB 1 R is also expressed peripherally, where its effects include promotion of liver fat accumulation, which consumes 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 CB 1 R activation include increased activity of lipogenic and gluconeogenic transcription factors. Thus, blockade of hepatic CB 1 R s could contribute significantly to the weight‐reducing and insulin‐sensitizing effects of CB 1 R antagonists. Additionally, upregulation of the hepatic CB 1 R may contribute to chronic liver inflammation, fibrosis and cirrhosis from causes including obesity, alcoholism and viral hepatitis. Peripheral CB 1 R antagonists induce weight loss and metabolic improvements in obese rodents; however, as there is evidence that hepatic CB 1 R s are predominately intracellular, due to high intrinsic clearance, many drugs may not effectively block these receptors and therefore have limited efficacy. Hepatoselective CB 1 R antagonists may be effective at reducing hepatic steatosis, insulin resistance and bodyweight in obese, diabetic patients, with far fewer side‐effects than first‐generation CB 1 R antagonists. Additionally, such compounds may be effective in treating inflammatory liver disease, such as non‐alcoholic steatohepatitis, reducing the likelihood of disease progression to cirrhosis or cancer.