The Role of Adipocyte Insulin Resistance in the Pathogenesis of Obesity-Related Elevations in Endocannabinoids

Abstract

OBJECTIVE-Obesity is associated with an overactive endocannabinoid (EC) system. The mechanisms responsible for increased ECs in obese individuals are poorly understood. Therefore, we examined the role of adipocyte insulin resistance in intracellular EC metabolism.METHODS-We used 3T3-L1 adipocytes and diet-induced obese (DIO) mice to examine the role of obesity and insulin resistance in the regulation and/or dysregulation of intracellular ECs.RESULTS-For the first time, we provide evidence that insulin is a major regulator of EC metabolism. Insulin treatment reduced intracellular ECs (2-arachidonylglycerol [2-AG] and anandamide [AEA]) in 3T3-L1 adipocytes. This corresponded with insulinsensitive expression changes in enzymes of EC metabolism. In insulin-resistant adipocytes, patterns of insulin-induced enzyme expression were disturbed in a manner consistent with elevated EC synthesis and reduced EC degradation. Expression profiling of adipocytes from DIO mice largely recapitulated in vitro changes, suggesting that insulin resistance affects the EC system in vivo. In mice, expression changes of EC synthesis and degradation enzymes were accompanied by increased plasma EC concentrations (2-AG and AEA) and elevated adipose tissue 2-AG.CONCLUSIONS-Our findings suggest that insulin-resistant adipocytes fail to regulate EC metabolism and decrease intracellular EC levels in response to insulin stimulation. These novel observations offer a mechanism whereby obese insulin-resistant individuals exhibit increased concentrations of ECs. Diabetes

Metabolic responses to long-term pharmacological inhibition of CB1-receptor activity in mice in relation to dietary fat composition

“…[14][15][16]18,21 It is, however, rather surprising in light of the findings by others showing that HF diets given to mice cause dysregulation of the ECS, either via alterations in the expression of CB 1 receptors, via alterations in the levels of endogenous ligands, or both. 17,[40][41][42] Also the fatty acid composition of dietary fat may influence endocannabinoid action. 43 For example, the presence or absence of n-3 PUFAs in the diet affects endocannabinoid levels in the brain, as shown by Berger et al 44 and Watanabe et al 45 Batetta et al 46 recently found that dietary n-3 PUFAs can reduce inflammatory markers and liver triglyceride levels, and these effects were associated with lower levels of endocannabinoid ligands in peripheral organs.…”

Role of insulin as a negative regulator of plasma endocannabinoid levels in obese and nonobese subjects

“…Previous data suggest that both glucose and insulin may affect EC biosynthesis and degradation in isolated cells (12,16,17). Therefore, in this study, we aimed at gaining direct evidence, in intervention studies carried out in two different cohorts of volunteers, of potential effects of either oral glucose load or insulin infusion on plasma EC levels.…”

“…Among the possible causes of the peripheral dysregulation of the EC system, the lack of negative control by insulin on EC levels has been suggested by previous studies (12,16,17). In particular, experiments in isolated cells have shown that conditions mimicking high glucose and/or insulin resistance can enhance EC levels in models of adipocytes and pancreatic b-cells (12,17).…”

“…In particular, experiments in isolated cells have shown that conditions mimicking high glucose and/or insulin resistance can enhance EC levels in models of adipocytes and pancreatic b-cells (12,17). In contrast, anandamide levels are reduced following incubation of 'normoglycemic' b-cells with insulin, or in the postprandial plasma of normoglycemic normoweight patients (12).…”

The potential use of cannabidiol in the therapy of metabolic syndrome

“…Az inzulin, D'Eon és munkatársai kutatásai alapján, csökkenti az endokannabinoidtermelést, és serkenti azok lebomlását [17]. Amikor az adipocyták inzulin iránti szenzitivitása csökken, újra megemelkedhet az endokannabinoidszint.…”