Fas mutation reduces obesity by increasing IL-4 and IL-10 expression and promoting white adipose tissue browning

Abstract

Brown adipose tissue generates heat via the mitochondrial uncoupling protein UCP1 to protect against obesity and hypothermia. Fas mutant MRL/lpr mice exhibit a significantly leaner phenotype compared to wild type MRL/MpJ mice. In this study, we evaluated the inflammatory cell population in the adipose tissue of MRL/lpr mice, which could potentially influence their lean phenotype. Furthermore, we compared beige fat activity between the MRL/MpJ and MRL/lpr mice. Fas mutation resulted in high body temperature, improved glucose tolerance, and decreased fat mass and adipocyte size. Fas mutation prevented high-fat diet-induced obesity and decreased the white adipose tissue M1:M2 ratio. When mice were fed a high-fat diet, UCP1, IL-4, IL-10, and tyrosine hydroxylase genes had significantly higher expression in Fas-mutant mice than in wild type mice. After a cold challenge, UCP1 expression and browning were also significantly higher in the Fas-mutant mice. In summary, Fas-mutant mice are resistant to high-fat diet-induced obesity due to increased IL-4 and IL-10 levels and the promotion of thermogenic protein activity and browning in their adipose tissues. STAT6 activation might contribute to M2 polarisation by increasing IL-4 and IL-10 levels while increases in M2 and tyrosine hydroxylase levels promote browning in response to Fas mutation. Weight gain and obesity are the main risk factors of type 2 diabetes mellitus, myocardial infarction, stroke, and atherosclerosis 1,2. Excess adipose tissue accumulation is accompanied by local inflammation characterised by the infiltration of inflammatory cells 3. Brown adipose tissue (BAT) is a key site for heat production in mammals and it has been previously targeted to promote weight loss 4,5. BAT generates heat via the action of the mitochondrial uncoupling protein 1 (UCP1) to protect against obesity and hypothermia 6. Increasing the metabolic activity of beige fat, brown fat, or both is essential for the treatment of obesity and metabolic diseases 7. Interestingly, increased activities of brown and beige adipocytes have been linked to obesity resistance in several genetically engineered mouse (GEM) models 7. The Fas receptor (Fas) is a member of the tumour necrosis factor (TNF)-receptor family. Fas/Fas ligand (FasL) interactions initiate apoptosis by inducing the activation of the Fas-associated death domain and the cleavage of caspase 8 8,9. Apoptosis mediated by Fas-FasL is a key mechanism for immune homeostasis and Fas plays an essential role in preventing autoimmunity by the deletion of potentially pathogenic autoreactive lymphocytes from the blood and tissues to maintain lymphocyte homeostasis and peripheral immune tolerance 10. According

Antisense oligonucleotide‐mediated knockdown ofMpzl3attenuates the negative metabolic effects of diet‐induced obesity in mice

“…Microscope images were taken at 20× and the number of cells and relative size (pixel area) were determined using the Adiposoft plug‐in for Fiji NIH Image J2 software (Galarraga et al, 2012; Schindelin et al, 2012). Analysis settings used were as described in Choi et al (2020).…”

SGLT2 Inhibitor-Induced Sympathoexcitation in White Adipose Tissue: A Novel Mechanism for Beiging

“…We have also previously demonstrated an increase in IL-10 protein levels in both the heart and kidney of BPH/2J mice after 2 weeks of Dapagliflozin treatment [ 14 ]. IL-10 may play a significant role in the beiging of WAT as Fas mutant mice, which exhibit a significantly leaner phenotype and express elevated IL-10, show elevated levels of beiging in response to cold exposure compared to wild-type mice [ 34 ]. Future studies should involve a wider exploration of the expression of adipokines in WAT of Dapagliflozin treated mice.…”

Crosstalk between Metabolic Disorders and Immune Cells

“…Fas expression was increased in adipocytes isolated from insulin-resistant mice and in the adipose tissues of obese and diabetic patients [ 86 ]. Fas mutant mice show a lean phenotype and prevent HFD-induced obesity by upregulating the expression levels of UCP1, IL-4, and IL-10 in WAT [ 87 ]. Thus, FAS/FAS ligand-mediated signaling appears to be more involved in controlling local inflammation in adipose tissue and promoting WAT browning, that is, TNF is associated with obesity via deactivation of thermogenesis [ 88 , 89 ].…”