Fat cell adrenergic receptors and the control of white and brown fat cell function.

Our current understanding of the relationship between the dopaminergic system and human brain disorders is based on two fundamental discoveries: dopamine-replacement therapy can alleviate Parkinson’s disease (1-3) and, secondly, many antipsychotic drugs are dopamine receptor antagonists (4-7). These discoveries have guided two major directions in dopamine-related basic research and drug design: to activate dopamine r ceptors left understimulated by the degeneration of the afferent dopamine-secreting cells and to prevent dopamine from binding to its receptor, according to the hypothesis that schizophrenia is the result of dopamine receptor overactivity (5, 8). Since blockade of the dopamine r ceptors (antipsychotic therapy) can lead to a state similar to that resulting from dopamine depletion (Parkinson’s therapy) and higher doses of dopamine can cause psychoses, the therapies of disorders resulting from dopamine imbalances are associated with adverse side effects. The ideal drug(s) that will treat one disorder without affecting the other has thus far not been found. However, the search for such a drug has led to the design of several dopamine r ceptor ligands that, in turn, have increased our understanding of the dopaminergic system. In particular, these studies have

Molecular Diversity of the Dopamine Receptors

It is well established that catecholamine-stimulated thermogenesis in brown fat requires β-adrenergic elevations in cyclic AMP (cAMP) to increase expression of the uncoupling protein 1 (UCP1) gene. However, little is known about the downstream components of the signaling cascade or the relevant transcription factor targets thereof. Here we demonstrate that cAMP- and protein kinase A-dependent activation of p38 mitogen-activated protein kinase (MAPK) in brown adipocytes is an indispensable step in the transcription of the UCP1 gene in mice. By phosphorylating activating transcription factor 2 (ATF-2) and peroxisome proliferator-activated receptor gamma (PPARγ) coativator 1α (PGC-1α), members of two distinct nuclear factor families, p38 MAPK controls the expression of the UCP1 gene through their respective interactions with a cAMP response element and a PPAR response element that both reside within a critical enhancer motif of the UCP1 gene. Activation of ATF-2 by p38 MAPK additionally serves as the cAMP sensor that increases expression of the PGC-1α gene itself in brown adipose tissue. In conclusion, our findings illustrate that by orchestrating the activity of multiple transcription factors, p38 MAPK is a central mediator of the cAMP signaling mechanism of brown fat that promotes thermogenesis.

p38 Mitogen-Activated Protein Kinase Is the Central Regulator of Cyclic AMP-Dependent Transcription of the Brown Fat Uncoupling Protein 1 Gene

Heterotrimeric G proteins in vertebrates constitute a family molecular switches that transduce the activation of a populous group of cell-surface receptors to a group of diverse effector units. The...

https://www.physiology.org/doi/pdf/10.1152/physrev.1999.79.4.1373

Physiological regulation of G protein-linked signaling.

The importance of beta-adrenergic signaling in the heart has been well documented, but it is only more recently that we have begun to understand the importance of this signaling pathway in skeletal muscle. There is considerable evidence regarding the stimulation of the beta-adrenergic system with beta-adrenoceptor agonists (beta-agonists). Although traditionally used for treating bronchospasm, it became apparent that some beta-agonists could increase skeletal muscle mass and decrease body fat. These so-called "repartitioning effects" proved desirable for the livestock industry trying to improve feed efficiency and meat quality. Studying beta-agonist effects on skeletal muscle has identified potential therapeutic applications for muscle wasting conditions such as sarcopenia, cancer cachexia, denervation, and neuromuscular diseases, aiming to attenuate (or potentially reverse) the muscle wasting and associated muscle weakness, and to enhance muscle growth and repair after injury. Some undesirable cardiovascular side effects of beta-agonists have so far limited their therapeutic potential. This review describes the physiological significance of beta-adrenergic signaling in skeletal muscle and examines the effects of beta-agonists on skeletal muscle structure and function. In addition, we examine the proposed beneficial effects of beta-agonist administration on skeletal muscle along with some of the less desirable cardiovascular effects. Understanding beta-adrenergic signaling in skeletal muscle is important for identifying new therapeutic targets and identifying novel approaches to attenuate the muscle wasting concomitant with many diseases.

O Herbsman

Papers

A cAMP response element in the beta 2-adrenergic receptor gene confers transcriptional autoregulation by cAMP.