Role of regulatory T cells in obesity and insulin resistance
department or school: Medicine, Faculty of
department or school: Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Wu, Dan
issued: 2019-10-21T17:53:41Z
issued: 2019
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Adipose tissue (AT)-resident regulatory T cells (Tregs) are important regulators of local and systemic inflammation and metabolism. We have previously found that insulin receptor signaling inhibits Treg suppressive function in vitro, and hyperinsulinemia is associated with alterations in visceral AT Tregs in vivo. To directly test the role of Treg-intrinsic insulin receptor signaling, we generated Foxp3(cre)InsR(fl/fl) mice and fed them either chow or high-fat diet (HFD) to induce hyperinsulinemia and obesity. Compared to Foxp3(cre) mice, Foxp3(cre)InsR(fl/fl) mice had improved glucose tolerance and insulin sensitivity after 13 weeks of HFD. This protective metabolic effect was associated with increased brown AT ST2+ Treg numbers and functions and dampened AT inflammation in Foxp3(cre)InsR(fl/fl) mice, rather than changes in food consumption or energy expenditure. Moreover, Foxp3(cre)InsR(fl/fl) mice were protected from age-associated glucose intolerance and insulin resistance as determined in 52-week-old mice. Unlike in the HFD cohort, visceral AT Treg numbers and functions were greatly reduced in aged Foxp3(cre)InsR(fl/fl) mice, leading to increased inflammation in the visceral AT. Surprisingly, elevated AT inflammation was associated with improved metabolic outcomes. Gene expression analysis revealed differential gene signatures in AT Tregs and total AT inflammation, suggesting that the underlying mechanisms contributing to the metabolic syndromes were distinct between the two insulin resistance models. Together, these data suggest that hyperinsulinemia contributes to metabolic syndrome in part by differentially affecting Treg control of AT inflammation in diet-induced versus age-associated metabolic syndrome. In mice, lean visceral AT is populated with anti-inflammatory cells, notably Tregs expressing the IL-33 receptor ST2. Conversely, obese AT contains fewer Tregs and more pro-inflammatory cells. In humans, however, there is limited evidence for a similar patt…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/72017
note: ROLE OF REGULATORY T CELLS IN OBESITY AND INSULIN RESISTANCE by Dan Wu B.Sc., The University of British Columbia, 2013 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) October 2019 © Dan Wu, 2019 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: ROLE OF REGULATORY T CELLS IN OBESITY AND INSULIN RESISTANCE submitted by Dan Wu in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Experimental Medicine Examining Committee: Megan Levings Supervisor Bruce Verchere Supervisory Committee Member Fumio Takei University Examiner James Johnson University Examiner Additional Supervisory Committee Members: Alice Mui Supervisory Committee Member iii Abstract Adipose tissue (AT)-resident regulatory T cells (Tregs) are important regulators of local and systemic inflammation and metabolism. We have previously found that insulin receptor signaling inhibits Treg suppressive function in vitro, and hyperinsulinemia is associated with alterations in visceral AT Tregs in vivo. To directly test the role of Treg-intrinsic insulin receptor signaling, we generated Foxp3creInsRfl/fl mice and fed them either chow or high-fat diet (HFD) to induce hyperinsulinemia and obesity. Compared to Foxp3cre mice, Foxp3creInsRfl/fl mice had improved glucose tolerance and insulin sensitivity after 13 weeks of HFD. This protective metabolic effect was associated with increased brown AT ST2+ Treg numbers and functions and dampened AT inflammation in Foxp3creInsRfl/fl mice, rather than changes in food consumption or energy expenditure. Moreover, Foxp3creInsRfl/fl mice were protected from age-associated glucose intolerance and insulin resistance as determined in 52-week-old mice. Unlike in the H…
has type: Thesis/Dissertation
date issued: 2019-11
is shown at: 10.14288/1.0384589
language: eng
degree discipline: Experimental Medicine
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/72017