The activation of brown and beige fat and role in insulin sensitivity

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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 PPARγ for their development, and both cell types are induced through the ß-adrenergic receptor (βAR)/PKA pathway. BAT and beige fat are activated through the sympathetic nervous system or by the use of βAR agonist drugs. Adipose tissue contains β3AR, and there have been attempts to treat obesity with β3 agonists. Currently, mirabegron (Myrbetriq®, Astellas) is a highly specific β3 agonist marketed for overactive bladder with minimal side effects at the recommended dose. In addition, the diabetes drug pioglitazone is a PPARγ 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 activating both BAT and beige adipose tissue and in improving insulin sensitivity. 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. Hypothesis 1. Chronic treatment of insulin resistant subjects with a β3 agonist will result in increased mass and activity of BAT and beige adipose tissue along with increased resting metabolic rate. Hypothesis 2. The combined treatment with both a TZD (PPARγ agonist) and a β3 agonist will result in an additional stimulation of BAT and beige adipose mass and activity. Hypothesis 3. The activation of BAT and beige adipose tissue will be associated with reduced skeletal muscle lipotoxicity and improvements in adipose tissue inflammation. Hypothesis 4. The activation of BAT and beige adipose tissue by combined TZD and β3 agonists will result in a greater improvement in insulin sensitivity than by monotherapy alone. These studies are important because the repurposing of these common drugs could synergistically improve many of the metabolic dysfunctions in obese individuals.