Krishna Chatterjee
FMedSci
Professor of Endocrinology
Department of Medicine
Research Interests
Our principal research interests are in genetic and molecular endocrinology, with particular emphasis on disorders of nuclear hormone synthesis and action. We are studying several human cohorts: first, congenital hypothyroidism (CH) that is familial, syndromic or on a consanguineous background; second, Resistance to Thyroid Hormone (RTH), defined broadly as abnormal circulating thyroid hormones with tissue refractoriness to hormone action; and lipodystrophic insulin resistance associated with PPARg gene defects. Candidate gene and whole exome approaches are used to identify novel genetic aetiologies mediating thyroid dysgenesis or hormonogenesis and defective hormone action. Human phenotypic studies elucidate mechanisms whereby thyroid hormones modulate energy balance (intake, expenditure) or act via receptor subtypes in tissues. In a multisystem selenoprotein deficiency disorder including thyroid deiodinases, we are investigating features (metabolic, photosensitivity) attributable to elevated ROS and the roles of selenoproteins of unknown function. Finally, we aim to translate our research into technologies (biochemical, genetic) which enhance our national diagnostic laboratory service and to develop biomarkers of hormone action and therapies (e.g. selective thyromimetics, PPARg modulators) that are applicable to commoner thyroid dysfunction or metabolic disorders.
Clinical research focusses on subjects with primary adrenal insufficiency (Addison's disease), including the role of dehydroepiandrosterone (DHEA) hormone treatment, optimising cortisol replacement and assessment of quality of life.
Our research is funded by the Wellcome Trust.
Selected Publications
Bochukova E*, Schoenmakers N*, Agostini M, Schoenmakers E, Rajanayagam O, Keogh JM, Henning E, Reinemund J, Gevers E, Sarri M, Downes K, Offiah A, Albanese A, Halsall D, Schwabe J, Bain M, Lindley K, Muntoni F, Vargha Khadem F, Dattani M, Farooqi S, Gurnell M, Chatterjee K. (2012). A Dominant Negative Mutation in the Thyroid Hormone Receptor Alpha Gene. New England Journal of Medicine, 366:243-249. PMID: 22168587.
Schoenmakers E, Agostini M, Mitchell C, Schoenmakers N, Papp L, Rajanayagam O, Padidela R, Ceron-Gutierrez L, Doffinger R, Prevosto C, Luan J, Montano S, Lu J, Castanet M, Clemons N, Groeneveld M, Castets P, Karbasschi M, Aitken S, Dixon A, Williams J, Campi I, Blount M, Burton H, Muntoni F, O'Donovan D, Dean A, Warren A, Brierley C, Baguley D, Guicheney P, Fitzgerald R, Coles A, Gaston H, Todd P, Holmgren A, Khanna KK, Cooke M, Semple R, Halsall D, Wareham N, Schwabe J, Grasso L, Beck-Peccoz P, Ogunko A, Dattani M, Gurnell M, Chatterjee K. (2010). Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans. J Clin Invest, 120(12):4220-35). PMID: 21084748. PMCID: PMC2993594.
Lopez M, Varela L, Vazquez MJ, Rodriguez-Cuenca S, Gonzalez CR, Velagapudi VR, Morgan DA, Schoenmakers E, Agassandian K, Lage R, de Morentin PB, Tovar S, Nogueiras R, Carling D, Lelliott C, Gallego R, Oresic M, Chatterjee K, Saha AK, Rahmoundi K, Dieguez C, Vidal-Puig A. (2010). Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med, 16(9):1001-8. PMID: 20802499. PMCID: PMC2935934.
Mitchell CS, Savage DB, Dufour S, Schoenmakers N, Murgatroyd P, Befroy D, Halsall D, Northcott S, Raymond-Barker P, Curran S, Henning E, Keogh J, Owen P, Lazarus J, Rothman DL, Farooqi IS, Shulman GI, Chatterjee K, Petersen KF. (2010). Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling and hyperphagia. J Clin Invest, 120(4):1345-54. PMID: 20237409.
