Smad3 Deficiency in Mice Protects Against Insulin Resistance and Obesity Induced by a High-Fat Diet

Abstract

1OBJECTIVE-Obesity and associated pathologies are major global health problems. Transforming growth factor-b/Smad3 signaling has been implicated in various metabolic processes, including adipogenesis, insulin expression, and pancreatic b-cell function. However, the systemic effects of Smad3 deficiency on adiposity and insulin resistance in vivo remain elusive. This study investigated the effects of Smad3 deficiency on whole-body glucose and lipid homeostasis and its contribution to the development of obesity and type 2 diabetes.RESEARCH DESIGN AND METHODS-We compared various metabolic profiles of Smad3-knockout and wild-type mice. We also determined the mechanism by which Smad3 deficiency affects the expression of genes involved in adipogenesis and metabolism. Mice were then challenged with a high-fat diet to study the impact of Smad3 deficiency on the development of obesity and insulin resistance.RESULTS-Smad3-knockout mice exhibited diminished adiposity with improved glucose tolerance and insulin sensitivity. Chromatin immunoprecipitation assay revealed that Smad3 deficiency increased CCAAT/enhancer-binding protein b-C/EBP homologous protein 10 interaction and exerted a differential regulation on proliferator-activated receptor b/d and proliferator-activated receptor g expression in adipocytes. Focused gene expression profiling revealed an altered expression of genes involved in adipogenesis, lipid accumulation, and fatty acid b-oxidation, indicative of altered adipose physiology. Despite reduced physical activity with no modification in food intake, these mutant mice were resistant to obesity and insulin resistance induced by a high-fat diet.CONCLUSIONS-Smad3 is a multifaceted regulator in adipose physiology and the pathogenesis of obesity and type 2 diabetes, suggesting that Smad3 may be a potential target for the treatment of obesity and its associated disorders. Diabetes 60: [464][465][466][467][468][469][470][471][472][473][474][475][476] 2011

SMAD3 Negatively Regulates Serum Irisin and Skeletal Muscle FNDC5 and Peroxisome Proliferator-activated Receptor γ Coactivator 1-α (PGC-1α) during Exercise

“…Tissue-Published reports show that the role of SMAD3 signaling in regulating energy homeostasis, WAT browning, and body weight is most pronounced under conditions of metabolic stress such as prolonged cold exposure or high fat feeding (30,31). Before investigating the role of SMAD3 in regulating irisin in obese mice, we first established an exercise regime that led to increased irisin and WAT browning in lean mice.…”

The regulatory protein SnoN antagonizes activin/Smad2 protein signaling and thereby promotes adipocyte differentiation and obesity in mice

“…Consistent with this view, transgenic mice expressing TGFβ1 in WAT and BAT led to reduced WAT and BAT (12). However, studies of the Smad3 knockout mice suggest that under physiological conditions in vivo, TGFβ/Smad3 signaling mainly regulates energy homeostasis and glucose metabolism (17,58). Smad3 loss protects against diet-induced obesity and insulin resistance and is accompanied by the "browning" of WAT adipocytes, leading to a marked increase in mitochondria biogenesis and basal respiration (17).…”

Adipogenesis at a glance

“…These pathways and regulators include glutathione (Vigilanza et al, 2010), the Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) pathway (Zhang et al, 2011), SMAD signalling (Marchildon et al, 2010;Tan et al, 2011), ribosomal protein S6 kinase 1 (S6K1) (Carnevalli et al, 2010) and components of the insulin signalling cascade, such as AKT ) and a newly discovered regulator of this pathway, inositol pyrophosphate (Chakraborty et al, 2010). New transcriptional regulators of stem cell fate that are controlled by these pathways also continue to be identified.…”