Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling

By H. Yadav, C. Quijano, Anil K. Kamaraju, O. Gavrilova, R. Malek, WeiPing Chen, P. Zerfas, Zhigang Duan, E. Wright, C. Stuelten and 6 more. Cell Metabolism, 2011

686 citations recorded by the source corpus.

SUMMARY 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-β1 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-β1 activity might be an effective treatment strategy for obesity and diabetes.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/005ad3ba2055a7cda802701a1ba593c9b8b5d2d9

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In Molecular Biology

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In Physiology

1. S. Kajimura
2. B. Spiegelman
3. Jun Wu
4. P. Cohen
5. Mitchell A. Lazar
6. H. Ohno
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Citations in the corpus

• Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. (2015, neutral): “Understanding BAT-mediated interor-gan communication would further uncover new roles for BAT in energy and glucose homeostasis.”
• Forming functional fat: a growing understanding of adipocyte differentiation (2011, background): “However, SMAD3-null mice are resistant to diet-induced obesity, and MEFs from these mice have diminished adipogenic potentia”
• Human BAT Possesses Molecular Signatures That Resemble Beige/Brite Cells (2012, background): “For example, inhibition of TGF-b signaling by neutralizing antibodies sufficiently increases whole body energy expenditure and counteracts diet-induced obesity, at least in part, by browning white fat in mice [47,48].”
• What We Talk About When We Talk About Fat (2014, neutral): “TGFb and its downstream effector Smad3 have been shown to exert both pro- and anti-adipogenic actions in different in vitro and ex vivo models (Choy et al., 2000; Yadav et al., 2011).”
• Adaptive thermogenesis in adipocytes: is beige the new brown? (2013, background): “Smad3 / mice have increased mitochondrial biogenesis in the WATs and are protected from diet-induced obesity and diabetes (Yadav et al. 2011).”
• Endoplasmic reticulum stress: molecular mechanism and therapeutic targets (2023, background): “225,226 Epigenetics is de fi ned as “ the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in DNA sequence.”
• Mechanisms of insulin resistance in obesity (2013, background): “Although some studies suggest that activation of β-oxidation protects insulin sensitivity [89,90], the mechanism might be release of energy in heat that prevents excessive ATP production.”