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Activation of Fas (CD95) in Adipocytes Contributes to High Fat Diet-Induced Insulin-Resistance


Wueest, S. Activation of Fas (CD95) in Adipocytes Contributes to High Fat Diet-Induced Insulin-Resistance. 2009, University of Zurich, Faculty of Science.

Abstract

The prevalence of type 2 diabetes and insulin resistance has risen dramatically over the last decades. Excess energy intake resulting in obesity and dysregulation of white adipose tissue (WAT) are important factors contributing to the development of these metabolic diseases. The objective of this thesis was to investigate the role of adipocyte-expressed Fas (CD95) in the development of obesity-induced insulin resistance. In addition, insulin sensitivity of large and small adipocytes of obese white adipose tissue was investigated and compared.
Activation of the Fas signalling pathway in cultured 3T3-L1 adipocytes leads to increased secretion of pro-inflammatory cytokines like IL-6 and KC (murine analogue of IL-8). Moreover, Fas activation in 3T3-L1 adipocytes has negative effects on insulin sensitivity as shown by reduced insulin-stimulated glucose uptake. In vivo, Fas expression is increased in isolated adipocytes of insulin resistant mice and in adipose tissue of obese and diabetic patients. Adipocyte-specific Fas-knockout (AFasKO) mice were partly protected from HFD-induced deterioration of glucose homeostasis, and their levels of pro-inflammatory factors in WAT were reduced. Moreover, AFasKO mice did not develop hepatic steatosis and maintained hepatic insulin sensitivity. Thus, Fas activation in adipocytes contributes to adipose tissue inflammation, hepatic steatosis and insulin resistance induced by obesity.
Hypertrophic adipocytes, a consequence of obesity, are known to secrete higher amounts of pro-inflammatory factors compared to small adipocytes. Thus, we hypothesized that large adipocytes may be more insulin resistant. Interestingly, we found that insulin sensitivity did not differ
between small and large adipocytes isolated from the epididymal fat pad of obese mice. However, large adipocytes secreted higher amounts of free fatty acids (FFA) compared to small adipocytes under basal conditions.
In conclusion, “dysregulated” adipocytes in obese white adipose tissue contribute to the development of local and/or systemic insulin resistance. Large, lipid loaded adipocytes secrete higher amount of FFA, which might negatively affect insulin sensitivity. Moreover, the Fas (CD95) pathway is up-regulated in obesity and seems to contribute to local and systemic insulin resistance via changes in the secretion pattern of cytokines.

The prevalence of type 2 diabetes and insulin resistance has risen dramatically over the last decades. Excess energy intake resulting in obesity and dysregulation of white adipose tissue (WAT) are important factors contributing to the development of these metabolic diseases. The objective of this thesis was to investigate the role of adipocyte-expressed Fas (CD95) in the development of obesity-induced insulin resistance. In addition, insulin sensitivity of large and small adipocytes of obese white adipose tissue was investigated and compared.
Activation of the Fas signalling pathway in cultured 3T3-L1 adipocytes leads to increased secretion of pro-inflammatory cytokines like IL-6 and KC (murine analogue of IL-8). Moreover, Fas activation in 3T3-L1 adipocytes has negative effects on insulin sensitivity as shown by reduced insulin-stimulated glucose uptake. In vivo, Fas expression is increased in isolated adipocytes of insulin resistant mice and in adipose tissue of obese and diabetic patients. Adipocyte-specific Fas-knockout (AFasKO) mice were partly protected from HFD-induced deterioration of glucose homeostasis, and their levels of pro-inflammatory factors in WAT were reduced. Moreover, AFasKO mice did not develop hepatic steatosis and maintained hepatic insulin sensitivity. Thus, Fas activation in adipocytes contributes to adipose tissue inflammation, hepatic steatosis and insulin resistance induced by obesity.
Hypertrophic adipocytes, a consequence of obesity, are known to secrete higher amounts of pro-inflammatory factors compared to small adipocytes. Thus, we hypothesized that large adipocytes may be more insulin resistant. Interestingly, we found that insulin sensitivity did not differ
between small and large adipocytes isolated from the epididymal fat pad of obese mice. However, large adipocytes secreted higher amounts of free fatty acids (FFA) compared to small adipocytes under basal conditions.
In conclusion, “dysregulated” adipocytes in obese white adipose tissue contribute to the development of local and/or systemic insulin resistance. Large, lipid loaded adipocytes secrete higher amount of FFA, which might negatively affect insulin sensitivity. Moreover, the Fas (CD95) pathway is up-regulated in obesity and seems to contribute to local and systemic insulin resistance via changes in the secretion pattern of cytokines.

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Additional indexing

Item Type:Dissertation
Referees:Konrad D, Verrey F
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2009
Deposited On:23 Sep 2009 14:53
Last Modified:05 Apr 2016 13:20
Number of Pages:38
Related URLs:http://opac.nebis.ch/F/?local_base=NEBIS&con_lng=GER&func=find-b&find_code=SYS&request=005860035
Permanent URL: https://doi.org/10.5167/uzh-20712

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