Metabolomics Study on ACOX1 and Obesity Treatment Published in Nature Communications: A TMIC Client Success Story
Dr. Irfan J. Lodhi and his team from Washington University School of Medicine have recently published in Nature Communication* for their research surrounding the manipulation of ACOX1, a liver gene, to treat obesity associated metabolic disorders.
Client Background and Research Interests
Dr. Lodhi’s lab at the Division of Endocrinology, Metabolism, & Lipid Research focuses on lipid metabolism, particularly within cellular organelles called peroxisomes, and its impact on energy homeostasis. Their research investigates how peroxisomes influence metabolic disorders like obesity and diabetes by studying pathways that involve the beta-oxidation of very long chain fatty acids (VLCFA). Specifically, they explore how peroxisomal enzymes, such as Acox1, affect liver gene expression and whole-body energy homeostasis, using mice with liver-specific knockout of Acox1 to elucidate these mechanisms.
Why Lipidomics?
To understand the mechanisms behind the promotion of adipocyte browning in response to hepatic Acox1 deficiency, Dr. Lodhi’s group conducted analysis involving treatment of white adipocytes with serum from Acox1-LKO mice. They observed this serum induced increased expression of genes related to adipocyte browning, such as UCP1 and COX4. Interestingly, this effect was absent when the cells were treated with delipidated serum, suggesting that circulating lipids play a crucial role in mediating adipocyte browning.
To identify these specific lipids involved in signaling, the researchers collaborated with TMiC’s Li Node to take advantage of the global lipidomics using UHPLC-QTOF-MS and MS/MS services. Lipidomics is a powerful analytical approach that allows for comprehensive profiling and quantification of lipid species within biological samples. By applying these advanced mass spectrometry-based methods, the researchers aimed to pinpoint the exact lipid(s) responsible for promoting adipocyte browning in the context of hepatic Acox1 deficiency. This global lipidomics approach provides critical insights into lipid signaling pathways that could potentially be targeted for therapeutic interventions in metabolic disorders such as obesity.
The Discovery
This project, utilizing TMIC’s global lipidomics analysis, discovered that liver-specific knockout of Acox1 (Acox1-LKO) protected mice from diet-induced obesity, adipose tissue inflammation, and systemic insulin resistance. Serum from Acox1-LKO mice promoted browning in cultured white adipocytes. Global serum lipidomics showed increased circulating levels of several species of omega VLCFAs that promote browning, mitochondrial biogenesis and Glut4 translocation through activation of the lipid sensor GPR120 in adipocytes.
Dr. Lodhi said, “Although we expected Acox1 inactivation to result in accumulation of VLCFAs, the selective increase of polyunsaturated omega-3 form of these fatty acids was surprising. It was also surprising that these fatty acids are released into circulation with inhibition of Acox1.”
Results and The Future
This research identifies hepatic peroxisomal beta-oxidation as an important regulator of metabolic homeostasis and suggests that manipulation of Acox1 or its substrates may treat obesity-associated metabolic disorders. Dietary supplementation of these beneficial lipids or inhibition of Acox1 enzyme activity has the potential to be an effective strategy to treat obesity-associated metabolic disorders.
For the next steps, Dr. Lodhi and his team are interested in the molecular pathways downstream of GPR120 activation that affect adipocyte browning and Glut4 translocation.
We eagerly await the future research endeavors of Dr. Lodhi in lipidomics and metabolomics and the ongoing investigation in this dynamic field.
Key Technologies in Lipidomics Offered at TMIC
- Global (Untargeted) Lipidomics Profiling. Using a cutting-edge method to analyze the lipidome in both positive and negative ionization. It typically detects, identifies and relatively quantifies more than 5,000 lipids for positive ionization and more than 2,000 lipids for negative ionization. This is a one-stop analysis where it includes all sample preparation, lipid extraction, LC-MS analysis, data analysis, lipid identification, data normalization, and statistical analysis (PCA, PLS-DA, Volcano plots).
- Sphingolipid Synthesis Metabolism. Quantification of sphingolipid biosynthesis phosphate intermediates, sphinganines, ceramides, sphingomyelins, sulfatides, cerebrosides, and gangliosides by UPLC-MRM/MS.
- Targeted Lipidomics. Extraction, separation, and quantification of 4 neutral lipid classes and 9 phospholipid classes using GC-FAMES-MS.
Lu, D., He, A., Tan, M. et al. Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling. Nat Commun 15, 4214 (2024). https://doi.org/10.1038/s41467-024-48471-2.
