Mechanobiology of adipocytes
File(s)
Author(s)
Cepa Areias, Anabela Cepa
Type
Thesis
Abstract
The expansion of visceral adipose tissue (VAT) is considered to be the most life-threatening form of obesity. It is highly correlated with the risk of developing metabolic complications such as type 2 diabetes, cardiovascular diseases and hypertriglyceridemia. VAT is confined in the abdominal space where it experiences compressive stresses. Here we hypothesise that these compressive stresses act as a mechanoregulatory mechanism to inhibit further increase of intracellular lipids and consequently control visceral adiposity. Furthermore, we hypothesise that in obesity such feedback is disrupted due to an excessive increase of adipocyte size and compressive stress.
To test this hypothesis, we engineered a 3D adipose tissue model comprising of a collagen scaffold seeded with 3T3-L1 adipocytes. This model was subjected to compressive stress under static load. We validated that this engineered tissue withstands different loads, resulting in different levels of compression. We found a decrease of intracellular lipid content in
a load-dependent manner, suggesting an increased lipolytic rate. This was associated with strong activation of the ERK pathway, that in turn activates important lipases, such as adipose triglyceride lipase (ATGL) and the hormone-sensitive lipase (HSL). Finally, overexpression of cavin-1 after compression suggests an altered adipocyte metabolism. We then investigated how adipocyte hypertrophy influences the effectiveness of this mechanical sensing. We found that 3T3-L1 adipocytes treated with a fatty acid cocktail resulted in an opposite response to the compression, inhibiting the HSL activity. In line with these in vitro results, compression of the gonadal fat in overweight mice also led to an inhibition of the HSL activity.
Taken together our results indicate that compressive stress acts as a catalyst for lipolysis in normal adipocytes, suggesting a homeostatic feedback mechanism which prevents further adipocyte expansion. However, in overweight animals, compressive stress appears to deactivate the lipolysis, disrupting the proposed feedback mechanism.
To test this hypothesis, we engineered a 3D adipose tissue model comprising of a collagen scaffold seeded with 3T3-L1 adipocytes. This model was subjected to compressive stress under static load. We validated that this engineered tissue withstands different loads, resulting in different levels of compression. We found a decrease of intracellular lipid content in
a load-dependent manner, suggesting an increased lipolytic rate. This was associated with strong activation of the ERK pathway, that in turn activates important lipases, such as adipose triglyceride lipase (ATGL) and the hormone-sensitive lipase (HSL). Finally, overexpression of cavin-1 after compression suggests an altered adipocyte metabolism. We then investigated how adipocyte hypertrophy influences the effectiveness of this mechanical sensing. We found that 3T3-L1 adipocytes treated with a fatty acid cocktail resulted in an opposite response to the compression, inhibiting the HSL activity. In line with these in vitro results, compression of the gonadal fat in overweight mice also led to an inhibition of the HSL activity.
Taken together our results indicate that compressive stress acts as a catalyst for lipolysis in normal adipocytes, suggesting a homeostatic feedback mechanism which prevents further adipocyte expansion. However, in overweight animals, compressive stress appears to deactivate the lipolysis, disrupting the proposed feedback mechanism.
Version
Open Access
Date Issued
2019-06
Date Awarded
2019-11
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Overby, Professor Darryl
Publisher Department
Bioengineering
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)