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Elaiophylin reduces body weight and lowers glucose levels in obese mice by activating AMPK

ABSTRACT: Obesity is an epidemic affecting 13% of the global population and increasing the risk of many chronic diseases. However, only several drugs are licensed for pharmacological intervention for the treatment of obesity. As a master regulator of metabolism, the therapeutic potential of AMPK is widely recognized and aggressively pursued for the treatment of metabolic diseases. We found that elaiophylin (Ela) rapidly activates AMPK in a panel of cancer cell lines, as well as primary hepatocytes and adipocytes. Meanwhile, Ela inhibits the mTORC1 complex, turning on catabolism and turning off anabolism together with AMPK. In vitro and in vivo studies showed that Ela does not activate AMPK directly; instead, it increases cellular AMP/ATP and ADP/ATP ratios, leading to AMPK phosphorylation in a LKB1-dependent manner. AMPK activation induced by Ela caused changes in diverse metabolic genes, thereby promoting glucose consumption and fatty acid oxidation. Importantly, Ela activates AMPK in mouse liver and adipose tissue. As a consequence, it reduces body weight and blood glucose levels and improves glucose and insulin tolerance in both ob/ob and high fat diet-induced obese mouse models. Our study has identified a novel AMPK activator as a candidate drug for the treatment of obesity and its associated chronic diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE182566 | GEO | 2021/10/27

REPOSITORIES: GEO

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Project description:Obesity is a global pandemic and a key risk factor for several neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease, or dementia. The neurovascular unit (NVU), essential for blood-brain barrier (BBB) integrity and comprised of endothelial cells, glial cells (microglia and astrocytes), and neurons, plays an important role in the pathogenesis of neurodegenerative diseases. However, molecular mechanisms underlying the effects of obesity on endothelial and other cells of and its contribution to neurodegeneration remains largely unknown. In this study we aimed to decipher in-dept molecular modifications induced by obesity in cells of neurovascular unit by integrative multiomics analysis of endothelial cells, neurons, microglial cells, and astrocytes from the hippocampus of ob/ob mice. Hippocampus were isolated from ob/ob and C57BL/6J male mice at 17-18 weeks of age. Gene expression profiles of cells of hippocampus were obtained using single nuclei RNA sequencing (snRNAseq) and data analyzed using in-dept bioinformatic analyses. snRNAseq and UMAP analysis revealed 19 cell types in hippocampus. Comparisons of global gene expression profiles identified different global profiles between ob/ob and WT for each of the cell types of the NVU. Statistical analyses revealed 4463 DEGs in neuronal cells, 1386 DEGs in astrocytes, 125DEGs in endothelial cells, and 155 DEGs in microglia cells, suggesting that obesity significantly impacts the expression profiles of NUV cells. Enrichment analyses revealed that these genes are involved in cellular processing like focal adhesion, cell interactions, inflammation, and metabolism. Changes in the expression in endothelial cells were positively correlated with genomic changes in other cell types, changes that we correlated with tendency in increase in BBB observed using functional MRI. Taken together, obesity exert significant cell-specific changes in global gene expression, genes that are associated with development of Alzheimer’s disease or dementia.

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Elaiophylin reduces body weight and lowers glucose levels in obese mice by activating AMPK

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