Investigation of PGC-1α function in zebrafish

Animal life must carefully balance energetic resources with physiological demands to promote growth and ensure survival. Energy serves as a valuable resource to cope with ever-changing environmental demands and requires complex regulatory networks to ensure efficient energy utilization. In mammals, PGC-1α (Peroxisome Proliferator Activated Receptor Co-Activator 1 α) is a master regulator of metabolism coordinating many essential metabolic processes. However, the importance of PGC-1α is currently unknown amongst lower vertebrates, despite controversy suggesting divergent roles for PGC-1α in teleost species. Here, I describe the creation of a mutant zebrafish line dedicated to uncovering the role of PGC-1α in zebrafish. In chapter 2, I disrupted an evolutionary conserved region upstream of the PGC-1α promoter, simultaneously increasing PGC-1α expression in skeletal muscle 4-fold and decreasing PGC-1α expression in cardiac muscle 4-fold. This mutation increased O2 consumption in white muscle fibres and doubled the resting metabolism in juvenile zebrafish demonstrating that PGC-1α retains its role as a metabolic regulator in fish. In chapter 3, I hypothesized that PGC-1α mutant zebrafish experience impaired growth due to having a decreased metabolic efficiency. Mutant zebrafish larvae displayed decreased heart rate alongside increased yolk fatty acid (FA) content, indicating decreased FA metabolism during early development. Surprisingly, mutant adult zebrafish had increased FA metabolism, resisted growth when presented with a high-fat diet and decreased Dihomo-Gamma-Linoleic-Acid in skeletal muscle, a FA that prevents mitochondrial leakage. In summary, this mutation greatly impedes the metabolic function of zebrafish and provides a promising model for the continued study of PGC-1α in lower vertebrate muscles.