Fas activation in adipocytes impairs insulin‐stimulated glucose uptake by reducing Akt

Abstract

a b s t r a c tFas (CD95) belongs to the superfamily of the tumor necrosis factor (TNF) receptors. Besides its key role in apoptosis, Fas contributes to non-apoptotic pathways such as cell proliferation and inflammation. In 3T3-L1 adipocytes, activation of Fas by Fas ligand decreased insulin-stimulated glucose uptake, without affecting cell viability. This decrease in glucose uptake was accompanied by reduced protein expression and diminished phosphorylation of Akt. Similarly, insulin-stimulated glucose incorporation and protein levels of Akt were increased in isolated adipocytes from Fas deficient mice when compared to wild-type mice. In conclusion, Fas activation in adipocytes decreases Akt expression and thereby impairs insulin sensitivity.

Fas activates lipolysis in a Ca2+-CaMKII-dependent manner in 3T3-L1 adipocytes

“…2 ), consistent with our earlier observation ( 11 ), and without affecting their viability as assessed by Terminal deoxynucleotidyltransferase dUTP nick end labeling assay (see supplementary Fig. I ) and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide determination ( 19 ). Fractional reesterifi cation did not decrease upon FasL incubation (basal: 68.0 ± 2.6%; 6 h FasL: 64.0 ± 6.0%; 12 h FasL: 63.6 ± 5.5%; P = 0.8).…”

“…We recently showed that treatment of 3T3-L1 adipocytes with 2 ng/ml FasL for 12 h reduced protein levels of Akt/ PKB (protein kinase B) ( 19 ). Moreover, a recent publication reported that deletion of rictor, an essential component of the Akt kinase mammalian target of rapamycin complex 2 (mTORC2), increases basal lipolysis as well as phosphorylation of HSL at Ser563 in adipocytes ( 34 ).…”

“…Treatment of differentiated 3T3-L1 adipocytes with 2 ng/ml FasL for 12 h signifi cantly increased to this well-established role of Fas in apoptosis, Fas activation contributes to nonapoptotic signaling pathways, including cell proliferation ( 9,13 ) and the induction of infl ammatory responses in different cell types (14)(15)(16)(17)(18). Moreover, we have recently reported that Fas is increasingly expressed in WAT of obese subjects and that Fas-defi cient and adipocyte-specifi c Fas knockout mice are partly protected from high-fat diet-induced insulin resistance ( 11,19 ), implicating a role for Fas in the pathogenesis of obesityassociated insulin resistance. Although the underlying mechanism remains incompletely understood, livers of adipocyte-specifi c Fas knockout mice had lower levels of total ceramides, which are potentially metabolized from NEFA delivered to the liver from adipose tissue.…”

Non-alcoholic fatty liver disease, vascular inflammation and insulin resistance are exacerbated by TRAIL deletion in mice

“…Fas has also been implicated in NAFLD in people 27 , and in experimental models 28, 29 . Reduced hepatic steatosis was also observed in mice with Fas deletion specifically from adipocytes 30 . These data imply that TNF ligands may promote NAFLD pathogenesis via their cognate receptors.…”

Adipose tissue inflammation: a cause or consequence of obesity-related insulin resistance?

“…Supporting the importance of apoptosis in adipose tissue inflammation, mice with a conditional deletion of a key pro-apoptotic molecule (Bid) are protected from adipocyte apoptosis, adipose tissue immune cell infiltration and insulin resistance [85]. Moreover, adipocyte specific inactivation of the death receptor Fas (CD95) improves insulin sensitivity and reduces hepatic steatosis as well as adipose tissue inflammation in high fat diet induced obese mice [86], whereas activation of Fas in adipocytes stimulates pro-inflammatory cytokine production and causes adipocyte dysfunction [87,88]. Importantly, we could translate many of the associations between Fas expression and the phenotype into the human situation [84].…”