A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome

Abstract

Glucocorticoids are known to promote the development of metabolic syndrome through the modulation of both feeding pathways and metabolic processes; however, the precise mechanisms of these effects are not well-understood. Recent evidence shows that glucocorticoids possess the ability to increase endocannabinoid signaling, which is known to regulate appetite, energy balance, and metabolic processes through both central and peripheral pathways. The aim of this study was to determine the role of endocannabinoid signaling in glucocorticoid-mediated obesity and metabolic syndrome. Using a mouse model of excess corticosterone exposure, we found that the ability of glucocorticoids to increase adiposity, weight gain, hormonal dysregulation, hepatic steatosis, and dyslipidemia was reduced or reversed in mice lacking the cannabinoid CB 1 receptor as well as mice treated with the global CB 1 receptor antagonist AM251. Similarly, a neutral, peripherally restricted CB 1 receptor antagonist (AM6545) was able to attenuate the metabolic phenotype caused by chronic corticosterone, suggesting a peripheral mechanism for these effects. Biochemical analyses showed that chronic excess glucocorticoid exposure produced a significant increase in hepatic and circulating levels of the endocannabinoid anandamide, whereas no effect was observed in the hypothalamus. To test the role of the liver, specific and exclusive deletion of hepatic CB 1 receptor resulted in a rescue of the dyslipidemic effects of glucocorticoid exposure, while not affecting the obesity phenotype or the elevations in insulin and leptin. Together, these data indicate that glucocorticoids recruit peripheral endocannabinoid signaling to promote metabolic dysregulation, with hepatic endocannabinoid signaling being especially important for changes in lipid metabolism.corticosterone | 2-AG | anandamide | obesity | liver O besity and associated cardiometabolic diseases, such as type 2 diabetes, represent major contributors to morbidity and mortality (1, 2). Persistent exposure to environmental and psychological stress and the concomitant increase in circulating glucocorticoids (GCs; the primary stress hormones) are believed to be contributing factors to the epidemic of obesity and metabolic syndrome (3-6). Furthermore, patients receiving exogenous GCs subsequent to an organ transplant or for the treatment of inflammatory-related illnesses show several symptoms of the metabolic syndrome (7). Despite this relationship, the mechanisms by which GCs produce these changes in weight regulation and metabolism remain unclear.It has been clearly shown that GCs can mobilize the endocannabinoid (eCB) system, which is essential for many of the effects of GCs, including negative feedback regulation of the hypothalamic-pituitary-adrenal axis, suppression of sexual behavior, and alterations in memory consolidation (8-11). eCBs are also potent regulators of feeding and metabolism, with effects that parallel those of GCs, such as increased feeding, reduced energy expenditure, fat accumulation ...

Neurobiological Interactions Between Stress and the Endocannabinoid System

“…For example, exposure of humans to the Trier social stress test has been found to elevate circulating levels of 2-AG (Hill et al, 2009d) or AEA (Dlugos et al, 2012), indicating that stress exposure in humans similarly elevates an eCB signal. Although it is not clear why AEA was found to elevate, instead of decrease, in response to stress, as is found in the rodent brain studies, however, it is worth noting that both chronic stress and corticosterone treatment are found to increase circulating levels of AEA despite reducing central AEA in rodents (Bowles et al, 2012(Bowles et al, , 2015Hill et al, 2008a). Consistent with this, circulating AEA levels have been found to correlate with cortisol in humans , suggesting that peripheral glucocorticoids may increase circulating AEA in humans.…”

Metabolic comorbidities in Cushing's syndrome

“…Scerif et al (55) showed significant differences in GC-treated WT and cannabinoid receptor type 1 KO mice, and more recently, similar data showed the role of the cannabinoid system in GC-induced changes (82).…”

Somatic and Neuroendocrine Changes in Response to Chronic Corticosterone Exposure During Adolescence in Male and Female Rats

“…Specifically, in mice, chronic corticosterone treatment leads to significant weight gain and increased markers of the metabolic syndrome (23,28,29), whereas rats show significant weight loss (12,13,17). Allthough it is unclear what mediates these diametrically opposed results in mice and rats, it should be noted that circulating corticosterone level induced by oral corticosterone treatment are significantly higher in mice than rats, despite being exposed to similar doses (23).…”