Hillgartner, Frank Bradley, PhD
Nutritional regulation of expression of fibroblast growth factor-21, a novel hepatokine that attenuates obesity and diabetes
General Research Subject: Type 2 Diabetes
Focus: Signal Transduction (Non-Insulin Action)\Hormones, Signal Transduction (Non-Insulin Action)\Transcriptional Regulation
Type of Grant: Basic Science
Project Start Date: January 1, 2012
Project End Date: December 31, 2014
Diabetes Type: Type 2 diabetes
Fibroblast growth factor 21 (FGF21) is a recently identified hormone that reverses obesity and diabetes when injected into experimental animals. In previous research, we found that chenodeoxycholic acid (CDCA), a component of the bile secreted into the gastrointestinal tract, enhances FGF21 production in liver, the primary organ that secretes FGF21 in the body. The mechanism for this effect involves the activation of the FGF21 gene. We also observed that fibroblast growth factor 19 (FGF19), a hormone secreted by the intestine, enhances FGF21 production by the liver. In contrast to CDCA, FGF19 regulation of FGF21 production does not involve activation of the FGF21 gene. The goal of this research project is to develop new pharmacological and nutritional approaches to enhance FGF21 production and reverse obesity and diabetes. As a key step in achieving this goal, we will determine how CDCA and FGF19 stimulate FGF21 production. With respect to CDCA regulation of FGF21 production, we will identify the FGF21 gene sequences and associated proteins that mediate the effects of CDCA on FGF21 gene expression. We will also characterize the role of cell signaling enzymes in mediating the effect of CDCA on FGF21 gene expression. With respect to FGF19 regulation of FGF21 production, we will determine whether alterations in FGF21 synthesis and/or FGF21 degradation mediate the increase in FGF21 production caused by FGF19. The information obtained from this grant application will be vital in developing new drugs and/or nutritional supplements to enhance FGF21 production in the body and reduce obesity and diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The research in this grant proposal addresses the development of novel therapeutic strategies for ameliorating type 2 diabetes. Fibroblast growth factor 21 (FGF21) is a recently identified hormone that is secreted by the liver. Previous research has shown that pharmacological administration of FGF21 causes a striking reversal of diabetes in animal models of type 2 diabetes. Another attractive feature of FGF21 administration is that it causes very few side effects. These observations have generated intense interest in FGF21 as a potential therapy for treating type 2 diabetes in humans. Unfortunately, the effectiveness of FGF21 administration in ameliorating diabetes in humans has been hampered by the rapid degradation of FGF21 in the body. An alternative strategy to enhance FGF21 levels/action in humans is to increase the endogenous production of FGF21 in the body. This ADA research proposal will explore novel nutritional mechanisms that control the production of FGF21 by the liver. One such mechanism is activated by bile acids, natural compounds that are synthesized in the liver and secreted into the gastrointestinal tract in response fat consumption. We have shown that bile acids cause a robust increase in FGF21 secretion by the liver. Another nutritional mechanism is activated by fibroblast growth factor 19 (FGF19), a gastrointestinal hormone that is structurally related to FGF21. FGF19 also increases the secretion of FGF21 by the liver. Knowledge gained from our studies investigating how bile acids and FGF19 stimulate FGF21 production will ultimately be used to develop new nutritional and pharmacological approaches to increase endogenous FGF21 production and reverse type 2 diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The manipulation of FGF21 levels/action in the body represents a very promising approach to combat type 2 diabetes based on studies investigating the effects of recombinant FGF21 administration in experimental animals. Accordingly, the use of recombinant FGF21 administration as a therapy for treating diabetes in humans is currently in phase one trials. It is highly conceivable that in the next 5 years, alternative approaches to increase FGF21 levels/action will be developed based on our studies analyzing nutritional mechanisms controlling endogenous FGF21 production in the body. In support of this possibility, it has been shown that consumption of certain bile acids attenuates diabetes in experimental animals. One may speculate that this effect is mediated by an elevation in FGF21 production in the body. Hence, our studies may lead to the development of non-toxic bile acid derivatives to treat and prevent diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
As an undergraduate majoring in nutrition, I became interested in how carbohydrates and fats were metabolized in the body. This interest spurred a career in research (34 years) investigating the mechanisms controlling carbohydrate and fat metabolism. As dysregulation of carbohydrate and lipid metabolism is a prominent feature of diabetes, it is natural that my research has focused on this disease. Another impetus for studying diabetes is the very high incidence of diabetes in my home state of West Virginia. This ADA award will play a crucial role in expanding our efforts in a high impact area of diabetes research. From a personal standpoint, this is one of the most exciting projects that I have supervised in my laboratory.
In what direction do you see the future of diabetes research going?
I see diabetes research expanding in two areas. The first area is the use of genetic analyses to undercover new factors contributing to the etiology of type 2 diabetes. I expect that the identification of these factors will lead to additional nutritional and/or pharmacological approaches for treating diabetes. This is how the FGF21 research field began. The second area is the development of psycho-social strategies aimed at modifying behavior contributing to obesity and type 2 diabetes. From a practical standpoint, behavioral modification is an effective approach for treating and preventing obesity-induced insulin resistance and type 2 diabetes.
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