In the Krishnan Lab, we are dedicated to understanding the genetic underpinnings of metabolism in the fish Astyanax mexicanus, a unique species that exhibits remarkable adaptations to metabolic challenges. Our research aims to shed light on the evolution of gene regulatory networks in these obese, yet metabolically healthy, cave-dwelling fish.
Metabolic syndrome encompasses a constellation of closely linked heritable traits including hyperglycemia, excess adiposity, fatty liver, and hypertension. With nearly 1 in 10 adults affected by diabetes and a third of the US population grappling with obesity, there is an urgent need for a deeper understanding of the genetic factors at play. While numerous genetic loci associated with metabolic disorders have been identified, the knowledge of protective loci remains limited.
Exploring organisms that have evolved to survive under extreme environmental stresses could provide valuable insights for developing new strategies to enhance human health. The cave-dwelling fish Astyanax mexicanus has emerged as a promising model for studying metabolic resilience – the ability to maintain good health despite metabolic conditions that would be harmful to most organisms. Unlike their river-dwelling relatives, the cavefish exhibit higher blood glucose, insulin resistance, and have increased body fat. However, despite these traits, which are typically linked to disease, cavefish seem to avoid common complications such as advanced glycation end-product buildup and chronic inflammation. Furthermore, their ability to store more fat and maintain high blood glucose levels also makes them extremely starvation resistant, an essential adaptation for surviving in nutrient-scarce cave habitats.
In our lab, we are interested in discovering the genetic basis and molecular mechanisms underlying these extreme metabolic adaptations by addressing three core questions:
- How do cavefish synthesize and store excess fat?
- How do they mobilize stored fat when faced with limited food resources?
- How do they mitigate the adverse effects of excess fat accumulation?
Building on previous studies, we have observed significant divergence in metabolic pathways between cavefish and surface fish, driven by coding, non-coding, and gene expression changes. Using a multi-omics approach such as transcriptomics, epigenomics, and metabolomics, we aim to identify key genetic factors and physiological pathways driving this divergence. Additionally, we leverage liver-derived cell lines from both surface fish and cavefish as powerful in vitro systems for molecular dissection of metabolic traits.
Our studies shed light on the evolutionary forces shaping cavefish physiology and also draw a bridge to human health. Our mission is to extend our findings beyond the lab to pave the way for innovative approaches in addressing metabolic disorders in humans.
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