eprintid: 23329
rev_number: 21
eprint_status: archive
userid: 3271
dir: disk0/00/02/33/29
datestamp: 2017-08-17 09:44:21
lastmod: 2018-03-09 10:17:27
status_changed: 2017-08-17 09:44:21
type: doctoralThesis
metadata_visibility: show
creators_name: Meln, Irina
title: Conditioning fat for the future: adipose tissue expansion during childhood
subjects: 500
subjects: 570
divisions: 140001
divisions: 850300
adv_faculty: af-14
cterms_swd: Obesity
cterms_swd: White adipose tissue
cterms_swd: Adipocyte progenitor cells
cterms_swd: High-fat diet
cterms_swd: Gene expression profiling
cterms_swd: Co-culture system
abstract: Obesity has become a global health problem for both children and adults. White adipose tissue (WAT) displays unique plasticity upon excessive feeding by expanding its mass through proliferation and differentiation of resident adipocyte progenitor cells (AP). Studies have shown that excessive accumulation of WAT is pre-determined during early childhood. However, mechanisms of the body weight programming and effect of WAT expansion during childhood on metabolic disease risk later in life are still elusive. In order to investigate regulation of AP expansion by obesogenic diet, we established a diet-induced obesity model. We observed a rapid gain in body weight and increased accumulation of WAT already one week after high-fat diet (HFD) feeding in young, sexually immature female mice, but not adult mice. Moreover, HFD induced WAT growth via proliferation of APs and partially through mature adipocyte hypertrophy. Employing an isocaloric, pair feeding approach, we found that dietary fat content is able to induce proliferation of APs, while the amount of consumed calories seems to promote inflammation. Moreover we demonstrated that AP proliferation could occur without initial hypertrophy of mature adipocytes. Although we demonstrated that the concentration of insulin-like growth factor 1 (IGF-1) was regulated by calorie load as little as 2 days of HFD, it was not changed upon isocaloric HFD thus could not fully explain the proliferation we observed in APs. Additionally, we found lipids transiently increased after feeding and could be potentially involved in AP activation. In order to identify genes involved in regulating AP responses in the niche upon excessive feeding during childhood, we performed gene expression profiling from whole tissue and specific cellular subpopulations of WAT. A large portion of the differentially expressed genes from WAT profiles were associated with key events in tissue remodeling and cell-to-cell communication, such as inflammation, cytokine production, and extracellular matrix proteins/remodeling enzymes. In order to functionally validate candidate genes, a novel co-culture system with APs and feeder niche-like cells was established to mimic WAT physiological conditions. This system was used for siRNA screening by high-content microscopy to identify alterations in cell proliferation and differentiation. Several gene targets related to increased proliferation of APs in response to HFD feeding have been validated including epithelial membrane protein 1 (EMP1), which known to play a role in cell junctions. EMP1 modulation in feeder cells (siRNA mediated knockdown or overexpression) altered AP-derived colony growth. Our results suggested that high fat feeding induces activation of the network of cell-cycle related genes triggering AP proliferation in early development.
date: 2018
id_scheme: DOI
id_number: 10.11588/heidok.00023329
ppn_swb: 1653589469
own_urn: urn:nbn:de:bsz:16-heidok-233290
date_accepted: 2016-12-21
advisor: HASH(0x556120ab8018)
language: eng
bibsort: MELNIRINACONDITIONI2018
full_text_status: public
place_of_pub: Heidelberg, Germany
citation:   Meln, Irina  (2018) Conditioning fat for the future: adipose tissue expansion during childhood.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/23329/1/Irina%20Meln.pdf