Enhanced lipogenesis through Pparγ helps cavefish adapt to food scarcity

Nutrient availability varies seasonally and spatially in the wild. While many animals, such as hibernating animals or migrating birds, evolved strategies to overcome periods of nutrient scarcity,^1,2 the cellular mechanisms of these strategies are poorly understood. Cave environments represent an example of nutrient-deprived environments, since the lack of sunlight and therefore primary energy production drastically diminishes the nutrient availability.³ Here, we used Astyanax mexicanus, which includes river-dwelling surface fish and cave-adapted cavefish populations, to study the genetic adaptation to nutrient limitations.^4-9 We show that cavefish populations store large amounts of fat in different body regions when fed ad libitum in the lab. We found higher expression of lipogenesis genes in cavefish livers when fed the same amount of food as surface fish, suggesting an improved ability of cavefish to use lipogenesis to convert available energy into triglycerides for storage into adipose tissue.^10-12 Moreover, the lipid metabolism regulator, peroxisome proliferator-activated receptor γ (Pparγ), is upregulated at both transcript and protein levels in cavefish livers. Chromatin immunoprecipitation sequencing (ChIP-seq) showed that Pparγ binds cavefish promoter regions of genes to a higher extent than surface fish and inhibiting Pparγ in vivo decreases fat accumulation in A. mexicanus. Finally, we identified nonsense mutations in per2, a known repressor of Pparγ, providing a possible regulatory mechanism of Pparγ in cavefish. Taken together, our study reveals that upregulated Pparγ promotes higher levels of lipogenesis in the liver and contributes to higher body fat accumulation in cavefish populations, an important adaptation to nutrient-limited environments.