Claudia Doege, MD

Obesity is a major health concern in the U.S. The brain, and in particular the hypothalamus is critical for the regulation of body weight. The human hypothalamus is one of the most complex regions of the brain containing more than 500 distinct cell types. Harnessing the power of cutting-edge single-cell multiomic and spatial transcriptomic technologies, we are investigating the molecular signature of all the cells involved in the regulation of body weight. We can then assemble this information into a three-dimensional map, providing the resource for rational obesity drug design based on human biology. Furthermore, we are studying how obesity genes modify the function of human stem cell-derived hypothalamic neurons. These cells have molecular signatures that are consistent with the pathophysiology of the patients and permit the studies to unravel the mechanisms of human obesity. Our approaches may ultimately identify therapeutically tractable hypothalamic pathways not previously implicated in obesity and thus, to develop novel therapeutic strategies.


Recent Publications

  1. Herb BR, Glover HJ, Bhaduri A, Colantuoni C, Bale TL, Siletti K, Hodge R, Lein E, Kriegstein AR, Doege CA, Ament SA. Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the human hypothalamus. Sci Adv. 2023; 9(45):eadf6251. Co-corresponding author
  2. Zhu N, LeDuc CA, Fennoy I, Laferrère B, Doege CA, Shen Y, Chung WK, Leibel RL. Rare predicted loss of function alleles in Bassoon (BSN) are associated with obesity. NPJ Genom Med. 2023;8(1):33.
  3. De Rosa MC, Glover HJ, Stratigopoulos G, LeDuc CA, Su Q, Shen Y, Sleeman MW, Chung WK, Leibel RL, Altarejos J, Doege CA. Gene expression atlas of energy balance brain regions. JCI Insight. 2021;6(16):e149137.
  4. Wang L, Liu Y, Stratigopoulos G, Panigrahi S, Sui L, Zhang Y, Leduc CA, Glover HJ, De Rosa MC, Burnett LC, Williams DJ, Shang L, Goland R, Tsang SH, Wardlaw S, Egli D, Zheng D, Doege CA, Leibel RL. Bardet-Biedl syndrome proteins regulate intracellular signaling and neuronal function in patient-specific iPSC-derived neurons. J Clin Invest. 2021;131(8):e146287. Co-corresponding author
  5. Pahl MC, Doege CA, Hodge KM, Littleton SH, Leonard ME, Lu S, Rausch R, Pippin JA, De Rosa MC, Basak A, Bradfield JP, Hammond RK, Boehm K, Berkowitz RI, Lasconi C, Su C, Chesi A, Johnson ME, Wells AD, Voight BF, Leibel RL, Cousminer DL, Grant SFA. Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant complex traits. Nat Commun. 2021;12(1):6749. Co-first author
  6. Hammond RK, Pahl MC, Su C, Cousminer DL, Leonard ME, Lu S, Doege CA, Wagley Y, Hodge KM, Lasconi C, Johnson ME, Pippin JA, Hankenson KD, Leibel RL, Chesi A, Wells AD, Grant SFA. Biological constraints on GWAS SNPs at suggestive significance thresholds reveal additional BMI loci. Elife. 2021;10:e62206.
  7. Lasconi C, Pahl MC, Cousminer DL, Doege CA, Chesi A, Hodge KM, Leonard ME, Lu S, Johnson ME, Su C, Hammond RK, Pippin JA, Terry NA, Ghanem LR, Leibel RL, Wells AD, Grant SFA. Variant-to-Gene-Mapping Analyses Reveal a Role for the Hypothalamus in Genetic Susceptibility to Inflammatory Bowel Disease. Cell Mol Gastroenterol Hepatol. 2021;11(3):667-682.
