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  • The mechanism underlying the anorectic effect of

    2022-08-05

    The mechanism underlying the anorectic effect of OXM is well established. It is centrally mediated via GLP-1 receptor activation, confirmed by both pharmacological blockade of the GLP-1 receptor, and using GLP-1 receptor knock-out mice [2], [11], [12]. However, the mechanism by which it increases energy expenditure remains controversial, and both the glucagon and GLP-1 receptors have been implicated. Specific alteration to the OXM peptide has allowed the effect of activating the different receptors to be investigated. Glucagon and OXM have glutamine, a neutral polar residue at position 3 [6]. In contrast, both GLP-1 and its naturally occurring analogue Exendin-4 (Ex-4), have an acidic glutamate residue in this position and are unable to activate the glucagon receptor. Using targeted peptide engineering to substitute the third residue of OXM with glutamic SC75741 (OXMQ3E), the peptide maintains its activity at the GLP-1 receptor, but loses its ability to activate the glucagon receptor. The action of native OXM has been compared to OXMQ3E in mice. Both peptides suppressed food intake to a similar degree, but weight loss was significantly greater in the OXM group. This additional weight loss indirectly suggests that the glucagon activity in OXM increases energy expenditure [13]. Similarly, in a study comparing OXM analogues engineered to have differing potency at the GLP-1 and GCG receptors, peptides with more glucagon action caused greater weight loss in mice despite causing only a small food intake reduction [14]. Together, these studies suggest that glucagon receptor activation by OXM causes increased energy expenditure, however, other potential explanations for the results, such as increased diuresis or faecal excretion, have not been excluded. Moreover, when OXM is administered via an intracerebroventricular infusion, OXM increases intrascapular brown adipose tissue (BAT) sympathetic activation; GLP-1 receptor knockout prevents this. As activation of BAT increases energy dissipation through thermogenesis, this study suggests the GLP-1 receptor has a role in energy expenditure, at least when OXM is given intracerebroventricularly [15]. Contributing to the uncertainty as to which receptor increases energy expenditure is the difficulty of directly measuring the energy expenditure effects of OXM. The studies mentioned above all use surrogate markers of energy expenditure: comparison of weight loss with food intake, or sympathetic nerve activity in BAT. Indeed, no studies to date have shown an increase in oxygen consumption following OXM administration. This has not been fully explained but may reflect the relative insensitivity of most metabolic cages [16], compounded with the short half-life of OXM, which necessitates multiple daily injections of OXM. A significant increase in energy expenditure in rodents has been measured directly with several different OXM analogues [17], [18], [19]. The reproducibility of these results lends credibility to the idea that OXM does affect energy expenditure. Analogues are increasingly being used to investigate the physiology of peptide hormones, since manipulation of native peptides can increase the half-life and potency of the hormones [17], [19]. We developed a sustained-release OXM analogue, OX-SR. This differs from native OXM by 5 amino acids between residues 16 and 27. These changes allow OX-SR to form a subcutaneous depot, enabling administration as a single daily subcutaneous injection. We directly measured the energy expenditure caused by this analogue within metabolic cages and compared this to the effects of inhibition of both the glucagon and GLP-1 receptors. We were therefore able to effectively determine the relative contribution of these receptors on the energy expenditure effects of OXM.
    Methods
    Results
    Discussion Peptide analogues are a useful tool in the investigation of hormone physiology. To this end, the OXM analogue OX-SR was developed. OX-SR was slightly more potent at both the glucagon and GLP-1 receptors than OXM. It had a sustained release from a subcutaneous depot, taking 6 days for plasma levels to be undetectable compared to 1 day for the same dose of OXM be cleared. OX-SR and OXM had similar plasma half-lives following IV infusion (within the same order of magnitude),suggesting that OX-SR is cleared at a similar rate to OXM by peptidases such as DPPIV and Neprilysin [8]. These characteristics enabled a single low dose of OX-SR to be administered and its physiological effects measured, without the stress associated with repeat administration of OXM.