This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Development of obesity is associated with abnormal lipid metabolism that frequently includes an increase in oxidation of fatty acids as fuels. This increased reliance on fatty acids in turn suppresses carbohydrate metabolism, leading to impaired glucose disposal via the glucose-fatty acid cycle. In this way fatty acids can contribute to impaired glucose tolerance and insulin resistance. The overall objective of the Kliewer lab is a better understanding of the regulation of fatty acid and carbohydrate oxidation. Recently, much of the focus has been on understanding the adaptive response to starvation. Mammals have evolved complex metabolic and behavioral responses to survive extended periods of nutrient deprivation. A key aspect of the overall adaptive response is the shift from carbohydrates to ketone bodies as a primary fuel source. During fasting and starvation, fatty acids are mobilized from white adipose tissue (WAT) to liver, where they are oxidized to acetyl-CoA. The acetyl-CoA is then used to synthesize ketone bodies, including [unreadable]-hydroxybutyrate and acetoacetate, which are reconverted to acetyl-CoA in other tissues and oxidized in the tricarboxylic acid cycle to produce energy. During prolonged fasts, ketone bodies provide nearly half of the body's total energy and up to 70% of the energy required by the brain. Fibroblast growth factor 21 (FGF21) is a member of a subfamily of FGFs. Recent findings show that FGF21, which is expressed in liver and pancreas, also regulates metabolism and in particular may be sensitive to peroxisome proliferator-activated receptor [unreadable] (PPAR[unreadable]), a nuclear receptor activated by fatty acids. While it is known that pharmacological administration of FGF21 has broad metabolic effects, little is known about its physiological function. Recently we have examined the interaction of FGF21 induction, hepatic PPAR[unreadable], and the ketogenic response to fasting.