These studies represent the first demonstration that defects distal to the adrenergic receptor may also contribute to catecholamine resistance, and suggest that IKKε and TBK1 can attenuate the β-adrenergic/cAMP pathway in response to β-adrenergic stimuli in adipocytes in a cell-autonomous manner, and further that induction of these kinases during obesity may account for decreased energy expenditure by reducing sensitivity of adipocytes to β-adrenergic stimulation. The gene discussed is TBK1; the disease is obesity due to melanocortin 4 receptor deficiency.