Fibroblast Growth Factor Receptor 4 (FGFR4) Deficiency Improves Insulin Resistance and Glucose Metabolism under Diet-induced Obesity Conditions

Abstract

Background:The role of FGFR4 in glucose and energy metabolism is not well defined. Results: FGFR4-deficient mice display improved glucose metabolism and insulin sensitivity under high fat conditions. Conclusion: These improvements are mediated in part by bile acid actions and induction of endocrine hormones. Significance: FGFR4 antagonists alone, or in combination with other agents, could serve as a novel treatment for diabetes.

MitoNEET Deficiency Alleviates Experimental Alcoholic Steatohepatitis in Mice by Stimulating Endocrine Adiponectin-Fgf15 Axis

“…The increased adiponectin in ethanol-fed mNTKO mice might lead to ileum Fgf15 induction. On the other hand, injection of adeno-associated virus-expressing Fgf15 in mice increased adipose adiponectin synthesis (22). Therefore, it is possible that the ileum Fgf15 production might be induced by ethanol feeding to mNTKO mice, which, in turn, increased adipose adiponectin production.…”

“…For instance, circulating adiponectin and Fgf15 were concomitantly elevated in Fgfr4 knock-out mice leading to improvement in glucose metabolism, insulin sensitivity, and reduction in body weight under high fat diet feeding (22). Emerging evidence also demonstrates a role of adiponectin in regulating bile acid homeostasis.…”

“…Growing evidences suggest an association and cross-talk between adipocyte-derived adiponectin and ileum Fgf15 in the regulation of hepatic bile acid homeostasis, lipid metabolism, and inflammation (22)(23)(24)(25)(26)(27). For instance, circulating adiponectin and Fgf15 were concomitantly elevated in Fgfr4 knock-out mice leading to improvement in glucose metabolism, insulin sensitivity, and reduction in body weight under high fat diet feeding (22).…”

Mice abundant in muricholic bile acids show resistance to dietary induced steatosis, weight gain, and to impaired glucose metabolism

“…This phenotype is shared with several other mouse models such as germ-free, fibroblast growth factor receptor 4-deficient, and antibiotic-treated mice [3,8]. Interestingly, these three mouse models are all resistant to dietary induced glucose intolerance [9][10][11][12]. We hypothesized that the presence of high levels of MCAs would be important for this resistance and that, accordingly, Cyp8b1 -/-mice should be resistant to glucose intolerance as well.…”

Utilities of AAV vectors in in vivo phenotypic screening and functional studies

“…In most applications, AAV can also replace the need for transgenic animals. (2) High levels of TOI expression can be achieved, and the expression levels are more precisely titratable than with HTV by injecting different amounts of AAV particles [7]. (3) The high transduction efficiency in liver and in multiple tissues, allowing greater than 95% of parenchymal cells to express TOI, expands the ability to study not only secreted proteins but also transmembrane proteins.…”