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| Status |
Public on Jul 30, 2024 |
| Title |
Control of cholesterol-induced adipocyte inflammation by the Nfe2l1-Atf3 pathway |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
While adipocytes are critical pillars of energy metabolism, their dysfunction is linked to adipose tissue (AT) inflammation, insulin resistance, and ectopic lipotoxicity in cardiometabolic diseases. However, he mechanisms causing adipocyte inflammation and insulin resistance remain unclear. Here, we show that excess cholesterol induces adipocyte dysfunction, which is suppressed by the transcription factor Nfe2l1 (nuclear factor erythroid derived-2, like-1). Nfe2l1 is required to sustain proteasome function in adipocytes and proteotoxic stress induces adipocyte inflammation via the activation of Atf3. In humans, the Nfe2l1-proteasome pathway is inversely correlated to body mass index (BMI) in an adipose-depot specific manner. In mice, loss of adipocyte Nfe2l1 caused AT inflammation with a pronounced infiltration of macrophages and T cells. Mice lacking adipocyte Nfe2l1 displayed severe adipocyte dysfunction during diet-induced obesity (DIO), characterized by lower adipokine levels, steatosis, glucose intolerance and insulin resistance. Nfe2l1ΔAT mice on an Apoe-deficient (Apoe-/-) background fed a cholesterol-rich Western Diet (WD), developed a lipoatrophy-like syndrome, dyslipidemia, and enhanced atherosclerosis. Our results reveal an important role for proteasome-mediated proteostasis in adipocytes and indicate that Nfe2l1 is linked to metabolic health in humans and preclinical mouse models. Promoting proteostasis in adipocytes may thus alleviate inflammation in obesity, potentially averting adverse cardiometabolic outcomes.
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| Overall design |
To investigate the impact of Nfe2l1 and Atf3 on cholesterol homeostasis, we generated primary white adipocytes from murine subcutaneous adipose tissue in which we silenced Nfe2l1, Atf3 and both of them with siRNAs. To induce cholesterol loading of the adipocytes, we treated them with 400 µM cholesterol conjugated to methyl-β-cyclodextrin for 6 h. We sequenced four replicates for each condition.
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| Web link |
https://doi.org/10.1101/2024.07.22.604614
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| Contributor(s) |
Jethwa C, Bartelt A |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Jul 25, 2024 |
| Last update date |
Jul 30, 2024 |
| Contact name |
Carolin Jethwa |
| E-mail(s) |
carolin.muley@med.uni-muenchen.de
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| Organization name |
Ludwig-Maximilians-University
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| Department |
Institute for Cardiovascular Prevention
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| Lab |
Bartelt Lab
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| Street address |
Max-Lebsche-Platz 30
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| City |
Munich |
| ZIP/Postal code |
81377 |
| Country |
Germany |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (32)
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| GSM8421799 |
primary white adipocyte,scramble, control treatment, biol rep 1 |
| GSM8421800 |
primary white adipocyte,scramble, control treatment, biol rep 2 |
| GSM8421801 |
primary white adipocyte,scramble, control treatment, biol rep 3 |
| GSM8421802 |
primary white adipocyte,scramble, control treatment, biol rep 4 |
| GSM8421803 |
primary white adipocyte,siNfe2l1, control treatment, biol rep 1 |
| GSM8421804 |
primary white adipocyte,siNfe2l1, control treatment, biol rep 2 |
| GSM8421805 |
primary white adipocyte,siNfe2l1, control treatment, biol rep 3 |
| GSM8421806 |
primary white adipocyte,siNfe2l1, control treatment, biol rep 4 |
| GSM8421807 |
primary white adipocyte,siAtf3, control treatment, biol rep 1 |
| GSM8421808 |
primary white adipocyte,siAtf3, control treatment, biol rep 2 |
| GSM8421809 |
primary white adipocyte,siAtf3, control treatment, biol rep 3 |
| GSM8421810 |
primary white adipocyte,siAtf3, control treatment, biol rep 4 |
| GSM8421811 |
primary white adipocyte,siNfe2l1+siAtf3, control treatment, biol rep 1 |
| GSM8421812 |
primary white adipocyte,siNfe2l1+siAtf3, control treatment, biol rep 2 |
| GSM8421813 |
primary white adipocyte,siNfe2l1+siAtf3, control treatment, biol rep 3 |
| GSM8421814 |
primary white adipocyte,siNfe2l1+siAtf3, control treatment, biol rep 4 |
| GSM8421815 |
primary white adipocyte,scramble, 400 µM cholesterol, biol rep 1 |
| GSM8421816 |
primary white adipocyte,scramble, 400 µM cholesterol, biol rep 2 |
| GSM8421817 |
primary white adipocyte,scramble, 400 µM cholesterol, biol rep 3 |
| GSM8421818 |
primary white adipocyte,scramble, 400 µM cholesterol, biol rep 4 |
| GSM8421819 |
primary white adipocyte,siNfe2l1, 400 µM cholesterol, biol rep 1 |
| GSM8421820 |
primary white adipocyte,siNfe2l1, 400 µM cholesterol, biol rep 2 |
| GSM8421821 |
primary white adipocyte,siNfe2l1, 400 µM cholesterol, biol rep 3 |
| GSM8421822 |
primary white adipocyte,siNfe2l1, 400 µM cholesterol, biol rep 4 |
| GSM8421823 |
primary white adipocyte,siAtf3, 400 µM cholesterol, biol rep 1 |
| GSM8421824 |
primary white adipocyte,siAtf3, 400 µM cholesterol, biol rep 2 |
| GSM8421825 |
primary white adipocyte,siAtf3, 400 µM cholesterol, biol rep 3 |
| GSM8421826 |
primary white adipocyte,siAtf3, 400 µM cholesterol, biol rep 4 |
| GSM8421827 |
primary white adipocyte,siNfe2l1+siAtf3, 400 µM cholesterol, biol rep 1 |
| GSM8421828 |
primary white adipocyte,siNfe2l1+siAtf3, 400 µM cholesterol, biol rep 2 |
| GSM8421829 |
primary white adipocyte,siNfe2l1+siAtf3, 400 µM cholesterol, biol rep 3 |
| GSM8421830 |
primary white adipocyte,siNfe2l1+siAtf3, 400 µM cholesterol, biol rep 4 |
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| Relations |
| BioProject |
PRJNA1140179 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE273101_gene_count.txt.gz |
3.0 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
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