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Updated: Jun 26, 2026
Differentiated Mouse Adipocytes in Primary Culture: A Model of Insulin Resistance
Published on: February 17, 2023
Macrophage-derived human resistin exacerbates adipose tissue inflammation and insulin resistance in mice
Mohammed Qatanani1, Nava R Szwergold, David R Greaves
1Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6149, USA.
Abstract:
Resistin is an adipokine that contributes to insulin resistance in mice. In humans, however, studies investigating the link between resistin and metabolic disease are conflicting. Further complicating the matter, human resistin is produced mainly by macrophages rather than adipocytes. To address this important issue, we generated mice that lack adipocyte-derived mouse resistin but produce human resistin in a pattern similar to that found in humans, i.e., in macrophages (humanized resistin mice). When placed on a high-fat diet, the humanized resistin mice rapidly developed accelerated white adipose tissue (WAT) inflammation, leading to increased lipolysis and increased serum free fatty acids. Over time, these mice accumulated lipids, including diacylglycerols, in muscle. We found that this resulted in increased Pkcq pathway activity, leading to increased serine phosphorylation of Irs-1 and insulin resistance. Thus, although the site of resistin production differs between species, human resistin exacerbates WAT inflammation and contributes to insulin resistance.
Insights
Human resistin, produced by macrophages, exacerbates white adipose tissue inflammation and contributes to insulin resistance, even when its production site differs from mice. This study clarifies resistin
Area of Science:
- Metabolic disease research
- Adipokine signaling
- Insulin resistance mechanisms
Background:
- Resistin's role in insulin resistance is debated, with conflicting studies in humans.
- Human resistin is primarily produced by macrophages, unlike in mice where adipocytes are the main source.
- Understanding human resistin's specific contribution to metabolic dysfunction is crucial.
Purpose of the Study:
- To investigate the impact of human resistin, produced in a human-like pattern (macrophage-derived), on metabolic health.
- To elucidate the mechanisms by which human resistin contributes to insulin resistance.
Main Methods:
- Generation of humanized resistin mice lacking adipocyte resistin but expressing human resistin in macrophages.
- High-fat diet feeding to induce metabolic stress.
- Analysis of white adipose tissue (WAT) inflammation, lipolysis, serum free fatty acids, muscle lipid accumulation, and insulin signaling pathway activation (including Pkcq and Irs-1 phosphorylation).
Main Results:
- Humanized resistin mice on a high-fat diet exhibited accelerated WAT inflammation, increased lipolysis, and elevated serum free fatty acids.
- Muscle lipid accumulation, specifically diacylglycerols, was observed over time.
- Increased Pkcq pathway activity and serine phosphorylation of Irs-1 were linked to insulin resistance.
Conclusions:
- Despite species-specific differences in resistin production sites, human resistin significantly exacerbates WAT inflammation.
- Human resistin directly contributes to the development of insulin resistance through specific molecular pathways.
- This study provides a valuable model for dissecting the role of human resistin in metabolic disease.
