Fibroblast Growth Factor-21 (FGF21) in Domestic Cats
Type of DegreePhD Dissertation
General Veterinary Medicine
Restriction TypeAuburn University Users
MetadataShow full item record
Fibroblast growth factors (FGFs) are a group of structurally homologous yet functionally pleiotropic proteins. Unlike canonical and intracellular FGFs, the FGF19 subfamily, which includes FGF15/19, FGF21, and FGF23, act as endocrine hormones that regulate phosphate, bile acid, and metabolic homeostasis, respectively. Research in human and rodent models demonstrates the potential of these endocrine FGFs to treat various diseases. Data from studies evaluating the metabolic effects of FGF21 pathway activation show improved lipid homeostasis and insulin sensitivity, decreased severity of non-alcoholic steatohepatitis, and potential use as a therapeutic for pancreatitis. Even though cats commonly suffer from metabolic diseases, including obesity, pancreatitis and hepatic lipidosis, there are no studies evaluating FGF21 in cats and only rare studies in other non-laboratory domestic species. This dissertation serves as the first exploration of FGF21 in domestic cats and probes how the FGF21 pathway can be utilized as a future therapy in veterinary medicine. Chapter 1 of this dissertation reviews the endocrine FGF family, focusing on the physiology and current research. FGF19/FGF15 serves as a mechanism of bile homeostasis. FGF23, a bone-derived hormone, regulates urinary phosphate retention and active vitamin D levels. FGF21, the main focus of this dissertation, is an endocrine link between the liver and adipose tissue, regulating metabolic homeostasis. This literature review further discusses what is known about FGF21 within domestic animals and veterinary medicine. Chapter 2 is a prospective preliminary cross-sectional study utilizing purpose-bred, male-neutered, 6-year-old, obese and overweight cats administered either a recombinant human FGF21 mimetic modified for increased thermal and confirmational stability or saline control over a 14-day treatment period. Treatment with FGF21 resulted in significant weight loss (~5.93%) compared to control and a trend toward decreased intrahepatic triglyceride content. Cats treated with FGF21 had reduced serum alkaline phosphatase. No significant changes were noted in liver elasticity, serum, liver, metabolic parameters, or gut microbiome composition. This chapter demonstrates that in obese and overweight cats, activation of the FGF21 pathway can safely induce weight loss with trends to improve liver lipid content. Manipulation of the FGF21 pathway has promising potential as a therapeutic for feline obesity. Further studies are needed to see if FGF21 pathway manipulation can be therapeutic for feline metabolic disease. Chapter 3 explores the FGF21 pathway utilizing banked feline tissues in clinically normal and selected diseased cats. This study evaluated the distribution of transcript and protein expression of FGF21, and its co-receptors, Fibroblast Growth Factor Receptor 1c and β-klotho in key tissues. Relative to the lowest expressing tissue, the highest expression of FGF21 was in the liver, with strong and consistent immunohistochemical reactivity in formalin-fixed paraffin-embedded liver sections. Contrary to other species, FGF21 is not highly expressed in adipose tissues despite the presence of FGF21 co-receptors. This chapter proposes that the retention of the FGF21 endocrine pathway and the loss of the FGF21 autocrine/paracrine pathway in the adipose tissues may be responsible for the unique differences in the feline response to FGF21 mimetics. Additionally, the immunohistochemical expression of FGF21 in cases of spontaneous feline pancreatitis was examined, with strong FGF21 immunoreactivity within macrophages, which may represent M2 polarity. This dissertation provides a starting point for evaluating the FGF21 pathway within domestic animals, including cats. These findings suggest that there are unique signaling pathways and therapeutic potential to target the FGF21 pathway, and further studies are needed to determine if FGF21 therapies will be a viable option in a clinical setting.