Leptin Levels Are Negatively Correlated with 2-Arachidonoylglycerol in the Cerebrospinal Fluid of Patients with Osteoarthritis

Abstract

BackgroundThere is compelling evidence in humans that peripheral endocannabinoid signaling is disrupted in obesity. However, little is known about the corresponding central signaling. Here, we have investigated the relationship between gender, leptin, body mass index (BMI) and levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the serum and cerebrospinal fluid (CSF) of primarily overweight to obese patients with osteoarthritis.Methodology/Principal FindingsPatients (20 females, 15 males, age range 44-78 years, BMI range 24-42) undergoing total knee arthroplasty for end-stage osteoarthritis were recruited for the study. Endocannabinoids were quantified by liquid chromatography – mass spectrometry. AEA and 2-AG levels in the serum and CSF did not correlate with either age or BMI. However, 2-AG levels in the CSF, but not serum, correlated negatively with CSF leptin levels (Spearman’s ρ -0.48, P=0.0076, n=30). No such correlations were observed for AEA and leptin.Conclusions/SignificanceIn the patient sample investigated, there is a negative association between 2-AG and leptin levels in the CSF. This is consistent with pre-clinical studies in animals, demonstrating that leptin controls the levels of hypothalamic endocannabinoids that regulate feeding behavior.

Quantitative profiling of endocannabinoids and related N-acylethanolamines in human CSF using nano LC-MS/MS

“…In addition, the RSDs of QCs and duplicates used during the analysis of healthy subjects are reported in Table 5. The concentrations of AEA and 2-AG are in line with the previous studies (37). In addition to the compounds shown in Table 3, several putatively annotated NAEs were observed in human CSF (supplemental Fig.…”

Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling

“…Accordingly, antagonism of OX-A action at OX-1R does not only counteract the impairment of POMC expression and α-MSH signaling, but, similarly to what has been found with CB 1 R antagonists (32), also reduces hyperphagia, body weight, and steatosis in obese mice. The finding that OX-A modulates the function of CB 1 R, for which it has no significant inherent affinity, by acting on the biosynthesis of its ligand provides yet another mechanism through which endocannabinoids, which affect food intake in a dual manner (33), exert hyperphagic actions at hypothalamic CB 1 R. This finding is also relevant to the well-established inverse relationship between leptin and endocannabinoid signaling in obesity, anorexia, or inflammatory pain, which is also observed in humans (34,35). Indeed, hypothalamic 2-AG levels increase significantly in models of genetic [ob/ob and db/db mice (2)] or diet-induced (20) leptin signaling deficiency and obesity, where a significant increase of OX-A signaling to many target areas, including the ARC, is also observed (7,20).…”

Intrathecal morphine administration reduces postoperative pain and peripheral endocannabinoid levels in total knee arthroplasty patients: a randomized clinical trial

“…Patient controlled analgesia was initiated in the post-anesthesia care unit and was available to the patients during the entire postoperative period. For more details see previous work [40, 41].…”