Obesity is a major risk factor for several metabolic disorders including insulin resistance, diabetes, and cardiovascular diseases. Chronic imbalance of calorie intake and expenditure results in storage of excess unused energy resulting in obesity and related metabolic dysfunctions. While most obesity therapies are focused on reducing the calorie intake and exercise, recent studies suggest that targeting cellular energy expenditure could be a fascinating alternative approach. Brown adipose tissue (BAT) not only has a remarkable calorie burning capacity, but it could also promote triglyceride clearance and glucose disposal. Induction of brown adipose mass and activity in relevant tissues are linked to relieve symptoms of various metabolic disorders such as diabetes, insulin resistance, and cardiovascular diseases. Follistatin (Fst), an extracellular protein that binds and antagonizes several members of the transforming growth factor beta (TGF-β)/myostatin (Mst) superfamily, promotes brown adipose characteristics in both white and brown adipose tissues by targeting distinct molecular pathways. Inhibition of Mst, on the other hand, leads to significant upregulation of adipose browning in white adipose tissues. This chapter will summarize most recent developments in targeting adipose tissue and their functional characteristics to explore therapeutic potential of Fst and TGF-β/Mst signaling to modulate adipose tissue metabolic functions to combat obesity and related metabolic syndromes.