Evidence of Hyperphagia and Fatty Acid Mobilization in Leptin Receptor Deficient Rainbow Trout (Oncorhynchus mykiss)

Authors: Mankiewicz, Jamie; Picklo, Matthew; Idso, Joseph; Cleveland, Beth

Submitted to: Biomolecules EISSN 2218-273X
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/26/2022
Publication Date: 3/29/2022
Citation: Mankiewicz, J.L., Picklo, M.J., Idso, J.P., Cleveland, B.M. 2022. Evidence of hyperphagia and fatty acid mobilization in leptin receptor deficient rainbow trout (Oncorhynchus mykiss). Biomolecules EISSN 2218-273X. 12(4):516. https://doi.org/10.3390/biom12040516.
DOI: https://doi.org/10.3390/biom12040516

Interpretive Summary: Leptin is a hormone with many functions but is primarily known for regulating metabolism and suppressing food intake. While we understand much about leptin in mammals, we still have much to learn about its function in fishes. To help clarify the role of leptin in rainbow trout, we used a tool for gene editing, CRISPR/Cas9, to knockout the leptin receptor (LepR) genes. We compared normal wildtype (WT) and mutant fish that were either fed to satiation daily or were feed deprived for 6-weeks. The LepR mutants consumed greater amounts of food which led to heavier body weight, faster growth rate, increased fat stores, and also increased fatty acid content in key metabolic tissues. This study provides new insights on the role of leptin signaling in nutrient partitioning during feeding and fatty acid mobilization during fasting in rainbow trout and identifies a specific neuropeptide in the brain that my be responsible for mediating leptin signaling.

Technical Abstract: Leptin is a pleiotropic hormone that is known for regulating appetite and metabolism. To help elucidate the role of leptin in rainbow trout, we used CRISPR/Cas9 genome editing to disrupt the leptin receptor genes. We compared wildtype (WT) and mutant fish that were either fed to satiation or feed deprived for 6-weeks. The LepR mutants exhibited a hyperphagic phenotype, which led to heavier body weight, faster specific growth rate, increased viscero- and hepatosomatic indices, and greater condition factor. Muscle glycogen, plasma leptin, and lepa1 transcripts were also elevated in fed LepR mutant fish. A range of hypothalamic genes involved in feed regulation were measured (agrp, npy, orexin, cart-1, cart-2, pomc-a1, pomc-b). No differences were detected between fed WT and mutants except for pomc-b, where levels were 7.5-fold higher in LepR fed mutants. This suggests that leptin signaling in the brain is likely mediated in part through pomc-b. All species of fatty acids measured were higher in muscle of fed mutant fish compared to WT, albeit not significant. Furthermore, fasted mutants exhibited significantly lower muscle fatty acid content, demonstrating a key role for leptin signaling in nutrient partitioning during feeding and fatty acid mobilization during fasting in a teleost fish.