Dysregulation of peripheral endocannabinoid levels in hyperglycemia and obesity: Effect of high fat diets.

Increasing evidence indicates that endocannabinoid (EC) signalling is dysregulated during hyperglycemia and obesity, particularly at the level of anandamide (AEA) and/or 2-arachidonoylglycerol (2-AG) concentrations in tissues involved in the control of energy intake and processing, such as the liver, white adipose tissue and pancreas. Here we review this previous evidence and provide new data on the possible dysregulation of EC levels in organs with endocrine function (adrenal glands and thyroid), involved in energy expenditure (brown adipose tissue and skeletal muscle), or affected by the consequences of metabolic disorders (heart and kidney), obtained from mice fed for 3, 8 and 14 weeks with two different high fat diets (HFDs), with different fatty acid compositions and impact on fasting glucose levels. Statistically significant elevations (in the skeletal muscle, heart and kidney) or reductions (in the thyroid) of the levels of either AEA or 2-AG, or both, were found. Depending on the diet, these changes preceded or accompanied the development of overt obesity and/or hyperglycemia. In the adrenal gland, first a reduction and then an elevation of EC levels were observed. In the brown fat, a very early elevation of both AEA and 2-AG normalized levels was observed with one of the diets, whereas delayed decreases were explained by an increase of the amount of fat tissue weight induced by the HFDs. The potential implications of these and previous findings in the general framework of the proposed roles of the EC system in the control of metabolic, endocrine and cardiovascular and renal functions are discussed.