Introduction: The uncoupling proteins (UCPs) are involved in lipid metabolism and belong to a family of mitochondrial anionic transporters. In poultry, only one UCP homologue has been identified and experimentally shown to be associated with growth, feed conversion ratio, and abdominal fat according to its predominant expression in bird muscles. In endotherm birds, cell metabolic e ciency can be tuned by the rate of mitochondrial coupling. Thus, avUCP may be a key contributor to controlling metabolic rate during particular environmental changes. Methods: This study aimed to perform a set of in-silico investigations primarily focused on the structural, biological, and biomimetic functions of avUCP. Thereby, using in silico genome analyses among 8 avian species (chicken, turkey, swallow, manakin, sparrow, wagtail, pigeon, and mallard) and a series of bioinformatic approaches, we provide phylogenetic inference and comparative genomics of avUCPs and investigate whether sequence variation can alter coding sequence characteristics, the protein structure, and its biological features. Complementarily, a combination of literature mining and prediction approaches was also applied to predict the gene networks of avUCP to identify genes, pathways, and biological crosstalk associated with avUCP function. Results: The results showed the evolutionary alteration of UCP proteins in dierent avian species. Uncoupling proteins in avian species are highly conserved trans membrane proteins as seen by sequence alignment, physiochemical parameters, and predicted protein structures. Taken together, avUCP has the potential to be considered a functional marker for the identification of cell metabolic state, thermogenesis, and oxidative stress caused by cold, heat, fasting, transfer, and other chemical stimuli stresses in birds. It can also be deduced that avUCP, in migrant or domestic birds, may increase heat stress resistance by reducing fatty acid transport/boxidation and thermoregulation alongside antioxidant defense mechanisms. The predicted gene network for avUCP highlighted a cluster of 21 genes involved in response to stress and 28 genes related to lipid metabolism and the proton buering system. Finally, among 11 enriched pathways, crosstalk of 5 signaling pathways including MAPK, adipocytokine, mTOR, insulin, ErbB, and GnRH was predicted, indicating a possible combination of positive or negative feedback among pathways to regulate avUCP function. Discussion: Genetic selection for fast-growing commercial poultry has unintentionally increased susceptibility to many kinds of oxidative stress, and so avUCP could be considered as a potential candidate gene for balancing energy expenditure and reactive oxygen species production, especially in breeding programs. In conclusion, avUCP can be introduced as a pleiotropic gene that requires the contribution of regulatory genes, hormones, pathways, and genetic crosstalk to allow its finely-tuned function.
