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Abstract
Adipose tissue plays a major role in regulating whole-body insulin sensitivity and energy metabolism. To accommodate surplus energy, the tissue rapidly expands by increasing adipose cell size (hypertrophy) and cell number (hyperplasia). Previous studies have shown that enlarged, hypertrophic adipocytes are less responsive to insulin, and that adipocyte size could serve as a predictor for the development of type 2 diabetes. In the present study, we demonstrate that changes in adipocyte size correlate with a drastic remodeling of the actin cytoskeleton. Expansion of primary adipocytes following 2 weeks of high-fat diet (HFD)-feeding in C57BL6/J mice was associated with a drastic increase in filamentous (F)-actin as assessed by fluorescence microscopy, increased Rho-kinase activity, and changed expression of actin-regulating proteins, favoring actin polymerization. At the same time, increased cell size was associated with impaired insulin response, while the interaction between the cytoskeletal scaffolding protein IQGAP1 and insulin receptor substrate (IRS)-1 remained intact. Reversed feeding from HFD to chow restored cell size, insulin response, expression of actin-regulatory proteins and decreased the amount of F-actin filaments. Together, we report a drastic cytoskeletal remodeling during adipocyte expansion, a process which could contribute to deteriorating adipocyte function.
Highlights
Adipose tissue plays a major role in regulating whole-body insulin sensitivity and energy metabolism[1]
We demonstrate that expansion of primary adipocyte is associated with a drastic actin re-organization, increased F/G actin ratio, and an altered protein expression favoring actin polymerization
The fact that actin re-organization was found to correlate with adipocyte size in several adipose tissue depots, irrespective of the diet of the mice, leads us to believe that the cytoskeletal re-organization is caused by cell expansion rather than by other effects caused by high-fat diet (HFD)-feeding
Summary
Adipose tissue plays a major role in regulating whole-body insulin sensitivity and energy metabolism[1]. Others have shown that F-actin functions as a physical barrier preventing docking and fusion of chromaffin vesicles with the plasma membrane[28] These studies suggest that actin remodeling is required during adipocyte maturation, and plays a role to sustain both insulin signaling and glucose transport under normal conditions. We demonstrate that adipocyte expansion is characterized by a drastic actin re-organization, together with a changed expression of actin-modulating proteins and increased Rho-kinase activity favoring actin polymerization. These changes were completely reversible during adipocyte shrinkage, concomitant with restored cellular insulin response
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