The Activation of Brown and Beige Fat and Role in Insulin Sensitivity

There has been much interest in exploiting brown adipose tissue (BAT) and beige adipose tissue for the treatment of obesity and related complications. Although brown and beige adipocytes are derived from different precursors and display unique patterns of gene expression markers, both cells have increased mitochondrial content and express UCP1, which uncouples oxidative respiration to generate heat. In addition, both brown and beige adipocytes require PPARƒ×ƒnfor their development, along with induction through the ƒÒ-adrenergic receptor (£]AR)/PKA pathway. Activation of the sympathetic nervous system or the use of £]AR agonists activate BAT and beige fat. Adipose tissue contains £]3AR, and there have been attempts to treat obesity with £]3 agonists. Currently, mirabegron (MyrbetriqR, Astellas) is a highly specific £]3 agonist marketed for overactive bladder with minimal side effects at the recommended dose. In addition, pioglitazone is a PPAR£^ agonist which reduces inflammation and improves insulin sensitivity. We hypothesize that the combination of pioglitazone and mirabegron will be more effective than either drug alone at increasing both BAT and beige adipose activity and in improving insulin resistance. We hypothesize that the mechanism of this improvement in insulin sensitivity will result from an increased partitioning of lipid into oxidative pathways, improved metabolic flexibility and decreased adipose inflammation. The specific aims are: Hypothesis 1. Chronic treatment of insulin resistant subjects with a £]3 agonist will result in increased activity of both BAT and beige adipose tissue. Hypothesis 2. The combined treatment with both a TZD (PPAR£^ agonist) and a £]3 agonist will result in an additional stimulation of BAT and beige adipose activity. Hypothesis 3. The activation of BAT and beige adipose tissue will result in improvements in adipose tissue inflammation and increased energy expenditure Hypothesis 4. The activation of BAT and beige adipose tissue by combined TZD and £]3 agonists will result in a greater improvement in insulin sensitivity than by TZD alone.