PMC:3951193 / 56833-61128
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/3951193","sourcedb":"PMC","sourceid":"3951193","source_url":"http://www.ncbi.nlm.nih.gov/pmc/3951193","text":"Diet and weight change\nDozens of animal studies and human cohort studies have shown that diets rich in fats and sugars alter levels of AEA, 2-AG, their metabolic enzymes, and CB1. The reverse causality is also true—many studies show that CB1 agonists stimulate the consumption of fat and sugar. The rewarding properties of palatable foods are attenuated by CB1 blockade and in CB1 −/− knockouts. Stimulation of feeding behavior by CB1 agonists occurs across the phylogenetic scale, from humans to Hydra, although there is no molecular evidence for CB1 orthologs in invertebrates other than the boneless chordates Ciona intestinalis and Branchiostoma floridae. Reviews on this topic are available [7], [228], [229], which we do not intend to duplicate here.\nUpregulation of the eCB system in obese humans seems to be driven by excessive production of eCBs in several peripheral tissues such as visceral adipose tissue, liver, pancreas, and skeletal muscle. Differences arise between central (intra-abdominal) adipocytes versus peripheral (subcutaneous) adipocytes, with additional variations due to gender, age, and genetic polymorphisms in metabolic enzymes. Visceral adiposity particularly correlates with elevated levels of 2-AG in blood plasma [230]. Increases in circulating eCBs likely reflect spillover from adipose tissues and liver parenchyma, where CB1 activation promotes de novo lipogenesis and reduces insulin sensitivity, respectively. In mice with diet-induced obesity, CB1 mRNA and protein levels increased in the hippocampus, compared to lean controls [231]. Furthermore, hippocampal slices from obese mice showed increased CB1 functionality, with no sign of CB1 desensitization. We find it surprising that sustained elevations of eCB ligands do not result in CB1 downregulation. This may be due to the fact that such elevations are not as dramatic as those caused, for example, by chronic MAGL inhibition. The lack of downregulation may contribute to the hedonic aspects of overeating, and influence cognitive processes.\nWeight loss by caloric restriction or fasting predictably modulates the eCB system. Animal studies have demonstrated the complexities arising in adipose tissue versus the central nervous system (Table 2). In human studies, weight loss from caloric restriction has produced conflicting results. Engeli et al. [232] measured CB1 and FAAH gene expression, and serum AEA and 2-AG, in obese postmenopausal women. They reported no changes after 5% weight loss from caloric restriction. Bennetzen et al. [233] analyzed a younger population of obese men and women; a 10–12% weight loss resulted in elevated 2-AG levels in gluteal adipose tissues, with no change in AEA levels. Weight loss increased CB1 mRNA in abdominal adipose tissues but decreased CB1 mRNA in gluteal adipose tissues.\n10.1371/journal.pone.0089566.t002 Table 2 Effects of short- and long-term caloric restriction upon the brain eCB system in animal studies. In centrally obese men, decreased plasma AEA and 2-AG levels accompanied a weight loss intervention consisting of both caloric restriction and exercise. Only 2-AG levels correlated with decreased visceral adipose tissue, plasma triglycerides and insulin resistance, and improved HDL-cholesterol levels [234]. However, the influence of caloric restriction and exercise separately was not analyzed in this study. You et al. [235] measured CB1 and FAAH mRNA in subcutaneous abdominal and gluteal adipose tissue in overweight or obese postmenopausal women. Caloric restriction resulted in 11% weight loss, which led to a reduction in gluteal CB1 and FAAH gene expression but no significant changes in abdominal adipose tissue. You and associates also tested the effects of exercise, see below. A 12-week hospital-based weight loss program (moderate caloric restriction along with counseling by dieticians and physical activity teachers) resulted in a mean weight loss of 9.5% and a significant reduction in salivary AEA levels, while salivary 2-AG, OEA and PEA did not significantly change [236].\nIn summary, increased food intake, adiposity, and elevated levels of AEA and 2-AG apparently spiral in a feed-forward mechanism. Weight loss from caloric restriction breaks the cycle, possibly by reducing CB1 expression and reducing eCB levels.","divisions":[{"label":"Title","span":{"begin":0,"end":22}},{"label":"Table 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