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The sympathetic nervous system regulates the activity and expression of uncoupling protein 1 (UCP1) through the three β-adrenergic receptor subtypes and their ability to raise intracellular cyclic AMP (cAMP) levels. Unexpectedly, we recently discovered that the cAMP-dependent regulation of multiple genes in brown adipocytes, including Ucp1, occurred through the p38 mitogen-activated protein kinases (MAPK) (W. Cao, K. W. Daniel, J. Robidoux, P. Puigserver, A. V. Medvedev, X. Bai, L. M. Floering, B. M. Spiegelman, and S. Collins, Mol. Cell. Biol. 24:3057-3067, 2004). However, no well-defined pathway linking cAMP accumulation or cAMP-dependent protein kinase (PKA) to p38 MAPK has been described. Therefore, in the present study using both in vivo and in vitro models, we have initiated a retrograde approach to define the required components, beginning with the p38 MAPK isoforms themselves and the MAP kinase kinase(s) that regulates them. Our strategy included ectopic expression of wild-type and mutant kinases as well as targeted inhibition of gene expression using small interfering RNA. The results indicate that the β-adrenergic receptors and PKA lead to a highly selective activation of the p38α isoform of MAPK, which in turn promotes Ucp1 gene transcription. In addition, this specific activation of p38α relies solely on the presence of MAP kinase kinase 3, despite the expression in brown fat of MKK3, -4, and -6. Finally, of the three scaffold proteins of the JIP family expressed in brown adipocytes, only JIP2 coimmunoprecipitates p38α MAPK and MKK3. Therefore, in the brown adipocyte the recently described scaffold protein JIP2 assembles the required factors MKK3 and p38α MAPK linking PKA to the control of thermogenic gene expression. [ABSTRACT FROM AUTHOR]

The family of adrenergic receptors (ARs) expressed in adipocytes includes three sibling βARs and two αAR cousins. Together they profoundly influence the mobilization of stored fatty acids, secretion of fat-cell derived hormones, and the specialized process of nonshivering thermogenesis in brown adipose tissue. The two types of fat cells that compose adipose tissue, brown and white, are structurally and functionally distinct. Studies on the mechanisms by which individual βAR regulates these cell-specific functions have recently uncovered new signal transduction cascades involved in processes traditionally ascribed to adenylyl cyclase/cAMP/protein kinase A system. They illustrate how βAR signaling can orchestrate a coordinated set of intracellular responses for fine control of metabolic balance. [ABSTRACT FROM AUTHOR]