Bird evolution by insulin resistance

• Published in: Trends in endocrinology and metabolism 2021-10, Vol.32 (10), p.803-813
• Main Author: Satoh, Takumi
• Format: Article
• Language: English
• Subjects: Animals; birds; Birds - metabolism; Humans; insulin resistance; Insulin Resistance - genetics; Insulins; Kelch-Like ECH-Associated Protein 1; mass extinction; NF-E2-Related Factor 2; NRF2; Oxygen; Reactive Oxygen Species - metabolism; theropods
• ISSN: 1043-2760; 1879-3061
• DOI: 10.1016/j.tem.2021.07.007

Drift of oxygen concentrations in the atmosphere was one of the main drivers of the evolution of vertebrates. The drop in oxygen concentrations at the Permian–Triassic (PT) boundary may have been the biggest challenge to vertebrates. This hypoxic condition forced theropods to lose certain genes to maximize their efficiency of oxygen usage. Recent studies show that omentin and insulin-sensitive glucose transporter 4 (GLUT4) are missing in the bird genome. Since these gene products play essential roles in maintaining insulin sensitivity, this loss forced theropods to become insulin resistant. Insulin resistance may have been the key to allowing theropods to become hyperathletic under hypoxic conditions and to outcompete mammals during the Triassic period. A second challenge was the gradual increase in oxygen concentrations during the late Jurassic, Cretaceous, and Tertiary periods when reactive oxygen species (ROS) leakage from mitochondria became a problem. Since the simplest solution was the expansion of body size, some theropods became bigger to reduce ROS leakage per volume. Another solution was the development of a constitutively active countermeasure against ROS. A recent study shows that Neoaves have constitutively active nuclear factor erythroid 2-related factor 2 (NRF2) due to deletion of the C-terminal part of the KEAP1 protein, thus allowing Neoaves to express antioxidant enzymes to overcome ROS leakage. Birds are well known to have long lifespans despite their high oxygen consumption. In mammals, high oxygen consumption induces reactive oxygen species (ROS) leakage and shortens the lifespan. By contrast, birds have high oxygen consumption without this ROS leakage, a phenomenon termed the ‘Bird Paradox’. This paradox has attracted many investigators to speculate about the protective mechanisms at work to overcome this ROS leakage.I propose that theropods developed insulin resistance to adapt themselves to the low-oxygen environment of the Triassic period. This insulin resistance may have allowed theropods to maximize the efficiency of oxygen usage, almost outcompeting mammals during the Triassic period.Another epoch-making event was constitutive nuclear factor erythroid 2-related factor 2 (NRF2) activation induced by deletion of the C-terminal part of Kelch-like ECH-associated protein (KEAP1), preventing ROS leakage, just in Neoaves but not in the Palaeognathae, thus suggesting that this deletion may have occurred during the early Tertiary period.