PPARγ activation in adipocytes is sufficient for systemic insulin sensitization
Open accessAbstract
Although peroxisome proliferator-activated receptor gamma (PPARgamma) agonists such as thiazolidinediones (TZDs) are widely used to treat type 2 diabetes, how its activation in individual tissues contributes to TZD's therapeutic action remains controversial. As TZDs are known to have receptor-independent effects, we sought to establish gain-of-function animal models to delineate the receptor's insulin-sensitizing actions. Unexpectedly, we find that selective activation of PPARgamma in adipocytes, but not in macrophages, is sufficient for whole-body insulin sensitization equivalent to systemic TZD treatment. In addition to improved adipokine, inflammatory, and lipid profiles, PPARgamma activation in mature adipocytes normalizes serum insulin without increased adipogenesis. Co-culture studies indicated that PPARgamma-activated adipocytes broadly suppress induction of inflammatory cytokines and C-X-C family chemokines in macrophages. Collectively, these data describe an "adipocentric" model in which adipose activation of PPARgamma is sufficient for complete insulin sensitization and suggest a specific application for fat selective PPARgamma modulators in diabetic therapy.
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Thiazolidinediones, such as rosiglitazone, potently activate PPARγ and lower blood glucose levels in patients with T2DM.
“Finally, thiazolidinediones, such as rosiglitazone, potently activate PPARγ and lower blood glucose levels in patients with T2DM.”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [273]
Thiazolidinediones improve skeletal muscle glucose disposal via upregulation of GLUT1, decrease liver glucose output, and improve the lipid-buffering capacity of WAT and hepatic steatosis.
“Thiazolidinediones improve skeletal muscle glucose disposal via upregulation of GLUT1, decrease liver glucose output, and, as a primary target, improve the lipid-buffering capacity of WAT and as such improve hepatic steatosis (270, 273).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [273]
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- Authors
- Sugii, S., Olson, P., Sears, D. D., Saberi, M., Atkins, A. R., Barish, G. D., Hong, S.-H., Castro, G. L., Yin, Y.-Q., Nelson, M. C., Hsiao, G., Greaves, D. R., Downes, M., Yu, R. T., Olefsky, J. M., & Evans, R. M.
- Affiliations
- Salk Institute for Biological Studies (US)
- University of California San Diego (US)
- University of Oxford (GB)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-12-29
- Volume
- 106
- Issue
- 52
- Pages
- 22504-22509
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2794650
- OpenAlex
- W1986938616
- Cited by
- 255
- References
- 37
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 4 · 2023: 10 · 2022: 13 · 2021: 18 · 2020: 13 · 2019: 17 · 2018: 17 · 2017: 15 · 2016: 19 · 2015: 25 · 2014: 14 · 2013: 22 · 2012: 23
- FWCI
- 7.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute (DK057978)
- March of Dimes Foundation
- Leona M. and Harry B. Helmsley Charitable Trust
- British Heart Foundation
- National Institutes of Health (DK062434, DK057978)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK057978, DK057978, DK062434, R01DK057978, R24DK090962, U19DK062434)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD027183, HD027183)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- PPARγ, adipocytes, insulin sensitization, thiazolidinediones, type 2 diabetes, adipose tissue, macrophages, adipokines, inflammation, chemokines, adipogenesis
- MeSH terms
- Pioglitazone, Animals, Cell Line, Humans, Hypoglycemic Agents, Insulin, Macrophages, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Rats, Zucker, Recombinant Fusion Proteins, Signal Transduction, Gene Expression, Inflammation Mediators, Chemokines, 3T3-L1 Cells, Thiazolidinediones, PPAR gamma, Mice, Rats, Adipocytes, White
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