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Description
Abstract
Resident macrophages in adipose tissue account for much of the cytokine expression with obesity. We
described the expression of thrombospondin (TSP1), a pleiotropic adipokine, in insulin resistant subjects.
Through its anti-angiogenic properties and its ability to activate TGFI3, TSP1 may be an important part of the
adipocyte/macrophage interaction that results in simultaneous impairment of angiogenesis and increased TGF-
13-mediated fibrosis and inflammation. We recently demonstrated that macrophages also infiltrate skeletal
muscle with obesity that is strongly correlated with insulin resistance. Furthermore, the presence of
macrophages in co-culture with muscle cells, in the presence of palmitic acid to mimic an obese environment,
results in a synergistic increase in the expression and secretion of inflammatory cytokines from muscle cells,
all of which impair insulin action. We hypothesize that macrophages in both muscle and adipose tissues
promote the development of metabolic syndrome during obesity. To test this hypothesis, adipose (Aim 1) and
muscle tissue (Aim 2) from obese, insulin resistant compared to normal human subjects will be characterized.
Macrophage number, the proportion of macrophages that are classically versus alternatively activated, and the
proportion of macrophages in crown-like structures (in adipose) will be quantified, along with markers of the
TGF13 pathway, fibrosis, hypoxia, tissue remodeling and vascularity. To specifically determine the role of TSP1
and the TGF13 pathway in insulin resistance, adipose and muscle tissue fibrosis, hypoxia, and macrophage
function will be analyzed in high fat fed TSP1 null mice in Aim 3. A peptide that specifically blocks TSP1-
mediated TGFf3 activation will also be used in wild type, high fat fed mice to test the hypothesis that
macrophage infiltration and fibrosis in adipose and muscle will be ameliorated in the absence of TSP1,
resulting in improved insulin sensitivity. Aim 4 is the intervention aim in which the mechanisms underlying the
beneficial effects of aerobic exercise training on insulin sensitivity will be determined. Following 12 weeks of
training in obese and lean subjects, changes in muscle and adipose macrophage number, activation state, the
TSP1/TGF13 pathway, and inflammation in response to a single bout of eccentric exercise will be quantified
relative to insulin sensitivity. Finally, in Aim 5, the effects of different macrophage populations on adipocytes
and muscle cells will be studied in vitro. The expression of genes involved in adipogenesis, extracellular matrix,
and the TGF13 pathway will be monitored in adipocytes following macrophage co-culture. These will also be
quantified in muscle cells, as well as the response to insulin. We will determine whether mechanical
stimulation of myotubes to mimic exercise will alter the muscle cell response to macrophages.
Status | Finished |
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Effective start/end date | 6/1/05 → 3/31/15 |
Funding
- National Institute Diabetes & Digestive & Kidney: $1,579,323.00
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