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Macrophage PPARγ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones
Open accessAbstract
PPAR gamma is required for fat cell development and is the molecular target of antidiabetic thiazolidinediones (TZDs), which exert insulin-sensitizing effects in adipose tissue, skeletal muscle, and liver. Unexpectedly, we found that inactivation of PPAR gamma in macrophages results in the development of significant glucose intolerance plus skeletal muscle and hepatic insulin resistance in lean mice fed a normal diet. This phenotype was associated with increased expression of inflammatory markers and impaired insulin signaling in adipose tissue, muscle, and liver. PPAR gamma-deficient macrophages secreted elevated levels of factors that impair insulin responsiveness in muscle cells in a manner that was enhanced by exposure to FFAs. Consistent with this, the relative degree of insulin resistance became more severe in mice lacking macrophage PPAR gamma following high-fat feeding, and these mice were only partially responsive to TZD treatment. These findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs.
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“Studies in PPARγ deficient mice exhibit impaired M2 macrophage function and susceptibility to diet-induced inflammation and insulin resistance [29,65–67].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [66]
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“thus providing a potential mechanism by which activation of macrophage PPARγ reduces inflammation and enhances insulin sensitivity (106).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [106]
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“Treatment of macrophages with the insulin-sensitizing drugs thiazolidinediones (TZDs), which are PPARγ ligands, polarizes macrophages toward the M2/antiinflammatory state, thus providing a potential mechanism by which activation of macrophage PPARγ reduces inflammation and enhances insulin sensitivity (106).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [106]
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Metadata
- Authors
- Hevener, A. L., Olefsky, J. M., Reichart, D., Nguyen, M. T. A., Bandyopadyhay, G., Leung, H.-Y., Watt, M. J., Benner, C., Febbraio, M. A., Nguyen, A.-K., Folian, B., Subramaniam, S., Gonzalez, F. J., Glass, C. K., & Ricote, M.
- Affiliations
- University of California San Diego (US)
- University of California System (US)
- The University of Melbourne (AU)
- Baker Heart and Diabetes Institute (AU)
- National Institutes of Health (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2007-06-01
- Volume
- 117
- Issue
- 6
- Pages
- 1658-1669
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1868788
- OpenAlex
- W2131598118
- Cited by
- 459
- References
- 71
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 9 · 2023: 9 · 2022: 10 · 2021: 10 · 2020: 13 · 2019: 17 · 2018: 23 · 2017: 22 · 2016: 18 · 2015: 28 · 2014: 32 · 2013: 49 · 2012: 41
- FWCI
- 16.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- Pfizer
- Takeda Pharmaceutical Company
- Ministerio de Economía y Competitividad
- National Institutes of Health (DK 074868, DK-063491, GM-069338)
- University of California, San Diego (DK063491)
- National Heart, Lung, and Blood Institute (P50HL056989, HL-56989)
- National Institute of General Medical Sciences (U54GM069338, GM 069338)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK063491, DK 074868, DK 60484, DK-33651, K01DK060484, R37DK033651, R21DK073227, P01DK074868, DK73227, R01DK033651, P30DK063491)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- PPARγ, macrophages, thiazolidinediones, insulin resistance, insulin sensitivity, skeletal muscle, liver, adipose tissue, impaired glucose tolerance, inflammation, insulin signaling, fatty acids, high-fat diet, antidiabetic drugs
- MeSH terms
- Animals, Base Sequence, Hypoglycemic Agents, Insulin Resistance, Liver, Macrophages, Mice, Transgenic, Promoter Regions, Genetic, Adipocytes, DNA Primers, Mice, Knockout, Muscle, Skeletal, Gene Expression Profiling, Thiazolidinediones, PPAR gamma, Mice
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