DSSS - Metabolic Adaptation to Nutrient Limitation in Vertebrates

Adaptation to food deprivation is widespread among animal species, reflecting the intimate connection between genotype, phenotype, and the environment. However, the genetic basis of physiological adaptations to nutrient availability remains an unresolved challenge of both organismal biology and modern evolutionary genetics. We are using the cavefish Astyanax mexicanus as a promising research organism to unravel the genetic basis of starvation resistance. A. mexicanus exists in two forms: a river-dwelling surface fish and a blind, depigmented cavefish. Whereas the surface forms live in a rich ecological environment, multiple distinct cave populations have evolved metabolic adaptations to nutrient limitations in caves. Importantly, the surface and cave morphs remain interfertile and can be bred in the laboratory. Using recently developed genetic and genomic tools, we have shown that cavefish evolved a massive capacity for fat storage due to increased appetite, adipogenesis, and lipogenesis. In addition, we found that cavefish display elevated blood sugar levels and insulin resistance caused by a mutation in their insulin receptor. Unlike humans with the same mutation, cavefish do not display diabetes markers and live long and healthy lives. Furthermore, cavefish develop hypertrophic visceral adipocytes without obvious signs of inflammation due to reduced amounts of pro-inflammatory cytokines. In a more recent series of studies, we showed that cavefish are thriftier due to decreased muscle mass, improved glycogen production, and efficient recycling of amino acids. As all these extreme adaptations have no negative consequences on the metabolic health, immune response, and lifespan in these fish, it suggests that cavefish develop these phenotypes as part of their starvation resistance and have evolved resilience phenotypes that allow them to tolerate deviations from normal vertebrate physiology. This positions cavefish as a promising model to gain mechanistic insights into disease phenotypes from an evolutionary and adaptive perspective.