Project 466849

Insulin has saved millions of lives world widely for a century, while GLP-1 as an incretin, stimulates insulin secretion postprandially. GLP-1 receptor (GLP-1R) agonists (GLP-1RAs) including liraglutide (Lira) are therapeutic agents for subjects with diabetes or obesity. Scientists have learned for years that GLP-1 and GLP-1RAs exert extra-pancreatic functions, which explains their capability in treating insulin resistance. Our lab is particularly interested in hepatic function of GLP-1RAs and have revealed recently that hepatic hormone FGF21 is the linkage molecule that mediates functions of Lira in reducing body weight and improving metabolic homeostasis in high fat diet challenged mice. As GLP-1R is not expressed in mouse or human liver, we hypothesize that brain GLP-1R mediates effects of peripheral Lira administration on stimulating hepatic FGF21 production; that Lira and other GLP-1 based drugs also improves FGF21 sensitivity, which contributes to insulin sensitivity improvement; and that the GLP-1/FGF21 axis also functions in white adipose tissues (WAT), which contributes to improved metabolic homeostasis. A) I will test whether the stimulatory effect of peripheral Lira treatment on FGF21 expression is attenuated in brain specific GLP-1R knockout mice. B) I will establish both in vitro and in vivo tools to measure FGF21 sensitivity, and assess whether improvement on FGF21 sensitivity leads to improved insulin sensitivity. C) I will test whether Lira treatment increases WAT browning and energy expenditure, and whether GLP-1R and adipose tissue produced FGF21 are involved. My study will deepen our knowledge on the extra-pancreatic function of GLP-1, and pave the way for the development of future therapeutic approach for metabolic disorders including T2D.