Related Experiment Video
Updated: Jul 12, 2025
Measurement of Fatty Acid β-Oxidation in a Suspension of Freshly Isolated Mouse Hepatocytes
Published on: September 9, 2021
Insulin sensitization by hepatic FoxO deletion is insufficient to lower atherosclerosis in mice
María Concepción Izquierdo1,2, Michael Harris1, Niroshan Shanmugarajah1,2
1Naomi Berrie Diabetes Center; Columbia University College of Physicians and Surgeons; New York, NY, 10032; USA.
Background–:
Type 2 diabetes is associated with an increased risk of atherosclerotic cardiovascular disease. It has been suggested that insulin resistance underlies this link, possibly by altering the functions of cells in the artery wall. We aimed to test whether improving systemic insulin sensitivity reduces atherosclerosis.
Methods–:
We used mice that are established to have improved systemic insulin sensitivity: those lacking FoxO transcription factors in hepatocytes. Three hepatic FoxO isoforms (FoxO1, FoxO3, and FoxO4) function together to promote hepatic glucose output, and ablating them lowers glucose production, lowers circulating glucose and insulin, and improves systemic insulin sensitivity. We made these mice susceptible to atherosclerosis in two different ways, by injecting them with gain-of-function AAV8.mPcsk9D377Y and by crossing with Ldlr-/- mice.
Results–:
We verified that hepatic FoxO ablation improves systemic insulin sensitivity in these atherosclerotic settings. We observed that FoxO deficiency caused no reductions in atherosclerosis, and in some cases increased atherosclerosis. These phenotypes coincided with large increases in circulating triglycerides in FoxO-ablated mice.
Conclusions–:
These findings suggest that systemic insulin sensitization is insufficient to reduce atherosclerosis.
Insights
Improving systemic insulin sensitivity did not reduce atherosclerosis in mice. In fact, it sometimes worsened the condition, highlighting that insulin sensitization alone is insufficient for treating atherosclerotic cardiovascular disease.
Area of Science:
- Metabolic disease research
- Cardiovascular research
- Molecular biology
Background:
- Type 2 diabetes increases atherosclerotic cardiovascular disease risk, potentially via insulin resistance affecting artery wall cells.
- Investigating the link between systemic insulin sensitivity and atherosclerosis is crucial for understanding disease mechanisms.
- The role of hepatic insulin sensitivity in the development of atherosclerosis requires further elucidation.
Approach:
- Utilized mice lacking hepatic Forkhead box O (FoxO) transcription factors to enhance systemic insulin sensitivity.
- Induced susceptibility to atherosclerosis in these mice using AAV8.mPcsk9 gain-of-function or by crossing with Ldlr-/- mice.
- Verified improved systemic insulin sensitivity in FoxO-ablated mice within atherosclerotic models.
Key Points:
- Hepatic FoxO ablation successfully improved systemic insulin sensitivity in mouse models of atherosclerosis.
- FoxO deficiency did not reduce, and in some instances increased, atherosclerotic lesion development.
- A significant increase in circulating triglycerides was observed in FoxO-ablated mice.
Conclusions:
- Systemic insulin sensitization, achieved through hepatic FoxO ablation, is insufficient to mitigate atherosclerosis.
- The study suggests that targeting systemic insulin sensitivity alone may not be an effective strategy for preventing or treating atherosclerosis.
- Elevated triglycerides associated with improved insulin sensitivity warrant further investigation in the context of cardiovascular risk.
