The finding that served as the foundation for this dissertation is that physiological stressors provoke the transition to an energy-depleted state in the mouse liver. This is important because adenine nucleotides define energy state and couple to nearly all metabolic processes in the liver. Change in ATP, ADP, and AMP levels also impacts metabolic enzymes in the liver governing substrate trafficking. The stress-induced increase in hepatic AMP:ATP, at least in acute circumstances, was hypothesized to be mediated by glucagon receptor activation and associated gluconeogenic flux through cytosolic phosphoenolpyruvate carboxykinase (PEPCK). This hypothesis was confirmed using in vivo experiments, including a newly developed hyperglucagonemic-euglycemic (glucagon) clamp, in mice lacking the glucagon receptor or PEPCK. The regulatory consequences of the glucagon-mediated fall in energy state included hepatic activation of AMP-activated protein kinase (AMPK). AMPK is a low energy sensor and appears to mediate regulatory adaptations linked to hepatic glucagon receptor activation. This conclusion is based on evidence that hepatic glucagon activation stimulates an AMPK-dependent pathway characterized by increased phosphorylation of acetyl-CoA carboxylase (ACC) and expression of peroxisome proliferator-activated receptor รก and fibroblast growth factor 21 (FGF21) mRNA. These important factors modulate hepatic lipid oxidation and thus energy availability. The requirement for AMPK in this pathway was assessed using glucagon clamps in mice expressing an adenoviral-mediated dominant-negative form of AMPK. The potential long-term regulatory impact of the glucagon receptor-mediated transition to a hepatic energy-depleted state was based on studies in ob/+ and ob/ob mice chronically or acutely administered FGF21. These studies demonstrate that FGF21 has powerful hepato-centric effects to modulate glycemia and hepatic glucose flux. Acute FGF21 infusion results suggest a degree of resistance in obese, diabetic ob/ob mice that is overcome with chronic treatment. In conclusion, this dissertation introduces novel aspects of hepatic glucagon receptor activation and highlights the regulatory impact of adenine nucleotides. This work is important to understand metabolic regulation during stressors such as exercise and identify potential impairments in the liver associated with metabolic disease.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03302009-150224 |
| Date | 13 April 2009 |
| Creators | Berglund, Eric |
| Contributors | Owen P. McGuinness, Alvin C. Powers, Alyssa H. Hasty, Masakazu Shiota, Larry H. Swift |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu//available/etd-03302009-150224/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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