@article{d0833191e93d4b5eb32b57b2aaf4d794,
title = "Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity",
abstract = "Insulin resistance is a pathological state often associated with obesity, representing a major risk factor for type 2 diabetes. Limited mechanism-based strategies exist to alleviate insulin resistance. Here, using single-cell transcriptomics, we identify a small, critically important, but previously unexamined cell population, p21Cip1 highly expressing (p21high) cells, which accumulate in adipose tissue with obesity. By leveraging a p21-Cre mouse model, we demonstrate that intermittent clearance of p21high cells can both prevent and alleviate insulin resistance in obese mice. Exclusive inactivation of the NF-κB pathway within p21high cells, without killing them, attenuates insulin resistance. Moreover, fat transplantation experiments establish that p21high cells within fat are sufficient to cause insulin resistance in vivo. Importantly, a senolytic cocktail, dasatinib plus quercetin, eliminates p21high cells in human fat ex vivo and mitigates insulin resistance following xenotransplantation into immuno-deficient mice. Our findings lay the foundation for pursuing the targeting of p21high cells as a new therapy to alleviate insulin resistance.",
keywords = "Cellular senescence, NF-κB, diabetes, fat transplantation, senolytics, xenograft",
author = "Lichao Wang and Binsheng Wang and Gasek, {Nathan S.} and Yueying Zhou and Cohn, {Rachel L.} and Martin, {Dominique E.} and Wulin Zuo and Flynn, {William F.} and Chun Guo and Jellison, {Evan R.} and Taewan Kim and Prata, {Larissa G.P.Langhi} and Palmer, {Allyson K.} and Ming Li and Inman, {Christina L.} and Barber, {Lauren S.} and Al-Naggar, {Iman M.A.} and Yanjiao Zhou and Wenqiang Du and Kshitiz and Kuchel, {George A.} and Alexander Meves and Tamar Tchkonia and Kirkland, {James L.} and Paul Robson and Ming Xu",
note = "Funding Information: The authors are grateful to colleagues in the UConn Center on Aging for helpful and constructive discussion, Zhifang Hao for histology service, and Stefanie Farkas for administrative assistance. This work was supported in part by an ISG seed grant from UConn Health (M.X.), the Regenerative Medicine Initiative for Diabetes-Career Development Award from Mayo Clinic (M.X.), Glenn Foundation for Medical Research and AFAR Grant for Junior Faculty (M.X.), the Esperance Fellowship in Personalized Nutrition (N.S.G.), The Kenneth and Paula Munson Family Fund for Student Support in Health Sciences Fellowship (N.S.G. and T.K.), the Diana Jacobs Kalman/AFAR Scholarship for Research in the Biology of Aging (N.S.G.), the UConn/JAX-GM Training Program in Genomic Science T32HG010463 (R.L.C.), Robert and Arlene Kogod (J.L.K.), the Connor Group (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K.), the Noaber Foundation (J.L.K.), Travelers Chair in Geriatrics and Gerontology (G.A.K.), and NIH grants R37AG013925 (J.L.K.), K08CA215105 (A.M.), P01AG062413 (J.L.K.), R33AG061456 (J.L.K. T.T. and G.A.K.), P30AG067988 (G.A.K.), AG063528 (M.X.), AG066679 (M.X.), and AG068860 (M.X.). M.X. conceived the study. M.X. L.W. and B.W. designed the study. L.W. B.W. N.S.G. Yueying Zhou, D.E.M. C.G. T.K. A.K.P. C.L.I. L.S.B. I.M. and M.X. performed the mouse studies. R.L.C. W.Z. W.F.F. M.X. and P.R. contributed to the SCT analysis. B.W. and E.R.J. contributed to the flow cytometry analysis. N.S.G. B.W. Yueying Zhou, and L.P. contributed to the histological analysis. N.S.G. W.D. and K. contributed to TAFs analysis. M.L. and A.M. contributed to the RNAScope assay. Yanjiao Zhou, G.A.K. T.T. and J.L.K. contributed to manuscript preparation. M.X. wrote the manuscript with input from all coauthors. M.X. oversaw all experiments, data analysis, and manuscript preparation. M.X. A.K.P. T.T. and J.L.K. have a financial interest related to this research. Patents on senolytic drugs (including PCT/US2016/041646, filed at the US Patent Office) are held by Mayo Clinic. These studies were conducted in compliance with Mayo Clinic conflict of interest policies. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Funding Information: The authors are grateful to colleagues in the UConn Center on Aging for helpful and constructive discussion, Zhifang Hao for histology service, and Stefanie Farkas for administrative assistance. This work was supported in part by an ISG seed grant from UConn Health (M.X.), the Regenerative Medicine Initiative for Diabetes-Career Development Award from Mayo Clinic (M.X.), Glenn Foundation for Medical Research and AFAR Grant for Junior Faculty (M.X.), the Esperance Fellowship in Personalized Nutrition (N.S.G.), The Kenneth and Paula Munson Family Fund for Student Support in Health Sciences Fellowship (N.S.G. and T.K.), the Diana Jacobs Kalman /AFAR Scholarship for Research in the Biology of Aging (N.S.G.), the UConn /JAX-GM Training Program in Genomic Science T32HG010463 (R.L.C.), Robert and Arlene Kogod (J.L.K.), the Connor Group (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K.), the Noaber Foundation (J.L.K.), Travelers Chair in Geriatrics and Gerontology (G.A.K.), and NIH grants R37AG013925 (J.L.K.), K08CA215105 (A.M.), P01AG062413 (J.L.K.), R33AG061456 (J.L.K., T.T., and G.A.K.), P30AG067988 (G.A.K.), AG063528 (M.X.), AG066679 (M.X.), and AG068860 (M.X.). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2022",
month = jan,
day = "4",
doi = "10.1016/j.cmet.2021.11.002",
language = "English (US)",
volume = "34",
pages = "75--89.e8",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "1",
}