Metabolic disease: Turning 'bad' fat into 'good'
Nature Reviews Drug Discovery 10, 659 (September 2011)
Excess calories are stored as fat in white adipose tissue (WAT), which — over time — leads to the development of obesity and associated metabolic diseases. Although most current obesity therapies aim to reduce caloric intake, accumulating evidence suggests that increasing cellular energy expenditure may represent a promising alternative strategy. Now, Sushil Rane and colleagues in the Diabetes, Endocrinology and Obesity Branch of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), US National Institutes of Health (NIH), demonstrate that blocking the transforming growth factor-β (TGFβ)–SMAD3 signalling pathway promotes the acquisition of an energy-burning brown adipose tissue (BAT) phenotype in WAT, thus ameliorating obesity and diabetes in mouse models.
TGFβ controls the development, growth and function of diverse cell types by transmitting signals via dual serine/threonine kinase receptors and transcription factors called SMADs, particularly SMAD3. Previous studies have suggested that the TGFβ–SMAD3 pathway is involved in the regulation of insulin gene transcription and pancreatic islet β-cell function. In addition, TGFβ levels have been shown to correlate positively with obesity in mice and humans. With these findings in mind, Rane and colleagues set out to determine whether TGFβ signalling has a role in the pathogenesis of metabolic disease.
First, the authors characterized Smad3-knockout mice (Smad3−/− mice). Compared to wild-type mice, Smad3−/− mice exhibited enhanced insulin sensitivity and were protected from diet-induced obesity, insulin resistance and hepatic steatosis. Ablation of Smad3 also reduced body weight and fat mass without reducing caloric intake, markedly impaired white adipocyte differentiation, decreased the size of adipocytes and reduced adipokine levels. In addition, it decreased the levels of inflammatory cytokines and macrophages infiltrating WAT (adipose tissue inflammation is associated with obesity). Surprisingly, WAT adopted the morphology of BAT — an energy-dissipating, thermogenic tissue that is characterized by a dense mitochondrial population — and exhibited increased expression of brown adipogenesis markers. As a result, Smad3−/− mice were able to maintain a substantially higher body temperature even during prolonged exposure to cold, exhibited an increase in WAT mitochondrial biogenesis and function, and their metabolic rate was elevated.
Next, the authors investigated the mechanisms mediating this apparent conversion of WAT to BAT. Microarray analysis revealed that compared to control, WAT samples taken from Smad3−/− mice displayed statistically significant increases in the expression of genes corresponding to BAT, mitochondrial function and skeletal muscle biology (BAT and skeletal muscle share developmental origins). Complementary in vitro studies indicated that this was probably mediated by the regulation of the transcriptional co-activator peroxisome proliferator-activated receptor-γ coactivator 1α and the transcription factor PRDM16, which have key roles in controlling energy metabolism and brown adipocyte development.
Finally, they examined the therapeutic relevance of their findings. In leptin-deficient ob/ob mice and mice with diet-induced obesity, administration of a TGFβ-specific neutralization antibody (1D11) reduced SMAD3 activation in WAT and conferred protection against obesity, diabetes and hepatic steatosis. Interestingly, a closely related human version of this antibody, fresolimumab, is in clinical trials of pulmonary fibrosis, renal disease and cancer.
In summary, these findings indicate a key role for the TGFβ–SMAD3 signalling pathway in adipose tissue biology. Given that TGFβ-antagonist approaches are currently in the clinic, this may be a feasible strategy to treat obesity and associated metabolic diseases.
Sarah Crunkhorn- Copyright © 2011 Nature Publishing Group, a division of Macmillan Publishers Limited; used with permission
ORIGINAL RESEARCH PAPER
Yadav, H. et al. Protection from obesity and diabetes by blockade of TGF-β/Smad3 signalling.
Cell Metabolism 14, 67-79 (2011).
Tseng, Y-H. et al. Cellular bioenergetics as a target for obesity therapy.
Nature Rev. Drug Discov. 9, 465-482 (2010).