Cideb knockdown in mice increases mitochondrial fat oxidation and reverses hepatic steatosis and insulin resistance by the plasma membrane sn-1,2-DAGs-PKCε-insulin receptor kinase T1150 pathway.
Level 5 - mechanism / opinion, no new human data
Preclinical animal experiment without human clinical data
PubMed 40908405 · doi:10.1007/s00125-025-06539-8
What was done
Male C57BL/6J mice on a high-fat diet (HFD) were treated with a 2'-O-methoxyethyl antisense oligonucleotide (ASO) targeting *Cideb*. Researchers measured in vivo hepatic mitochondrial gluconeogenesis and tricarboxylic acid (TCA) cycle flux via Q-Flux, whole-body energy expenditure using the Comprehensive Lab Animal Monitoring System (CLAMS), and tissue-specific insulin sensitivity via hyperinsulinaemic-euglycaemic clamps with radiolabelled isotopes.
What was found
Compared with wild-type controls, *Cideb* ASO treatment increased whole-body energy expenditure by ~25% and reduced hepatic triacylglycerol by ~65%. The reduction in hepatic fat was associated with increased hepatic mitochondrial oxidation and reduced lipogenesis. *Cideb* knockdown also ameliorated insulin resistance via decreased plasma membrane sn-1,2-diacylglycerol (DAG)-protein kinase C (PKC)ε-insulin receptor kinase (IRK) T1150 phosphorylation in the liver and skeletal muscle.
Why it matters
The study outlines the mechanistic basis for how *CIDEB* inhibition protects against steatotic liver disease and insulin resistance, supporting its therapeutic potential for MASLD and type 2 diabetes.
Limits
The study is restricted to an animal model (male mice only), and exact animal counts per group are not reported in the abstract. Clinical translation to humans remains unproven, and long-term toxicity or off-target effects of the ASO are not detailed.
Cited by
- supports Accumulation of fat in the liver interferes with insulin action, leading to insulin resistance.