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  • Excessive adiposity is also a key pathogenic

    2022-01-24

    Excessive adiposity is also a key pathogenic factor in the development of CVD. Through reductions in bodyweight, GPR120 agonism is therefore also implicated as a potential therapy for obesity and heart and vessel disease. In addition to weight loss, when compared with their wild-type littermates, GPR120−/− mice fed a high fat diet develop dyslipidemia exhibiting decreased plasma levels of the unsaturated FAs linoleic, oleic and palmitoleic acid, while exhibiting increased plasma triglycerides and levels of the proinflammatory arachidonic Bestatin hydrochloride and saturated FAs palmitic acid and stearic acid, which was not seen in mice fed a chow diet [5]. Furthermore, Oh et al.[8] showed that the ability of α-LA to reduce plasma triglycerides is lost in GPR120 knockout mice. These results confirm the potential for GPR120 in protecting from diet-induced dyslipidemia. High circulating levels of saturated fats and triglycerides are a known risk factor for the development of atherosclerotic lesions and subsequent heart failure, infarct and stroke. Further to this, GLP-1 is also capable of improving cardiomyocyte glucose uptake [66], which might suggest a role in enhancing cardiac metabolic function in the presence of insulin resistance and overt T2DM. Therefore GPR120 agonism could be a valid target for abrogating cardiovascular complications seen in metabolic disease.
    Concluding remarks Overall, GPR120 agonism appears likely to have positive outcomes on health and the current data suggest GPR120 activation to be a valid pharmaceutical target for the treatment of metabolic disease. However the findings of Wu et al.[16] demonstrating that GPR120 activation promoted tumor formation and angiogenesis suggest that GPR120 agonists could be contraindicated in terms of cancer promotion and progression. Thus, despite promising early findings in terms of metabolic health, it is important to note that research into the systemic functions of GPR120 is largely in its initial stages of preclinical studies. To prescribe GPR120 agonists with confidence for the treatment of obesity, T2DM and/or CVD, it will be important that future studies examine in detail the effects of GPR120 agonists in tissues that are involved in maintaining metabolic health, such as skeletal and cardiac muscle, and also the cumulative effects on systemic parameters of metabolic health in the long term.
    Acknowledgements L.M.C. was supported by a scholarship (PB 10 M 5472) from the National Heart Foundation of Australia. A.J.M. was supported by the Australian Government's Collaborative Research Networks (CRN) program.
    Introduction Obesity has been associated with increased prevalence of cardiometabolic risk factors [1]. In fact, for a long time, body fat distribution, particularly ectopic fat deposition, has been indicated as a trigger to cardiovascular disease in obese adults [2], [3], [4]. It has been well established that chronic, low-grade inflammation plays a pivotal role not only in the progression of obesity, but also in the onset of vascular damage and cardiovascular diseases. One of the main contributors to this scenario is the consumption of high-fat (HF) diets, which induce several changes in genes associated with inflammatory responses. It is well established that saturated fatty acids induce not only the upstream activation of Toll-like receptor 2/4 (TLR 2/4), but also proteins involved in endoplasmic reticulum (ER) stress, leading to worsening of insulin signaling in endothelial tissue [5], [6]. Several reports have shown TLR-4 activation and ER stress engagement being causally associated with harmful cardiometabolic consequences [7], [8]. In addition, the direct effects of innate immune response and ER stress on the arterial wall seems to characterize the “first hit” of atherogenesis, contributing to atherosclerotic plaque development, progression and rupture [9], [10]. Different lines of investigation have provided some support to the excess of sugar intake as the main cause of metabolic disorders commonly associated with obesity [11], [12]. Although our understanding of how and which nutrient contributes most to obesity remains unclear, the replacement of saturated fat and high glycemic index foods with unsaturated fatty acids and low glycemic index food, respectively, can provide substantial cardiometabolic benefits [13], [14]. Mammals have an effective metabolic system engaged on converting excessive energy into lipids. In the de novo lipid synthesis mediated by acetyl-CoA carboxylase and fatty acid synthase pathways, palmitic acid (C16:0) is the first fatty acid produced [15]. Not surprisingly, C16:0 is one of the main TLR agonists that induce inflammatory injuries in myocardium [16] and aorta [17].