GLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose

• Published in: Nature communications Vol. 9; no. 1; p. 113
• Main Authors: Iwasaki, Yusaku, Sendo, Mio, Dezaki, Katsuya, Hira, Tohru, Sato, Takehiro, Nakata, Masanori, Goswami, Chayon, Aoki, Ryohei, Arai, Takeshi, Kumari, Parmila, Hayakawa, Masaki, Masuda, Chiaki, Okada, Takashi, Hara, Hiroshi, Drucker, Daniel J., Yamada, Yuichiro, Tokuda, Masaaki, Yada, Toshihiko
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.01.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 14/10; 631/378/1488/393; 64/60; 692/699/2743/137/773; 692/699/2743/393; Animal models; Animals; Anti-Obesity Agents - pharmacology; Blood Glucose - drug effects; Deactivation; Diabetes; Diabetes mellitus; Drugs; Eating - drug effects; Feeding; Food intake; Fructose - pharmacology; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide-1 Receptor - agonists; Glucagon-Like Peptide-1 Receptor - genetics; Glucagon-Like Peptide-1 Receptor - metabolism; Glucose; Glucose Intolerance - drug therapy; Glucose tolerance; Humanities and Social Sciences; Hyperglycemia; Hyperphagia; Hyperphagia - drug therapy; Inactivation; Intolerance; Male; Metabolic disorders; Metabolic rate; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Obesity; Obesity - drug therapy; Oral administration; Pharmacology; Rats; Rats, Wistar; Science; Science (multidisciplinary); Sensory neurons; Side effects; Signaling; Sugar; vagotomy; Vagus nerve; Vagus Nerve - drug effects; Vagus Nerve - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02488-y

Overeating and arrhythmic feeding promote obesity and diabetes. Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective anti-obesity drugs but their use is limited by side effects. Here we show that oral administration of the non-calorie sweetener, rare sugar d -allulose ( d -psicose), induces GLP-1 release, activates vagal afferent signaling, reduces food intake and promotes glucose tolerance in healthy and obese-diabetic animal models. Subchronic d -allulose administered at the light period (LP) onset ameliorates LP-specific hyperphagia, visceral obesity, and glucose intolerance. These effects are blunted by vagotomy or pharmacological GLP-1R blockade, and by genetic inactivation of GLP-1R signaling in whole body or selectively in vagal afferents. Our results identify d -allulose as prominent GLP-1 releaser that acts via vagal afferents to restrict feeding and hyperglycemia. Furthermore, when administered in a time-specific manner, chronic d -allulose corrects arrhythmic overeating, obesity and diabetes, suggesting that chronotherapeutic modulation of vagal afferent GLP-1R signaling may aid in treating metabolic disorders. The sweetener D-allulose has beneficial metabolic effects in animal models, but its mechanism of action was unclear. Here the authors report that D-allulose triggers GLP-1 release in the gut and GLP-1R signaling on vagal afferents, counteracting arrhythmic overeating, obesity and diabetes.