| Author: | Long, Kekao |
| Title: | The vital role of white adipose tissue in the regulation of intestinal homeostasis and systemic metabolism |
| Advisors: | Cheng, Kenneth (HTI) |
| Degree: | Ph.D. |
| Year: | 2021 |
| Subject: | Adipose tissues Intestines -- Microbiology Hong Kong Polytechnic University -- Dissertations |
| Department: | Department of Health Technology and Informatics |
| Pages: | xviii, 151 pages : color illustrations |
| Language: | English |
| Abstract: | Introduction: Adipose tissue not only stores energy but also controls metabolism. Subcutaneous white adipose tissue (sWAT) secretes beneficial adipokines, including bioactive hormones, cytokines and metabolites that affect the function of cells and tissues throughout the body. Recently, adipose tissues have been shown to play an important role in immunological regulation. However, little is known about their role in mucosal immunity and gut microbiota homeostasis. Method: To address this question, I employed our recently developed lipodystrophic mouse model, in which adipocyte MDM2 is genetically deleted (so-called Adipo-MDM2-KO mice). To investigate the role of sWAT in the regulation of intestinal function, sWAT from its wild-type (WT) littermates was transplanted into the Adipo-MDM2-KO mice. In addition, C57BL/6 mice were subjected to surgical removal of subcutaneous white adipose tissue (FR) or Sham operation (Sham). The effect of adipocytes on B cell was further explored using in vitro approaches. Primary adipocytes were isolated from sWAT. Splenic naïve B (B220+IgM+IgD+IgA-) cells were collected by flow cytometry, followed by treatment with conditional medium collected from different fat depots and its subpopulation of cells. Using the above in vivo and in vitro approaches, I provided a series of evidence supporting that sWAT is an important player for immune homeostasis in gut-associated tissues and lack of sWAT leads to severe intestinal dysbiosis. Key findings: 1) Adipo-MDM2-KO mice displayed a progressive fat loss as the previously reported. No fat could be found in 20-week-old Adipo-MDM2-KO mice, which was accompanied with severe gut dysfunctions, including increased gut permeability, endotoxemia, dysregulated gut microbiota compositions and altered gut structure. In addition, IgA class switching was impaired in the lamina propria (LP) and Peyer’s patches (PPs), two important intestinal immune structures, as reflected by decreased fecal IgA level, IgA coated bacteria, IgA+ B cells and its derived plasma cells but induction of fecal IgM and IgM+ B cell populations. The above data suggested that adipose tissue dysfunction affects gut immunity and its associated-microbiota homeostasis. 2) The gut dysfunction in Adipo-MDM2-KO mice could be largely rescued by subcutaneous fat transplantation, which included reduction of gut permeability and circulating LPS level and improvement of gut microbiota dysbiosis. Noticeably, aberrant IgA production in the intestine of KO mice could also be improved by fat transplantation. 3) The mice with surgical removal of sWAT also exhibited reduced production of fecal IgA and IgA+ B cell population in the intestines and altered gut microbiota composition. 4) In vitro experiments showed that conditioned media from explanted adipose tissues induced the population of IgA+ Plasma cells (PCs) from naïve B cells. 5) Adipocytes (isolated from sWAT) were key players in maintaining naïve B cell viability and to promote its differentiation to IgA+PCs. Conclusion: These findings from in vivo and ex vivo experiments indicated that sWAT is indispensable for intestinal homeostasis by promoting naïve B cell differentiation and IgA production in the intestine, as an endocrine manner. |
| Rights: | All rights reserved |
| Access: | open access |
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