D-Allulose Reduces Weight More Persistently than Oral Semaglutide While Both Equally Elevate Grip Strength in Diet-Induced Obese Mice

Background: Rare sugar D-Allulose, a zero-calorie sweetener, markedly ameliorates obesity. It reportedly stimulates the release of endogenous glucagon-like peptide 1 (GLP-1) to activate vagal afferent and directly influences the neurons in hypothalamic arcuate nucleus (ARH), thus evoking vagal and central nervous routes. D-Allulose can now be produced substantially, being expected for diet therapy. Oral form GLP-1 receptor agonist (GLP-1RA), Oral semaglutide (O-Sema), without injection markedly ameliorates obesity. It evokes only central nervous route. Thus, these GLP-1-based substances utilize common/distinct routes, suggesting common/distinct effects on obesity and related disorders including sarcopenia. To address it, this study precisely compared their effects. Methods: O-Sema and D-Allulose were administered to diet-induced obese mice under identical conditions, equivalent doses, oral gavage, and food/water deprivation. Acute and sub-chronic effects on food intake, body weight and grip strength were measured. Results: Acutely, D-Allulose rapidly and O-Sema slowly reduced feeding. Sub-chronically, D-Allulose and O-Sema profoundly reduced food intake and weight in the early period (0–3 days) of treatment. The weight loss was diminished with O-Sema but maintained with D-Allulose in the late period (4–10 days) and after termination of treatment. D-Allulose and O-Sema increased muscle strength. Mechanistically, D-Allulose and semaglutide similarly activated anorexigenic leptin-responsive neurons while only D-Allulose significantly inhibited orexigenic ghrelin-responsive neurons in ARH. Conclusions: D-Allulose and O-Sema equally elicit weight reduction possibly via the central nervous route including ARH anorexigenic neuron activation. The weight loss is rebounded with O-Sema, while it is maintained with D-Allulose possibly via combined vagal afferent and central nervous routes including ARH orexigenic neuron inhibition. Their optimal use potentially provides precise control of obesity and related disorders.