Protection from obesity and diabetes by blockade of TGF-β/smad3 signaling
Open accessAbstract
Imbalances in glucose and energy homeostasis are at the core of the worldwide epidemic of obesity and diabetes. Here, we illustrate an important role of the TGF-β/Smad3 signaling pathway in regulating glucose and energy homeostasis. Smad3-deficient mice are protected from diet-induced obesity and diabetes. Interestingly, the metabolic protection is accompanied by Smad3(-)(/-) white adipose tissue acquiring the bioenergetic and gene expression profile of brown fat/skeletal muscle. Smad3(-/-) adipocytes demonstrate a marked increase in mitochondrial biogenesis, with a corresponding increase in basal respiration, and Smad3 acts as a repressor of PGC-1α expression. We observe significant correlation between TGF-β1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-β signaling protects mice from obesity, diabetes, and hepatic steatosis. Together, these results demonstrate that TGF-β signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-β activity might be an effective treatment strategy for obesity and diabetes.
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Global deletion of Smad3 protects mice from weight gain on HFD, elevates Akt signaling in WAT, and induces a browning phenotype in WAT.
“Global deletion of Smad3 protects mice from weight gain on HFD, elevates Akt signaling in WAT, and induces a browning phenotype in WAT [28,29], highlighting the relevance of this signaling pathway in fat.”
From Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism (2024) · cites this paper as [28]
Increased recruitment of pro-inflammatory macrophages to muscle and adipose results in transforming growth factor β (TGFβ)-mediated fibrosis.
“Increased recruitment of pro-inflammatory macrophages to muscle167 and adipose81 results in transforming growth factor β (TGFβ)-mediated fibrosis.168”
From The Vasculature in Prediabetes (2018) · cites this paper as [168]
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- Authors
- Yadav, H., Quijano, C., Kamaraju, A. K., Gavrilova, O., Malek, R., Chen, W., Zerfas, P., Zhigang, D., Wright, E. C., Stuelten, C., Sun, P., Lonning, S., Skarulis, M., Sumner, A. E., Finkel, T., & Rane, S. G.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Rane, Sushil G.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2011-07
- Volume
- 14
- Issue
- 1
- Pages
- 67-79
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3169298
- OpenAlex
- W2156865358
- Cited by
- 709
- References
- 51
- Citations by year
- 2026: 39 · 2025: 46 · 2024: 73 · 2023: 54 · 2022: 63 · 2021: 69 · 2020: 50 · 2019: 48 · 2018: 52 · 2017: 43 · 2016: 35 · 2015: 43 · 2014: 35 · 2013: 28 · 2012: 27
- FWCI
- 20.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (Z01DK055106)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- TGF-β/Smad3 signaling, obesity, diabetes mellitus, glucose homeostasis, energy homeostasis, diet-induced obesity, white adipose tissue, brown adipose tissue, mitochondrial biogenesis, PGC-1α, hepatic steatosis, glucose tolerance, TGF-β1
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Antibodies, Adipose Tissue, Brown, Diabetes Mellitus, DNA-Binding Proteins, Energy Metabolism, Glucose Tolerance Test, Mice, Obese, Mitochondria, Obesity, Transcription Factors, Signal Transduction, Trans-Activators, Transforming Growth Factor beta, Mice, Knockout, Mice, Smad3 Protein, Adipose Tissue, White
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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