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Regulation of Macronutrient Intake by Fibroblast Growth Factor 21
by
Jensen-Cody, Sharon O
in
Medicine
/ Pharmacology
2020
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Regulation of Macronutrient Intake by Fibroblast Growth Factor 21
by
Jensen-Cody, Sharon O
in
Medicine
/ Pharmacology
2020
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Regulation of Macronutrient Intake by Fibroblast Growth Factor 21
Dissertation
Regulation of Macronutrient Intake by Fibroblast Growth Factor 21
2020
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Overview
Metabolic syndrome is a major health risk in the United States and imbalances in macronutrient intake can contribute to the development of this disease. While there is evidence in humans for independent appetites for macronutrients (fats, proteins, and carbohydrates), the mechanisms that determine appetites for specific macronutrients is lacking. Preferences for carbohydrates in particular can be strong, as sugars contribute a major source of energy. Little is known, though, about central integration of peripheral nutrient signals. Our studies seek to understand how fibroblast growth factor 21 (FGF21), a hepatic endocrine hormone, signals to the brain to regulate macronutrient consumption. FGF21 signals through a receptor complex comprised of FGF receptor complex 1 (FGFR1c), and its co-receptor, β-klotho (KLB). While FGFR1c is ubiquitously expressed, KLB is more selectively expressed, conferring FGF21’s specificity.In this work, we characterize KLB expression both centrally and in peripheral tissues to uncover potential target sites of FGF21 signaling. Furthermore, we show that FGF21 decreases sugar intake by signaling to glucose-sensing glutamatergic neurons within the ventromedial hypothalamus (VMH), while acting on glutamatergic neurons outside of the VMH to mediate sweet-taste preference. FGF21 is also required for the metabolic effects of protein deficient diets in lowering body weight and improving insulin sensitivity. Herein, we demonstrate that FGF21 signaling to glutamatergic neurons is required to facilitate low-protein diet-mediated body weight loss but is not required to mediate increases in insulin sensitivity. Through these studies, we have identified new mechanistic information into this liver-to-brain hormonal axis that regulate central pathways controlling energy homeostasis.
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