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    • The relationship between increased GPR expression in the

    2022-08-05

    The relationship between increased GPR120 expression in the EDL skeletal muscle and systemic glucose control is yet to be investigated. However, if the increased expression of GPR120 correlates with enhanced insulin-stimulated glucose uptake in skeletal muscle, particularly the EDL muscle, this might provide a mechanistic explanation behind enhanced systemic glycemic control. Similarly to the EDL muscle, GPR120 mRNA expression was also increased in cardiac tissue in response to diet-induced obesity in rats [15]. This could support a role for GPR120 in regulating Rat HGF / Hepatocyte Growth Factor Protein glucose uptake. Although the adult heart predominantly relies on FAs for energy substrate in the healthy state [60], obesity, diabetes and hypertrophic processes in the heart dysregulate the balance between glucose and FA oxidation 61, 62, 63, 64. The cumulative effect of this is decrements in cardiac efficiency and induction of cellular energetic stress caused by metabolic inflexibility. If activation of GPR120 can attenuate insulin resistance in cardiac muscle GPR120 agonists could also have a role in ameliorating cardiac dysfunction in metabolic disease. Furthermore, GLP-1 not only induces pancreatic insulin secretion in response to glucose but also has been shown to enhance glucose uptake directly in skeletal and cardiac muscle cells 65, 66. The consequence of these factors manifests in four separate but interrelated ways in which GPR120 agonist can: (i) enhance systemic glucose control through enhanced insulin signaling; (ii) increase GPR120 expression in muscle tissues; (iii) enhance GLP-1-mediated increase in glucose-stimulated insulin secretion from the pancreas; and (iv) enhance GLP-1-mediated muscle glucose uptake.
    GPR120 modulation of systemic metabolic health GPR120 is a ubiquitous receptor with pleiotropic functioning that supports a role for this receptor in mediating systemic metabolic health (Fig. 3). Regulation of adiposity is modulated by the propensity for adipocytes to store excess energy from ingested lipids and glucose in the form of fat. Partitioning of substrate (i.e. glucose and FAs) away from oxidative pathways predisposes to their storage in adipose tissues as an energy reserve. GPR120 is indeed suggested to be adipogenic 5, 7, 8, 21. Regardless of this, GPR120 knockout mice are more susceptible to diet-induced obesity than their wild-type counterparts [5], implying that GPR120 is protective against diet-induced obesity. Induction of a negative energy balance to promote weight loss must be considered from the point of view of decreased caloric intake and increased energy expenditure. GPR120 has the capacity to modulate taste preferences and induce GLP-1 and CCK which have anorectic and/or satiating effects, both of which have the capacity to regulate gross caloric intake 38, 67. However care must be taken to establish whether GPR120 agonism in taste cells will promote increased intake of energy-dense foods. With respect to increased energy expenditure, immature GPR120−/− mice (9–10 weeks of age) fed a high fat diet are also reported to have reduced energy expenditure during light phases [5]. Although this effect was not observed in mature GPR120−/− mice (15–16 weeks of age), decreased energy expenditure in young animals favors early increases in body mass that without a compensatory mechanism to reduce adiposity will then persist as age increases. Indeed, in the study by Ichimura et al.[5] bodyweight increased in GPR120-deficient mice from week 8 and persisted throughout the duration of the study. In line with increased adiposity, plasma levels of the adipokine leptin have been shown to be increased in GPR120−/− mice fed a high fat diet [5]. Leptin is secreted from adipocytes in a manner that is directly commensurate to systemic adiposity [68]. This is consistent with findings that plasma leptin was increased in GPR120 knockout mice fed a high fat diet [5]. Given that leptin is generally considered protective of obesity and promotes glucose and FA metabolism, the finding of hyperleptinemia in GPR120−/− animals [5] suggests the development of leptin resistance, which often arises subsequent to obesity [69]. However this effect on plasma leptin was not replicated in the study by Oh et al.[8], who demonstrated that leptin levels were unchanged in wild-type and GPR120-deficient mice maintained on a high fat diet. This indicates that further work is needed to qualify the effects of GPR120 on leptin secretion. Interestingly, GPR120 knockout had no effect on plasma adiponectin levels [5], which is again protective against obesity but is usually expressed in lower amounts in the obese state.