Related Experiment Video
Updated: Jul 4, 2026
Investigation of Macrophage Polarization Using Bone Marrow Derived Macrophages
Published on: June 23, 2013
Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance
Justin I Odegaard1, Roberto R Ricardo-Gonzalez, Alex Red Eagle
1Division of Endocrinology, Metabolism and Gerontology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305-5103, USA.
Abstract:
Macrophage infiltration and activation in metabolic tissues underlie obesity-induced insulin resistance and type 2 diabetes. While inflammatory activation of resident hepatic macrophages potentiates insulin resistance, the functions of alternatively activated Kupffer cells in metabolic disease remain unknown. Here we show that in response to the Th2 cytokine interleukin-4 (IL-4), peroxisome proliferator-activated receptor delta (PPARdelta) directs expression of the alternative phenotype in Kupffer cells and adipose tissue macrophages of lean mice. However, adoptive transfer of PPARdelta(-/-) (Ppard(-/-)) bone marrow into wild-type mice diminishes alternative activation of hepatic macrophages, causing hepatic dysfunction and systemic insulin resistance. Suppression of hepatic oxidative metabolism is recapitulated by treatment of primary hepatocytes with conditioned medium from PPARdelta(-/-) macrophages, indicating direct involvement of Kupffer cells in liver lipid metabolism. Taken together, these data suggest an unexpected beneficial role for alternatively activated Kupffer cells in metabolic syndrome and type 2 diabetes.
Insights
Alternatively activated Kupffer cells, regulated by PPARdelta, unexpectedly protect against metabolic dysfunction. This finding offers new insights into managing insulin resistance and type 2 diabetes.
Area of Science:
- Immunology
- Metabolic disease research
- Cellular biology
Background:
- Obesity-induced insulin resistance and type 2 diabetes are linked to macrophage activation in metabolic tissues.
- Inflammatory hepatic macrophages worsen insulin resistance, but the role of alternatively activated Kupffer cells is unclear.
Purpose of the Study:
- To investigate the function of alternatively activated Kupffer cells in metabolic disease.
- To determine the role of peroxisome proliferator-activated receptor delta (PPARdelta) in Kupffer cell alternative activation.
Main Methods:
- Utilized adoptive bone marrow transfer experiments in mice.
- Investigated gene expression in response to interleukin-4 (IL-4).
- Assessed hepatic dysfunction and systemic insulin resistance.
Main Results:
- PPARdelta directs the alternative activation phenotype in Kupffer cells and adipose tissue macrophages.
- Loss of PPARdelta in macrophages impairs Kupffer cell alternative activation, leading to hepatic dysfunction and insulin resistance.
- Kupffer cells directly influence liver lipid metabolism and hepatic oxidative metabolism.
Conclusions:
- Alternatively activated Kupffer cells play a beneficial role in metabolic syndrome and type 2 diabetes.
- PPARdelta is a key regulator of Kupffer cell function in metabolic health.
- Targeting Kupffer cell activation may offer therapeutic strategies for metabolic diseases.