  8. Yaghootkar H, Zhang Y, Spracklen CN, Karaderi T, Huang LO, Bradfield J, Schurmann C, Fine RS, Preuss MH, Kutalik Z, Wittemans LBL, Lu Y, Metz S, Willems SM, Li-Gao R, Grarup N, Wang S, Molnos S, Sandoval-Zárate AA, Nalls MA, Lange LA, Haesser J, Guo X, Lyytikäinen LP, Feitosa MF, Sitlani CM, Venturini C, Mahajan A, Kacprowski T, Wang CA, Chasman DI, Amin N, Broer L, Robertson N, Young KL, Allison M, Auer PL, Blüher M, Borja JB, Bork-Jensen J, Carrasquilla GD, Christofidou P, Demirkan A, Doege CA, Garcia ME, Graff M, Guo K, Hakonarson H, Hong J, Ida Chen YD, Jackson R, Jakupović H, Jousilahti P, Justice AE, Kähönen M, Kizer JR, Kriebel J, LeDuc CA, Li J, Lind L, Luan J, Mackey DA, Mangino M, Männistö S, Martin Carli JF, Medina-Gomez C, Mook-Kanamori DO, Morris AP, de Mutsert R, Nauck M, Prokic I, Pennell CE, Pradhan AD, Psaty BM, Raitakari OT, Scott RA, Skaaby T, Strauch K, Taylor KD, Teumer A, Uitterlinden AG, Wu Y, Yao J, Walker M, North KE, Kovacs P, Ikram MA, van Duijn CM, Ridker PM, Lye S, Homuth G, Ingelsson E, Spector TD, McKnight B, Province MA, Lehtimäki T, Adair LS, Rotter JI, Reiner AP, Wilson JG, Harris TB, Ripatti S, Grallert H, Meigs JB, Salomaa V, Hansen T, Willems van Dijk K, Wareham NJ, Grant SFA, Langenberg C, Frayling TM, Lindgren CM, Mohlke KL, Leibel RL, Loos RJF, Kilpeläinen TO. Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity. Diabetes. 2020 Dec;69(12):2806-2818.
  9. De Rosa MC, Chesi A, McCormack S, Zhou J, Weaver B, McDonald M, Christensen S, Liimatta K, Rosenbaum M, Hakonarson H, Doege CA, Grant SFA, Hirschhorn JN, Thaker VV. Characterization of rare variants in MC4R in African American and/or Latino children with severe early onset obesity. J Clin Endocrinol Metab. 2019;104(7):2961-2970.
  10. Quarta C, Fisette A, Xu Y, Colldén G, Legutko B, Tseng YT, Reim A, Wierer M, De Rosa MC, Klaus V, Rausch R, Thaker VV, Graf E, Strom TM, Poher AL, Gruber T, Le Thuc O, Cebrian-Serrano A, Kabra D, Bellocchi L, Woods SC, Pflugfelder GO, Nogueiras R, Zeltser L, Grunwald Kadow IC, Moon A, García-Cáceres C, Mann M, Treier M, Doege CA, Tschöp MH. Functional identity of hypothalamic melanocortin neurons depends on Tbx3. Nat Metab. 2019;1(2):222-235.
  11. Wang L, De Solis AJ, Goffer Y, Birkenbach KE, Engle SE, Tanis R, Levenson JM, Li X, Rausch R, Purohit M, Lee JY, Tan J, De Rosa MC, Doege CA, Aaron HL, Martins GJ, Bruning JC, Egli D, Costa R, Berbari N, Leibel RL, Stratigopoulos G. Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development. JCI Insight. 2019;4(3):e123337.
  12. Stratigopoulos G, De Rosa MC, LeDuc CA, Leibel RL, Doege CA. DMSO increases efficiency of genome editing at two non-coding loci. PloS One. 2018;13(6):e0198637. PubM
  13. Wang L, Sui L, Panigrahi SK, Meece K, Xin Y, Kim J, Gromada J, Doege CA, Wardlaw SL, Egli D, Leibel RL. PC1/3 Deficiency Impacts Pro-opiomelanocortin Processing in Human Embryonic Stem Cell-Derived Hypothalamic Neurons. Stem Cell Reports. 2017;8(2):264-277.