Dissertation
Regulation of learning and memory by fibroblast growth factor 21
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2022
DOI: 10.25820/etd.006508
Abstract
The liver is an essential organ responding to energy balance challenges by regulating glucose and lipid homeostasis. Hepatokines secreted from the liver are involved in many metabolic functions regulation by acting through multiple peripheral organs and central nervous system (CNS). Altered hepatokines levels and impaired signaling contribute to pathologies of metabolic syndromes, such as obesity, type 2 diabetes, cardiovascular diseases and related cognitive dysfunctions. FGF21 is one of the endocrine hormones primarily produced from the liver. FGF21 was shown to be important for maintaining energy homeostasis across species and is now a promising therapeutic reagent for treating metabolic syndromes.Circulating FGF21 is mainly produced from the liver and the basal plasma FGF21 level is low unless induced by metabolic challenges including, prolonged fasting, high carbohydrate/fat diet and low protein diet. Additionally, endoplasmic and mitochondria stresses regulate both peripheral and central FGF21 production. Both endogenous and pharmacological FGF21 function as a master regulator of metabolism. FGF21 enhances insulin sensitivity directly through acting on adipose tissues and the brain. FGF21 promotes weight loss in obesity and diabetes models by increasing energy expenditure. Pharmacological FGF21 administration remarkedly decreases liver fat in non-alcoholic steatohepatitis (NASH) animal models and human patients. Furthermore, multiple studies report FGF21 role in regulating macronutrient intake. For example, FGF21 reduces simple sugar intake and alcohol preferences in animal models by signaling through the CNS (i.e., ventral medial hypothalamus and basal lateral amygdala). Importantly, besides FGF21 functions in metabolism, recent studies suggest FGF21 potential role in neuron protection to alleviate metabolic disease associated cognitive impairment, aging and Alzheimer’s dementia. The work below highlights FGF21 function in memory regulation and the potential mechanism by which FGF21 regulates learning and memory processes. We demonstrate that FGF21 is expressed in the CNS (e.g, retrosplenial cortex), and central FGF21 is important for memory. Additionally, central FGF21 does not regulate energy homeostasis or macronutrient preferences. We also show that pharmacological FGF21 administration improves spatial memory and hippocampus is a potential target where FGF21 signals to regulate learning and memory processes. Altogether, our findings reveal a novel role of FGF21 in regulating learning and memory and mechanisms by which FGF21 facilitates memory formation.
Details
- Title: Subtitle
- Regulation of learning and memory by fibroblast growth factor 21
- Creators
- Bolu Zhou
- Contributors
- Matthew J Potthoff (Advisor)Yuriy M Usachev (Committee Member)Huxing Cui (Committee Member)Catherine Marcinkiewcz (Committee Member)Deniz Atasoy (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Pharmacology)
- Date degree season
- Summer 2022
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.006508
- Number of pages
- xi, 74 pages
- Copyright
- Copyright 2022 Bolu Zhou
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 65-74).
- Public Abstract (ETD)
Metabolic diseases and the associated cognitive impairment pose a major risk to the health of worldwide. While the approaches to alleviate metabolic syndromes are well-studied and developed, the treatment for neurodegeneration resulting from metabolic diseases is lacking. Studies on neurodegeneration are abundant, however, little is known about its mechanism and proper treatment is needed to be explored. Our studies reveal how a metabolic messenger, fibroblast growth factor 21 (FGF21), a liver endocrine hormone, regulates learning and memory processes. FGF21 is known to regulate energy homeostasis through acting in both peripheral tissues and the brain. FGF21 is a therapeutic agent in clinical trials to improve metabolic profiles in obesity and diabetes patients by decreasing body weight and increasing energy expenditure. FGF21 signals to a receptor complex consisting of FGF receptor complex 1 (FGFR1c) and an essential co-receptor β-clotho (KLB) to elicit its biological functions.
In this work, we characterized FGF21 expression in both peripheral tissue and central nervous system to comprehensively investigate FGF21 functions in cognition. We show that FGF21 treatment improves spatial learning and memory possibly by signaling to the hippocampus. Central FGF21 is required for maintaining spatial memory storage, however, does not regulate energy homeostasis or macronutrient intake. Herein, we demonstrate that pharmacological and central FGF21 are important in regulating spatial memory formation. Through these studies, we have identified a new role of FGF21 in regulating learning and memory processes beyond metabolic regulation.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9984285453502771
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