Abstract
During obesity, adipose tissue macrophages (ATM) are increased in concert with local inflammation and insulin resistance. Since the levels of sphingolipid (SLs) in adipose tissue (AT) are altered during obesity we investigated the potential impact of SLs on ATMs. For this, we first analyzed expression of SL metabolizing genes in ATMs isolated from obese mice. A marked induction of sphingosine kinase 1 (Sphk1) expression was observed in obese ATM when compared to lean ATM. This induction was observed in both MGL-ve (M1) and MGL1+ve (M2) macrophages from obese WAT. Next, RAW264.7 cells were exposed to excessive palmitate, resulting in a similar induction of Sphk1. This Sphk1 induction was also observed when cells were treated with chloroquine, a lysosomotropic amine impacting lysosome function. Simultaneous incubation of RAW cells with palmitate and the Sphk1 inhibitor SK1-I promoted cell death, suggesting a protective role of Sphk1 during lipotoxic conditions. Interestingly, a reduction of endoplasmic reticulum (ER) stress related genes was detected in obese ATM and was found to be associated with elevated Sphk1 expression. Altogether, our data suggest that lipid overload in ATM induces Sphk1, which promotes cell viability.
Highlights
White adipose tissue (WAT) acts as the major body storage for fat from which free fatty acids (FFAs) can be mobilized [1]
The third group is composed of two genes, sphingosine kinase 1 (Sphk1) and phosphatidic acid phosphatase type 2A (Ppap2a), which are highly elevated in high fat diet (HFD) fed mice F4/80+ macrophage galactose—specific lectin 1 (MGL1)- adipose tissue macrophages (ATM)
Considering that Sphk1 was the gene most prominently induced in sorted obese macrophages compared to lean/low-fat diet (LFD) models and given the pivotal role of Sphk1 activity for instance in pancreatic β-cell survival during lipotoxic conditions, we focussed on Sphk1 regulation and role in obese ATM [34,35]
Summary
White adipose tissue (WAT) acts as the major body storage for fat from which free fatty acids (FFAs) can be mobilized [1]. Over-nutrition and sedentary life promote an increase of WAT mass and adipocyte size, favouring obesity and imbalanced homeostasis of metabolism. Excessively FFAs are released into the circulation together with chemokines and pro-inflammatory cytokines, triggering further local recruitment of inflammatory cells in the adipose tissue. This cascade promotes a pro-inflammatory environment, which drives insulin resistance (IR) and type-2 diabetes [4]. The adaptive and innate immune system both contribute to the chronic low grade inflammatory status of obese WAT.
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