White Adipose Tissue Remodeling by Intermittent Fasting

To combat obesity and its associated metabolic abnormalities, various dietary regimens, such as intermittent fasting (IF), have been rigorously investigated. As a critical regulator of energy balance, understanding white adipose tissue (WAT) homeostasis and its response to dietary challenges is crucial to reveal the mechanisms of IF-mediated metabolic benefits. Particularly, recent studies highlighted the role of dysfunctional adipocyte progenitors (APs) in pathological remodeling of the WAT and impairment of adaptive tissue plasticity. However, while many studies have explored the preventive effects of IF, whether it exerts therapeutic benefits in animals displaying severe metabolic dysfunction is unclear. Furthermore, the cellular target of IF and its underlying mechanisms remain to be elucidated.First, to understand the heterogeneity of WAT depots, we performed CyTOF analysis on stromal and immune cells of inguinal WAT (IWAT) and perigonadal WAT (PWAT) under normal diet (ND) and high-fat diet (HFD). At steady state, IWAT and PWAT exhibited similar immune cell composition, but depot-unique AP subpopulations. Interestingly, under HFD, PWAT exhibited significant pro-inflammatory and pro-fibrotic changes, while IWAT was rather resistant to diet-induced immune and stromal changes. This suggests PWAT is a more suitable WAT depot to analyse when assessing diet-induced pathological changes. Our study demonstrates that IF confers therapeutic benefits on animals exhibiting severe obesogenic and diabetic phenotypes, including body weight and fat mass reduction and improved glucose/insulin homeostasis. In contrast to previous reports, these effects were observed in the absence of WAT browning. However, substantial resolution of WAT fibrosis was observed with IF, accompanied by reduction of pro-fibrotic and expansion of pro-adipogenic APs. Single-nuclei sequencing analysis revealed significant enrichment of circadian pathway within the APs, which could be a key mediator of IF-induced WAT remodeling. Interestingly, animal models with circadian disruption exhibited higher WAT mass and pro-fibrotic WAT remodeling, suggesting that circadian disruption is a key mediator of WAT fibrosis. Importantly, animals lacking a functional circadian clock displayed diminished beneficial response to IF, further supporting the importance of circadian rhythm in IF-mediated metabolic benefits. Collectively, our findings highlight the novel role of AP circadian rhythm in WAT remodeling and metabolic response to IF.

Department dc:contributor.department

Laboratory Medicine and Pathobiology

Year dc:date.issued

2023

Author dc:creator

• Lee, Ju Hee

Advisors dc:contributor.advisor

• Sung, Hoon-Ki
• Lee, Warren

• Adipocyte progenitors
• Adipose tissue
• Adipose tissue fibrosis
• Circadian rhythm
• Intermittent fasting

Statement dc:rights

• Attribution 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by/4.0/

Handle dc:identifier.uri

http://hdl.handle.net/1807/138924

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/138924