Regulation of glucose homeostasis by FGF21

Abstract

Fibroblast Growth Factor 21 (FGF21) is an endocrine hormone derived from the liver that exerts pleiotropic effects on the body to maintain overall metabolic homeostasis. During the past decade, there has been an enormous effort to understand the physiological roles of FGF21 in regulating metabolism and to identify the mechanism for its potent pharmacological effects to reverse diabetes and obesity. Through both human and rodent studies, it is now evident that FGF21 is dynamically regulated by nutrient sensing and consequently functions as a critical regulator of nutrient homeostasis. In addition, recent studies with new genetic and molecular tools have provided critical insight into the actions of this exciting endocrine factor. Dissection of these FGF21regulated pathways has tremendous potential for new targeted therapies to treat metabolic disease. The goals of this thesis are 1) to identify FGF21's physiological role as a carbohydrate-regulated signal of macronutrient-specific satiety and 2) to determine the mechanism and tissues responsible for mediating the pharmacological effects of FGF21. To address the first goal, we used different FGF21 genetic knockout mouse models to determine if loss of FGF21 would affect macronutrient preference. We found that loss of FGF21 led to an increase in simple sugar intake whereas this had no effect on other macronutrients such as lipid or protein. To further characterize the relationship between carbohydrates and FGF21, in vitro and in vivo techniques revealed that FGF21 transcription in the liver increased in response to carbohydrate intake and this was dependent on the presence of a transcription factor activated by carbohydrates, ChREBP. We next addressed whether or not increased FGF21 levels would affect preference for simple sugars. We found that in response to increased circulating levels of FGF21, either v through genetic overexpression or pharmacological administration, FGF21 would lead to a significant decrease in caloric and non-caloric sweeteners. Finally, we were able to determine that FGF21 was signaling to the hypothalamus to mediate this suppression of simple sugar intake through region specific knockout of the co-receptor beta-klotho. To address the pharmacological actions of FGF21, we generated an adiposespecific KLB KO mouse using mice that express Cre-recombinase under the adiponectin promoter. These mice lack the co-receptor for FGF21 in adipose tissue and are a more reliable adipose knockout model than previous studies that have used aP2-Cre mice. We were able to determine that the acute glucose lowering effects of FGF21 are mediated through direct signaling to adipose tissue and that FGF21 enhances insulin sensitivity by increasing glucose uptake in brown adipose tissue. However, FGF21 mediates its chronic effects, including lowering body weight and triglycerides, by signaling to some other non-adipose tissue. Overall our work has shown that FGF21 can significantly regulate glucose metabolism through multiple mechanisms.