Altered endocannabinoid signalling after a high-fat diet in Apoe−/− mice: relevance to adipose tissue inflammation, hepatic steatosis and insulin resistance

• Published in: Diabetologia 2011-11, Vol.54 (11), p.2900-2910
• Main Authors: Bartelt, A., Orlando, P., Mele, C., Ligresti, A., Toedter, K., Scheja, L., Heeren, J., Di Marzo, V.
• Format: Article
• Language: English
• Subjects: Adipose Tissue, White - immunology; Adipose Tissue, White - metabolism; Animals; Apolipoproteins E - genetics; Apolipoproteins E - physiology; Biological and medical sciences; Cannabinoid Receptor Modulators - metabolism; Cells, Cultured; Diabetes. Impaired glucose tolerance; Dietary Fats - adverse effects; Endocannabinoids; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty Liver - immunology; Fatty Liver - metabolism; Fatty Liver - pathology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation; Hepatocytes - metabolism; Hepatocytes - pathology; Human Physiology; Inflammation Mediators - metabolism; Insulin Resistance; Internal Medicine; Lipid Metabolism; Liver - metabolism; Liver - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Other diseases. Semiology; Panniculitis - immunology; Panniculitis - metabolism; Receptor, Cannabinoid, CB1 - genetics; Receptor, Cannabinoid, CB1 - metabolism; RNA, Messenger - metabolism; Signal Transduction; Subcutaneous Fat - immunology; Subcutaneous Fat - metabolism
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-011-2274-6

Aims/hypothesis Apolipoprotein E (ApoE) deficiency is associated with reduced fat accumulation in white adipose tissue (WAT) and high liver triacylglycerol content. Elevated levels of endocannabinoids and cannabinoid receptor type 1 (CB 1 ) receptors in the liver and in epididymal vs subcutaneous WAT are associated with fatty liver, visceral adipose tissue, inflammatory markers and insulin resistance. Methods We investigated, in Apoe −/− and wild-type (WT) mice, the effect of a high-fat diet (HFD) on: (1) subcutaneous and epididymal WAT accumulation, liver triacylglycerols, phospholipid-esterified fatty acids, inflammatory markers in WAT and liver, and insulin resistance; and (2) endocannabinoid levels, and the gene expression levels of the Cb 1 receptor and endocannabinoid metabolic enzymes in liver and WAT. Results After a 16 week HFD, Apoe −/− mice exhibited lower body weight, WAT accumulation and fasting leptin, glucose and insulin levels, and higher hepatic steatosis, than WT mice. Glucose clearance and insulin-mediated glucose disposal following the HFD were slower in WT than Apoe −/− mice, which exhibited higher levels of mRNA encoding inflammatory markers (tumour necrosis factor-α [TNF-α], monocyte chemoattractant protein-1 [MCP-1], cluster of differentiation 68 [CD68] and EGF-like module-containing mucin-like hormone receptor-like 1 [EMR1]) in the liver, but lower levels in epididymal WAT. HFD-induced elevation of endocannabinoid levels in the liver or epididymal WAT was higher or lower, respectively, in Apoe −/− mice, whereas HFD-induced decrease of subcutaneous WAT endocannabinoid and CB 1 receptor levels was significantly less marked. Alterations in endocannabinoid levels reflected changes in endocannabinoid catabolic enzymes in WAT, or the availability of phospholipid precursors in the liver. Conclusions/interpretation Liver and adipose tissue endocannabinoid tone following an HFD is altered on Apoe deletion and strongly associated with inflammation, insulin resistance and hepatic steatosis, or lack thereof.