Cartwright D, O'Shea P, Rajanayagam O, Agostini M, Barker P, Moran C, Macchia E, Pinchera A, John R, Agha A, Ross HA, Chatterjee VK, Halsall DJ. (2009). Familial dysalbuminemic hyperthyroxinemia: a persistent diagnostic challenge. Clin Chem, 55(5):1044-6. PMID: 19282355.
Gurnell EM, Hunt PJ, Curran SE, Conway CL, Pullenayegum EM, Huppert FA, Compston JE, Herbert J, Chatterjee VK. (2008). Long-term DHEA replacement in primary adrenal insufficiency: a randomized, controlled trial. J Clin Endocrinol Metab, 93(2):400-9. PMID: 18000094. PMCID: PMC2729149.
Szatmari I, Töröcsik D, Agostini M, Nagy T, Gurnell M, Barta E, Chatterjee K, Nagy L. (2007). PPARgamma regulates the function of human dendritic cells primarily by altering lipid metabolism. Blood, 110(9):3271-80. PMID: 17664351.
Agostini M, Schoenmakers E, Mitchell CS, Szatmari I, Savage DB, Smith AG, Rajanayagam O, Semple RK, Luan J, Bath L, Zalin AN, Labib M, Kumar S, Simpson H, Blom D, Marais AD, Schwabe JWR, Barroso I, Trembath R, Wareham NJ, Nagy L, Gurnell M, O'Rahilly S, & Chatterjee VKK. (2006). Non-DNA binding, dominant-negative, human PPARγ mutations cause lipodystrophic insulin resistance. Cell Metab, 4(4):303-311. PMID: 17011503. PMCID: PMC1821092.
Agostini M, Gurnell M, Savage DB, Wood EM, Smith A, Rajanayagam O, Garnes KT, Levinson SH, Xu HE, Schwabe JW, Willson TM, O’Rahilly S, Chatterjee VKK. (2004). Tyrosine agonists reverse the molecular defects associated with dominant negative mutations in human PPARg. Endocrinology, 145(4):1527-38. PMID: 14657011.
Kallenberger BC, Love JD, Chatterjee VKK, Schwabe JWR. (2003). A dynamic
mechanism of nuclear receptor activation and its perturbation in a human disease. Nat Struct Biol, 10(2):136-40. PMID: 12536206.
Tinnikov A, Nordstrom K, Thoren P, Kindblom JM, Malin S, Rozell B, Adams M,
Rajanayagam O, Forrest D, Pettersson S, Ohlsson C, Chatterjee K, Vennstrom B. (2002). Retardation of post-natal development caused by a negatively acting thyroid hormone receptor
a1. EMBO J, 21(19):5079-87. PMID: 12356724.
PMCID: PMC129045.
Savage DB, Agostini M, Barroso I, Gurnell M, Luan JA, Meirhaeghe A, Harding A-H, Ihrke G, Soos MA, Rajanayagam O, George S, Berger D, Thomas EL, Bell JD, McCarthy M, Hattersley AT, Hitman GA, Levy J, Walker M, Meeran K, Ross R, Vidal-Puig A, Wareham NJ, O’Rahilly S, Chatterjee VKK, Schafer AJ. (2002). Digenic inheritance of severe insulin resistance in a human pedigree. Nat Genet, 31(4):379-84. PMID: 12118251.
Castanet M, Park S, Smith A, Bost M, Leger J, Lyonnet S, Pelet A, Czernichow
P, Chatterjee VKK, Polak M. (2002). A novel loss-of-function mutation in TTF-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate. Hum Mol Genet, 11(17):2051-9. PMID: 12165566.
Wentworth JM, Agostini M, Love J, Schwabe JW, Chatterjee, VKK. (2000). St John's wort, a herbal antidepressant, activates the steroid X receptor. J Endocrinol, 166(3):R11-6. PMID: 10974665.
Barroso I, Gurnell M, Crowley VEF, Agostini M, Schwabe JW, Soos MA, Maslen GLl, Williams TDM, Lewis H, Schafer AJ, Chatterjee VKK & O’Rahilly S. (1999). Dominant negative mutations in human PPARg are associated with severe insulin resistance, diabetes mellitus and hypertension. Nature, 402(6764):880-3. PMID: 10622252.