The studies outlined in this proposal are designed to prepare the PI, Dr. Kathleen Markan, with the technical and intellectual expertise required to become an expert in beige adipocyte development and metabolism. Specifically, Dr. Markan will perform in vivo metabolic phenotyping studies and perform ChIP-seq analysis and functional screening of putative TBX1 target genes using adipocytes isolated from the novel adipocyte specific TBX1 mouse models she has generated. Beige adipocytes display a tremendous capacity for energy expenditure and their biology is being actively studied as a potential means to treat human obesity meaning, Dr. Markan?s work will provide direct insights regarding processes that could be used to treat human obesity. With these goals in mind, the following studies are proposed: 1) determine if TBX1 adipocyte expression is both sufficient and necessary for the development of beige adipocytes by phenotyping TBX1 adipocyte-specific transgenic mice under lean and diet induced obese conditions and testing the ability of TBX1 adipocyte-specific knockout mice to defend core body temperature during a cold challenge. This application was thoughtfully designed to allow Dr. Markan to transition her work into independence and progress to tenure-track faculty status at the end of the award period. The work outlined above will be conducted by Dr. Markan under the supervision of her mentor Dr. Matthew Potthoff, Assistant Professor of Pharmacology and co-mentor Dr. Dale Abel, Director of the F.O.E. Diabetes Research Center and Chair of Internal Medicine, both at the University of Iowa. Dr. Markan will also be strongly supported and her progress closely monitored through direct and regular engagement with her team of collaborators and consultants. Through this K01 award, Dr. Markan will expand her technical and scientific knowledge base, acquire new skills and generate data that will lead to her success as an independent academic scientist. Both the Department of Pharmacology and the F.O.E. Diabetes Research Center at the University of Iowa provide a rich environment for conducting the proposed studies and Drs. Potthoff and Abel as well as the Department of Pharmacology are strongly committed to Dr. Markan?s success.

Public Health Relevance

Beige adipocytes possess the potential to increase energy expenditure and essentially ?burn off? the excess lipid present during obesity. TBX1 is the only identified transcription factor expressed in mouse and human beige adipocytes yet its function remains unknown. The studies described in this application would be the first to characterize the role of the transcription factor TBX1 in adipocytes both in vivo and in vitro.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK111758-02
Application #
9353812
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Spain, Lisa M
Project Start
2016-09-16
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Iowa
Department
Pharmacology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Klingelhutz, Aloysius J; Gourronc, Francoise A; Chaly, Anna et al. (2018) Scaffold-free generation of uniform adipose spheroids for metabolism research and drug discovery. Sci Rep 8:523
Markan, Kathleen R; Naber, Meghan C; Small, Sarah M et al. (2017) FGF21 resistance is not mediated by downregulation of beta-klotho expression in white adipose tissue. Mol Metab 6:602-610
BonDurant, Lucas D; Ameka, Magdalene; Naber, Meghan C et al. (2017) FGF21 Regulates Metabolism Through Adipose-Dependent and -Independent Mechanisms. Cell Metab 25:935-944.e4
Kolb, Ryan; Phan, Liem; Borcherding, Nicholas et al. (2016) Obesity-associated NLRC4 inflammasome activation drives breast cancer progression. Nat Commun 7:13007