Obesity and type 2 diabetes mellitus (T2DM) are increasingly prevalent worldwide. T2DM comes with a wide range of co-morbidities including cardiovascular, kidney and skin diseases. Whether these comorbidities are driven by long-term hyperglycemia, chronic inflammation and/or direct insulin resistance in these organs is still largely unclear. Moreover, little is known whether early insulin resistance in non-classical endocrine organs, like the skin, promotes T2DM development. We found that epidermal loss of insulin/IGF-1 signaling (IIS), short term high fat diet (HFD), or genetically obese mice share similar phenotypes including a change in stem cell activity, reduced stratification, impaired barrier function, and sensitized skin inflammatory responses, thus directly linking epidermal insulin resistance to diabetes-associated skin phenotypes. The overall aim of this proposal is to understand whether and how skin insulin resistance promotes T2DM and its associated skin morbidities. We will combine genetic mouse models, human T2DM patients as well as healthy and prediabetic cohorts, multi-omics and imaging to identify how diet-induced changes in epidermal insulin resistance is communicated within the skin and to other organs under normal and high fat diet conditions taking sex and external skin barrier challenges in account, and explore the predictive and therapeutic opportunities of our findings in humans.
Type 2 diabetes Mellitus (T2DM) is increasingly prevalent with rising premature mortality rates. Currently, over 6% of the worldwide population is affected, illustrating a great unmet need for new therapies to counteract this obesity-related pandemic. We will address the hypothesis that diet-induced changes in skin insulin sensitivity directly contribute to T2DM development and to its co-morbidities, and using human cohorts, will explore clinical and therapeutic implications of our findings.
Hanssen R, Rigoux L, Albus K, Kretschmer AC, Thanarajah SE, Chen W, Hinze Y, Giavalisco P, Steculorum S, Cornely OA, Brüning JC, Tittgemeyer M. (2023) Circulating uridine dynamically and adaptively regulates food intake in humans. Cell Rep. Med. 4: 100897, doi: 10.1016/j.xcrm.2022.100897
Peskoller M, Bhosale A, Göbel K, Löhr J, Miceli S, Perot S, Persa OD, Rübsam M, Shah J, Zhang H, Niessen, CM. (2022) How to build and regenerate a functional skin barrier: the adhesive and cell shaping travels of a keratinocyte. J. Invest. Dermatol. 42:1020-1025. doi: 10.1016/j.jid.2021.12.034 (https://www.youtube.com/watch?v=bRYX0hJHRS8)
Koester J, Miroshnikova Y, Ghatak S, Chacón-Martínez C, Morgner J, Li X, Atanassov I, Altmuller J, Birk DE, Koch M, Bloch W, Bartusel M, Niessen CM, Rada-Iglesias A, and Wickström S. Niche stiffening compromises stem cell potential during aging by reducing chromatin accessibility at bivalent promoters. Nature Cell Biology 23:771-781. doi: 10.1038/s41556-021-00705-x
Hanssen R, Kretschmer AC, Rigoux L, Albus K, Thanarajah SE, Sitnikow T, Melzer C, Cornely AC, BRuning. JC, Tittgemeyer M (2021)GLP-1 and hunger modulate incentive motivation depending on insulin sensitivity in humans. Mol. Metab. 45: 101163. DOI: 10.1016/j.molmet.2021.101163
Peters F*, Tellkamp F*, Brodesser S, Wachmuth E, Tosetti B, Karow U, Bloch W, Utermohlen O, Krönke M, Niessen CM (2020) Murine epidermal Ceramide Synthase 4 is a key regulator of skin barrier homeostasis. J. Investig. Derm. https://doi.org/10.1016/j.jid.2020.02.006
Nava MM, Miroshnikova YA, Biggs LC, Whitefield DB, MetgeF, Boucas J, Vihinen H, Jokitalo E, García Arcos JM, HoffmannB, Merkel R, Niessen CM, Dahl KN, and WickströmSA. (2020) Heterochromatin-driven nuclear softening protects the genome against mechanical stress-induced damage. Cell 181:800-817.e22. doi: 10.1016/j.cell.2020.03.052
OstermannAL, WunderlichCM, Schneiders L, Vogt MC, Woeste M, Belgardt, BF Niessen CM, MartinyB, SchaussAC, Frommolt P, Nikolaev N, Hövelmeyer RC, Sears RC KochPJ, Gunzel D., BrüningJC, Wunderlich FT.(2019) Intestinal insulin/IGF1 signalling through FoxO1 regulates epithelial integrity and susceptibility to colon cancer. Nature Metabolism, 1: 371-389
Clayton RW, Göbel K, Niessen CM, Paus R, van Steensel MAM, and Lim X. (2019) Homeostasis of the sebaceous gland and mechanisms of acne pathogenesis.Br J Dermatol. 2019 May 6. doi: 10.1111/bjd.17981. [Epub ahead of print] Review.
Peters, F, Vorhagen S, Brodesser S, Jacobshagen K, Brüning JC, Niessen CM#, Krönke M.#(2015) Ceramide synthase 4 regulates stem cell homeostasis and hair follicle cycling. J. Invest. Dermatol. 135:1501-9
Guenschmann, C., Stachelscheid H., Akyüz M.D, Schmitz A., Missero, C., Bruning, J.C. and Niessen CM (2013) IGF-1 controls epidermal morphogenesis via regulation of FoxO-mediated p63 inhibition. Developmental Cell 26(2): 176-87
Department Cell Biology of the Skin - CECAD Research Center
CMMC - PI - C 12
Executive Board Member
carien.niessen[at]uni-koeln.de
show more…+49 221 478 89512
+49 221 478 6360
Department Cell Biology of the Skin - CECAD Research Center
Joseph-Stelzmann-Str. 26
50931 Cologne
Center for Endocrinology, Diabetes and Preventive Medicine
CMMC - Co-PI - C 12
show more…Center for Endocrinology, Diabetes and Preventive Medicine
Current: Institute of Metabolic Science, Cambridge University, UK
https://endokrinologie.uk-koeln.de/forschung/ag-translationale-stoffwechselforschung/
Lab coordinator
Stéphanie Miceli
Senior scientist
Matthias M. Rübsam
PostDoc
Gladiola Goranci-Buzhala
PhD student
Hanyin Zhang, Aishwarya Bhosale
Skyler Perot, Lea Trojahn
Master student
Ta-Chieh Chen
medical student
Lukas Koch, Zirui Yu
Technician
Julia Löhr