FAAH and MGL activity were not different between healthy patients and those with metabolic syndrome or diagnosed T2M. FAAH and MGL activity did not correlate with blood pressure, heart rate or age, and may were not different in patients with a normal compared to high fasting glucose, or HbA1c and were not correlated with plasma insulin levels. FAAH or MGL activity in subcutaneous ad ipocytes was also not different between high and normal risk groups with regard to triglycerides, total cholesterol or HDL cholesterol. There was also no cor relation between FAAH or MGL activity with non HDL C. Discussion The primary aim of this study was to determine whether the activities of FAAH and MGL, two key catabolic en zymes of the ECS, are differentially affected by diabetes or other markers of the metabolic syndrome in obesity.

FAAH was raised in obese rats, but not obese diabetic rats, while MGL activity was elevated in both strains. FAAH and MGL activities positively correlated with body weight and blood glucose in the Zucker rats, but MGL activity correlated more strongly. By contrast, in severely obese humans, FAAH and MGL activity in adi pose tissue was not correlated with adiposity and were not different between healthy, type 2 diabetic, metabolic syndrome patients, or in patients with clinical elevated blood glucose, poor glycaemic control or hyperlipid aemia. FAAH and/or MGL activities were not different between visceral and subcutaneous adipose tissue de pots, except in the lean rats, where MGL activity was higher in visceral compared to subcutaneous adipocytes.

The effects of obesity/diabetes on FAAH and MGL activity in Zucker rats We found that FAAH and MGL enzyme activities in ma ture adipocytes are increased in Zucker rats compared to lean rats, and were positively correlated with body mass in the rat strains MGL activity was also correlated with blood glucose levels, and this relationship was stronger when the diabetic rats were removed from ana lysis. A relationship between FAAH and blood glucose was also observed without the diabetic rats. Given that MGL has distinct roles in lipolysis and signalling, the in creased activity of MGL in our studies may reflect an in crease in the endocannabinoid signalling role of MGL rather than lipolysis, since lipolytic enzymes are gener ally repressed in obesity.

MGL activity was raised in both the obese and obese diabetic rats suggesting a differen tial regulation of FAAH and MGL in diabetes in obesity. The physiological consequence of this differential effect of diabetes in obesity on enzyme activity is not clear. In obese diabetic Brefeldin_A humans, AEA, but not 2 AG, is increased in subcutaneous adipose tissue. An increase in AEA causing activation of CB1 could lead to unfavourable metabolic effects, however an increase in PEA and OEA, which are also degraded by FAAH, may be benefi cial.