Positive and negative control of Ucp1 gene transcription and the role of β-adrenergic signaling networks

Adrenergic receptor signaling in adipocytes controls not only the hydrolysis of triglycerides as fuel for other organs but is also a driver of brown adipocyte thermogenesis and energy consumption. As the appearance of these mitochondria-rich, thermogenically active cells in 'white' adipocyte depots is correlated with resistance to overnutrition and glucose intolerance, the molecular basis of their genesis and metabolic activity needs to be understood. β-adrenergic receptors regulate the enzymatic machinery for lipolysis and fuel utilization. They also coordinately stimulate the transcription of genes that support the specific functions of white and brown adipocytes. They accomplish this through the activation of a network of signaling pathways that include cAMP-dependent protein kinase and members of the mitogen-activated protein kinase family. In brown adipocytes, these kinases control the transcription of nuclear factors such as peroxisome proliferator-activated receptor-γ coactivator-1s, as well as other molecules discovered to respond to adrenergic signals, to increase mitochondrial biogenesis and uncoupling protein-1 (UCP1) expression. However, it is also important to understand the mechanisms that may actively repress these energy-wasting processes. Toward that end, we provide evidence for an important role for the nuclear receptor LXRα as a cAMP- and oxysterol-dependent transcriptional repressor of the Ucp1 gene. Adipocytes from LXRα-null mice have increased expression of most 'markers' of brown adipocytes, increased mitochondrial mass and uncoupled respiration. These studies reveal potential new targets and directions for controlling the relative levels of white versus brown adipocytes as a means of metabolic fuel utilization in the struggle against obesity and related metabolic diseases.