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  • Studies utilising GPR mice however report

    2022-05-13

    Studies utilising GPR55−/− mice, however, report different effects of GPR55 on body weight and insulin sensitivity. Genetic deletion of GPR55 appears to have no effect on overall body weight 5, 6, 7. However, one of these studies found increased fat deposition and insulin resistance in GPR55−/− mice owing to decreased physical activity, while no significant change in food intake or body weight was observed in these animals [6]. Furthermore, Moreno-Navarrete et al.[4] report that ob/ob mice had lower levels of GPR55 mRNA and protein in white adipose tissue compared to wild-type littermates, and rats fed a ‘high-fat’ diet had lower GPR55 expression compared to rats on a ‘low-fat’ diet. Collectively, these findings suggest that GPR55 plays different metabolic roles in distinct species, making the translation between rodents and human problematic. No clear disparity in pharmacology or signalling between rodent and human GPR55 has yet been described, making these findings difficult to reconcile. However, whole-body GPR55 knockout mice may have numerous compensatory changes in other genes that influence fat deposition and metabolism, leading to contradictory results. Alternatively, GPR55 knockout may exert effects on other systems that ultimately influence adipose physiology, such as adipose inflammation, a potential conflicting factor in the Meadows et al. study [6]. Selective GPR55 antagonists have recently become available, and these will enable more thorough elucidation of the role of GPR55 in fat deposition (Box 1).
    GPR55 and LPI Effects on Pancreatic Function Pancreatic β Ropivacaine HCl are crucial for maintaining proper insulin levels and glucose homeostasis. Thirty years ago, LPI was shown to stimulate insulin release from cultured pancreatic islets [8], but it took almost 20 years to identify GPR55 as the receptor involved. It is now known that GPR55 is expressed in rodent and human islets, and activation of the receptor increases insulin release from cultured rodent cells 9, 10. Furthermore, GPR55 agonists were shown to decrease glucose levels and increase plasma insulin levels [9] in rodents. This small number of rodent studies suggests that GPR55 may be therapeutically relevant for insulin sensitivity and glucose homeostasis; however, further research in this area is required.
    GPR55 and LPI Effects on the Gastrointestinal (GI) System GPR55 is expressed in the human GI tract [2], but its role in the gut remains largely unknown. In rodent, GPR55 is expressed in distinct regions of the gut including the duodenum, jejunum, ileum, and colon. It is known that GPR55 is expressed not only on the GI endothelial cells but also on the myenteric neurons of the colon, suggesting that it may play a role in GI motility. Indeed, activation of GPR55 appears to inhibit gut motility [11]. Furthermore, GPR55 also regulates intestinal inflammation. GPR55 antagonists reduce intestinal inflammation in in vivo rodent models [12]. These few studies raise the possibility that GPR55 modulators may represent novel therapeutics for intestinal disorders (Box 1); however more work will be necessary to elucidate the role of GPR55 in GI physiology.
    GPR55 and LPI Effects on Cancer While research into the GPR55–LPI signalling axis in metabolism is gradually coming to fruition, it has already been shown to exert multifarious effects on cancer. In the 1980s, LPI was shown to be released from thyroid cells and fibroblasts transformed with the oncogene Ras. LPI released from cancer cells can drive cell proliferation via autocrine activation of GPR55 on the cell surface, a significant finding because women with ovarian cancer have high plasma LPI levels [13]. GPR55 mRNA is expressed in tumors from diverse human cancers, ranging from brain to pancreatic cancer, and is expressed more highly in breast and pancreatic tumors of high histological grade compared to low-grade and healthy tissue [14]. GPR55 appears to be a causative factor because overexpression of GPR55 in cancer cell lines leads to increased proliferation whereas siRNA knockdown of GPR55 renders cells less proliferative [14]. Taken together, these studies suggest that increased GPR55 expression may induce cancer progression. In agreement with this hypothesis, it has recently been shown that GPR55 antagonists (Box 1) inhibit migration and adhesion of colon cancer cells and decrease liver metastasis in mice [15].