Michael J. Wolfgang
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Fatty acid oxidation is a fundamental metabolic pathway that is required to maintain cellular energetics of many disparate tissues. This is made evident by multi-systemic pathologies associated with inborn errors of fatty acid oxidation. However, the role of fatty acid oxidation varies among tissues ranging from ATP generation in the heart, to heat generation in brown adipose tissue, to the facilitation of gluconeogenesis and ketogenesis in the liver. To gain a better understanding of the roles of fatty acid oxidation in a tissue-specific manner in vivo, we generated mice with a conditional loss-of-function allele for Carnitine Palmitoyltransferase 2 (Cpt2), an obligate step in mitochondrial long-chain fatty acid β-oxidation. Utilizing Cre-dependent and tissue-specific excision of Cpt2 in vivo, we have explored the roles of fatty acid oxidation in adipocytes, hepatocytes, and macrophages among others. This has lead to many unexpected findings and novel tissue-specific roles for fatty acid oxidation. For example, the loss of fatty acid oxidation in the liver was surprisingly compatible with life as well as a 24hr fast. Mice with a loss in hepatic fatty acid oxidation were able to maintain systemic glucose homeostasis during a 24hr fast, but exhibited no production of ketone bodies. Systemic energy homeostasis was largely maintained by adaptations in hepatic and systemic oxidative gene expression mediated in part by a robust induction of Pparα target genes including procatabolic hepatokines Fgf21, Gdf15 and Igfbp1. This robust catabolic transcriptional response in the liver and in peripheral tissues resulted in mice that were resistant to weight gain and glucose intolerance on a high fat diet. This occurred even in the face of a genetically engineered energy deficit. These positive systemic benefits were balanced by an incredible accumulation of triglyceride in the liver, enhanced oxidative stress, and dyslipidemia following a fast. These studies should yield a better understanding of the tissue-specific roles and requirements for mitochondrial long-chain fatty acid β-oxidation in vivo.