Dissertation
Exploring FGF21's mechanism of acute insulin sensitization
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2023
DOI: 10.25820/etd.006887
Abstract
Fibroblast growth factor 21 (FGF21) in an endocrine hormone that regulates carbohydrate homeostasis and is also a potential drug target for treating diabetes and other metabolic diseases. Circulating FGF21 is derived primarily from the liver and signals through a receptor complex consisting of β-klotho (KLB) and FGFR1c on tissues including the central nervous system and adipose tissues to mediate its metabolic effects. Acute administration of FGF21 to rodents enhances insulin sensitivity through direct actions on brown adipose tissue (BAT). However, FGF21’s insulin-sensitizing effect is variable in adult humans as it depends on the FGF21 analog used. This inconsistency between rodents and humans could be because adult humans have less BAT than mice when normalized to total respective body weights. Since BAT and skeletal muscle are derived from the same progenitor cells, we wanted to know if skeletal muscle could serve as a target tissue for FGF21-mediated enhancement of insulin-stimulated glucose uptake in humans. To explore the mechanism for FGF21’s acute insulin-sensitizing effect while examining whether this effect could be applied to skeletal muscle, a tissue which lacks the obligate FGF21 coreceptor KLB, we generated a mouse model overexpressing KLB in skeletal muscle. FGF21 did not improve insulin sensitivity through KLB-expressing skeletal muscle. To investigate FGF21’s mechanism of improving insulin sensitivity through BAT, we employed a unique GLUT4 translocation reporter system that dynamically reports insulin sensitivity in real-time. Here we show that FGF21 enhances GLUT4 translocation in BAT and brown adipocytes. Furthermore, we used global phosphoproteomics to identify signaling intermediates that are phosphorylated by FGF21 in primary brown adipocytes. These studies provide unique insight into the insulin-sensitizing effects of FGF21 and highlights specific FGF21 signaling intermediates to be characterized in pursuit of a novel therapeutic strategy for diabetes.
Details
- Title: Subtitle
- Exploring FGF21's mechanism of acute insulin sensitization
- Creators
- Sheps King-McAlpin
- Contributors
- Matthew Potthoff (Advisor)Eric Taylor (Committee Member)Brian O'Neill (Committee Member)Julien Sebag (Committee Member)Songhai Chen (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacology
- Date degree season
- Autumn 2023
- DOI
- 10.25820/etd.006887
- Publisher
- University of Iowa
- Number of pages
- ix, 95 pages
- Copyright
- Copyright 2023 Sheps King-McAlpin
- Language
- English
- Date submitted
- 07/05/2023
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 72-95).
- Public Abstract (ETD)
Type 2 diabetes (T2D) is a global epidemic that is increasing at an alarming rate. This metabolic disorder is a risk factor for many other serious health problems including heart disease, stroke, kidney disease, nerve damage, and vision problems. T2D is not being effectively treated with diet, exercise, and current FDA-approved medications. So, there is a need for new therapies. Fibroblast growth factor 21 (FGF21) is a liver-derived hormone has been studied as a potential therapy for metabolic disorders. When given as a medication, FGF21 drastically decreases blood glucose (sugar) in diabetic mice. However, FGF21 does not decrease blood glucose in diabetic humans to nearly the same extent. We have a potential explanation for this discrepancy. We previously showed that FGF21 causes glucose uptake in mouse brown adipose tissue (BAT). This effect is dependent upon FGF21's ability to signal to BAT. Humans have much less BAT than mice. Furthermore, the little BAT that adult humans have oftentimes gets converted to white adipose tissue during the development of T2D. Since BAT is likely not available for FGF21's glucose-lowering effect in diabetic humans, we wanted to know if FGF21 can cause glucose uptake in human muscle tissue instead. We thought this may be possible because BAT and muscle tissue both have the physiological function of taking up glucose in response to healthy hormonal signaling in mammals. Both tissues also share developmental origin. Through genetic manipulation of FGF21 signaling in mice, we determined that FGF21 cannot increase glucose uptake in muscle tissue. Since FGF21's glucose-lowering effect is BAT-specific, we studied the signaling proteins in brown fat cells that facilitate this effect. We identified FGF21 signaling proteins to be further studied in the pursuit learning how FGF21 lowers blood glucose. A better understanding of this mechanism will help facilitate the development of new therapies for T2D.
- Academic Unit
- Neuroscience and Pharmacology
- Record Identifier
- 9984546751002771
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