Jaya Krishnan, Ph.D.

Millions of people worldwide are affected by metabolic disorders including diabetes, obesity and cardiovascular diseases. To find novel methods for intervention and new therapeutic targets, we turned to nature. The concept of looking for naturally available solutions isn’t new – airplanes, Velcro, wetsuits and more are all inspired by nature. Likewise, organisms can give us insights into preventing disease.

Organisms such as hibernating mammals, migratory birds, and – our favorite – the fat cavefish Astyanax mexicanus, have all adapted to store excess fat in their bodies so they can survive very long periods of low nutrient supplies. More than 150,000 years ago, the river-dwelling Astyanax mexicanus – the surface fish – got swept into and trapped in the lightless, nutrient-scarce caves in the Sierra del Abra region of Mexico, where they faced seasonal limitations in food availability, leading to extended periods of starvation. Astonishingly, they successfully survived in these habitats thanks to their adaptations. They evolved to binge eat whenever food is available, maintain high blood glucose levels, accumulate excess body fat, and develop fatty liver – all signs of metabolic disease – without any negative effects of toxicity or inflammation.

We investigate how this is possible and if we can study them to better understand human metabolic diseases such as diabetes and obesity. Research has pointed to altered stress response and energy utilization pathways as key players, so we study these processes in greater detail and seek to discover underlying genes that may cause these traits. Our goal is to unravel the molecular basis of their extraordinary survival strategies to gain insights for improving human metabolic health.

Welcome to the Krishnan Lab

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 with the ultimate goal of gaining insights into metabolism and metabolic syndrome in humans.

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 loci associated with metabolic disorders have been identified, the knowledge of protective alleles 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:

1. How do cavefish synthesize and store excess fat?
2. How do they mobilize stored fat when faced with limited food resources?
3. 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, including 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.

Education
B.Sc., Biochemistry (Honors), University of Delhi, 2007
M.Sc., Department of Genetics, University of Delhi, South Campus, India, 2009
Ph.D., Center for Cellular and Molecular Biology, India, Dr. Rakesh Mishra, 2009-2015,
Postdoctoral training, Stowers Institute for Medical Research, Kansas City, Dr. Nicolas Rohner, 2015-2022

Awards and Honors
Rotary Club Scholarship, 2007-08
Qualified Graduate Aptitude Test in Engineering exam for pursuing Ph.D., 2008
Full-time CSIR fellowship from the Govt. of India for 5 years, 2009
Travel grant by CICS, Govt. of India, 2014
Travel grant by CSIR, Govt. of India, 2014
Travel grant by the DST, Govt. of India, 2014
KV Rao Young Scientist Award for my Ph.D. research, 2015
Travel fellowship, Society for Developmental Biology, 2018
Best Poster Award, second prize, Young Investigator Science Retreat 2018, Stowers Institute for Medical Research, 2018
Hilde Mangold Postdoctoral Symposium Award, 80th Annual Society for Developmental Biology Meeting, 2021

Joined OMRF scientific staff in 2023

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Selected Publications

Krishnan, J., Wang, Y., Kenzior, O., Hassan, H., Olsen, L., Tsuchiya, D., Kenzior, A., Peuss, R., Xiong, S., Wang, Y., et al. (2022). Liver-derived cell lines from cavefish Astyanax mexicanus as an in vitro model for studying metabolic adaptation. Sci Rep 12, 10115.

Krishnan, J., Seidel, C.W., Zhang, N., Singh, N.P., VanCampen, J., Peuss, R., Xiong, S., Kenzior, A., Li, H., Conaway, J.W., et al. (2022). Genome-wide analysis of cis-regulatory changes underlying metabolic adaptation of cavefish. Nat Genet 54, 684-693.

Krishnan, J.*, Persons, J.L.*, Peuss, R.*, Hassan, H., Kenzior, A., Xiong, S., Olsen, L., Maldonado, E., Kowalko, J.E., and Rohner, N. (2020). Comparative transcriptome analysis of wild and lab populations of Astyanax mexicanus uncovers differential effects of environment and morphotype on gene expression. J Exp Zool B Mol Dev Evol. Nov;334(7-8):530-539 (* Equal contribution)

Krishnan, J., and Rohner, N. (2019). Sweet fish: Fish models for the study of hyperglycemia and diabetes. J Diabetes 11, 193-203 (Review article)

Kumar, R.P.*, Krishnan, J.*, Pratap Singh, N., Singh, L., and Mishra, R.K. (2013). GATA simple sequence repeats function as enhancer blocker boundaries. Nat Commun 4, 1844. (* Equal contribution)

Genes & Human Disease Research Program, MS 57
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104

E-mail: Jaya-Krishnan@omrf.org

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Manu Tomar
Postdoctoral Scientist

Tyler Guzman
Research Technician

Sumedha Mukhi
Research Technician III

Suzy Collins
Project Coordinator II