Maintaining glucose and lipid homeostasis is crucial for health, with dysregulation leading to metabolic diseases such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated fatty liver disease (MAFLD). This study identifies alkylation repair homolog protein 5 (ALKBH5), an RNA N6-methyladenosine (m6A) demethylase, as a major regulator in metabolic disease. ALKBH5 is up-regulated in the liver during obesity and also phosphorylated by protein kinase A, causing its translocation to the cytosol. Hepatocyte-specific deletion of Alkbh5 reduces glucose and lipids by inhibiting the glucagon receptor (GCGR) and mammalian target of rapamycin complex 1 (mTORC1) signaling pathways. Targeted knockdown of hepatic Alkbh5 reverses T2DM and MAFLD in diabetic mice, highlighting its therapeutic potential. This study unveils a regulatory mechanism wherein ALKBH5 orchestrates glucose and lipid homeostasis by integrating the GCGR and mTORC1 pathways, providing insight into the regulation of metabolic diseases.

Ever wonder how your body keeps your blood sugar and fats in check? It’s a delicate balancing act, and when it goes wrong, it can lead to serious health issues

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