Protection from Obesity and Diabetes by Blockade of TGF-β/Smad3 Signaling

Abstract

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.

TGF-β Contributes to Impaired Exercise Response by Suppression of Mitochondrial Key Regulators in Skeletal Muscle

“…The importance of the TGF-b/SMAD3 pathway for metabolic control in humans is suggested by a close association of BMI and circulating TGF-b1 levels (25), and the association of elevated plasma TGF-b1 and higher risk for type 2 diabetes (26). A rat model with insulin resistance and a low aerobic response to exercise shows increased activation of SMAD3-dependent gene expression after an acute exercise bout when compared with rats with a high aerobic response (27).…”

Effect of Obesity on Circulating Adipokines and Their Expression in Omental Adipose Tissue of Female Bariatric Surgery Patients

“…Smad-3 deficient mice are protected from diet-induced obesity and diabetes and the adipocytes had marked increases in mitochondrial biogenesis and respiration accompanied by increased PGC-1 mRNA (Yadav et al, (2011). There is other evidence for perturbation of mitochondrial function, specifically reactive oxygen species formation, due to TGF-1 since it enhanced mitochondrial reactive oxygen species formation in rodent hepatocytes (Albright et al, 2003) while preventing cell death due to caspase activation in synovial cells (Kawakami et al, 2004).…”

“…However, this does not necessarily mean that it plays a causal role since it is a multifunctional regulator of cellular metabolism. The recent findings of Yadav et al, (2011) suggest that the inhibition of TGF1 release and/or action might have favorable effects on the development of insulin resistance in obesity by uncoupling respiration in white fat thus preventing fatty acid accumulation.…”

Morphogenetics in brown, beige and white fat development

“…SMAD3 null mice, for which TGFb signaling is attenuated, show decreased white fat mass and are protected from diet-induced obesity. 30 Furthermore, SMAD3 null mice have increased brown-like adipocytes in white fat depots and increased mitochondria, indicating SMAD3 is a negative regulator of beige fat development.…”