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  • salinomycin As early as glucagon was shown to increase energ

    2021-09-24

    As early as 1957, glucagon was shown to increase salinomycin expenditure in rodents in both pair-feeding studies and through directly increasing oxygen consumption [23], [24]. This has more recently been confirmed in man, through indirect calorimetry during glucagon infusions [25], [26], [27]. This contrasts with GLP-1; in man, GLP-1 has been shown to either have no effect on energy expenditure [25], [26], [28], [29], or indeed may suppress energy expenditure [30]. In rodents, the results are also ambiguous, with GLP-1 agonists both transiently increasing [31], [32] and decreasing [33] oxygen consumption. In these experiments, OX-SR had a variable effect on food intake. Over the 3 days of the pair-feeding study, it increased food intake. In contrast, when administered alone in the metabolic cage experiments, OX-SR reduced food intake. GLP-1 is an established anorectic agent. Consistent with this, OX-SR-Glu3, a GLP-1 receptor agonist, caused a significant reduction in food intake compared to controls, and blocking endogenous GLP-1 with Ex 9–39 caused an increase in food intake. GLP-1 has a dose-dependent anorectic effect, progressively stronger at higher doses [26], [34], [35]. Glucagon also has a dose-dependent effect on food intake, but this is not linear: at low doses, it can cause a hyperphagia, whereas at high doses, it reduces food intake [36], [37]. The increase in food intake at low dose of glucagon is likely an attempt to compensate for the increased energy expenditure; similar hyperphagia is seen in other conditions of increased energy expenditure such as thyrotoxicosis and after beta-3 adrenergic agonist administration [38], [39]. In line with this, it appears that the glucagon activity of OX-SR can counteract the anorectic GLP-1 effect within the peptide. This glucagon activity led to a relative increase in food intake in the OX-SR group compared to the OX-SR-Glu3 group, and an absolute hyperphagia in the OX-SR group in the pair-feeding study. Dose finding studies using OXM analogues have shown that the balance between the anorectic effect of GLP-1 receptor activation, and GCG receptor-mediated energy expenditure is fine and non-linear. Small dose adjustments in OXM analogues can switch them from being anorectic to orexigenic. The balance is also affected by other ’background’ factors such as the age and size of the animal, and the type of cage [9]. These factors together may explain the variability in food intake seen within our experiments. Higher doses of OX-SR could have been used, with a more pronounced GLP-1 effect. This would have produced a more reproducible and significant reduction in food intake; however, this would result in substantial weight loss, which would raise significant welfare concerns. In man, the higher levels of GLP-1 activity are likely to manifest as unacceptable levels of nausea. Therefore the lower dose is more likely to represent a dose that would be acceptable in man. Glucagon also has a dose-dependent effect on energy expenditure, with increased energy expenditure at higher doses [25], [26]. Whether a similar dose response on energy expenditure is seen with oxyntomodulin and its analogues remains to be determined; though this would be expected given the glucagon activity, it may be that the mechanisms that suppress energy expenditure after GLP-1 administration become active and lower the overall energy expenditure effect. Understanding the relationship between the doses of GLP-1 and glucagon on energy expenditure will be important in optimising the energy expenditure effects of any OXM analogues developed to treat obesity. OX-SR did not increase locomotor activity in rats. Other studies using OXM analogues showed no change in physical activity in rodents [17], [18]. Indeed, when administered before the onset of the dark period, when rodents are most active, there was tendency for locomotor activity to be suppressed despite a significant increase in energy expenditure. When glucagon is administered to rodents, there is also increased energy expenditure but no change in locomotion, suggesting that both OXM and glucagon increase energy expenditure by upregulating energy-demanding metabolic processes [40]. These animal results contrast with the study by Wynne et al. in obese humans using native OXM [5] where there was no difference in resting energy expenditure following saline or OXM administration, but OXM did cause a significant increase in physical activity related energy expenditure. The difference in these results may reflect the environment in which the studies occurred: Wynne et al.’s participants were in a ‘free-living’ environment, whereas animals in metabolic cages have little scope for activity as the cages are small. It would be pertinent to see the effect of OXM and related analogues on animal given the opportunity to undertake greater voluntary activity, such as in a running wheel.