Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean.

Uncoupling protein-3 (UCP-3) is a recently identified member of the mitochondrial transporter superfamily that is expressed predominantly in skeletal muscle. However, its close relative UCP-1 is expressed exclusively in brown adipose tissue, a tissue whose main function is fat combustion and thermogenesis. Studies on the expression of UCP-3 in animals and humans in different physiological situations support a role for UCP-3 in energy balance and lipid metabolism. However, direct evidence for these roles is lacking. Here we describe the creation of transgenic mice that overexpress human UCP-3 in skeletal muscle. These mice are hyperphagic but weigh less than their wild-type littermates. Magnetic resonance imaging shows a striking reduction in adipose tissue mass. The mice also exhibit lower fasting plasma glucose and insulin levels and an increased glucose clearance rate. This provides evidence that skeletal muscle UCP-3 has the potential to influence metabolic rate and glucose homeostasis in the whole animal.

Tissue restricted expression of two human Frzbs in preadipocytes and pancreas.

Frzb is a newly discovered family of secreted glycoproteins that function to modulate signaling activity of Wnt. Frzb proteins share sequence homology with the extracellular domain of the Wnt receptor (frizzled) and are capable of binding to Wnt. Thus, Frzb functions to antagonize Wnt activity by sequestering Wnt and preventing its binding to the frizzled receptor. Since the initial identification of bovine and human Frzb, several related members of this family have been isolated from rodent and human. In this paper, we describe the cloning and expression of two human frzb homologues termed hFRP-1b and hFRP-2. These human FRPs share significant homology to mouse sFRP-1 and sFRP-2 (55 and 98% identity at amino acid level, respectively). Northern blot experiments revealed that these Frzb homologues have highly restricted tissue distribution. hFRP-1b is exclusively expressed in pancreatic tissue while high levels of hFRP-2 were found in adipose tissue. In addition, low levels of hFRP-2 were also observed in other tissues including heart, pancreas and muscle. Remarkably, FRP-2 is predominantly expressed in un-differentiated preadipocytes in both rodent and man. The expression of FRP-2 is also significantly reduced in fat pads from obese mice. Taken together, these data indicate that distinctive members of the Frzb family exhibit different expression patterns in vivo, suggesting their ability to modulate diverse aspects of Wnt signaling. The expression and dysregulation of sFRP-2 in fat and obesity also suggest a potential roles on the Wnt signaling pathway in the pathology of obesity and related metabolic diseases. Molecular cloning and expression of these Frzbs will allow detailed molecular and biochemical analysis of Wnt-Frzb interaction and their impact on Wnt-Frizzled receptor signal transduction.

The contribution of classical (beta1/2-) and atypical beta-adrenoceptors to the stimulation of human white adipocyte lipolysis and right atrial appendage contraction by novel beta3-adrenoceptor agonists of differing selectivities.

The role of beta3- and other putative atypical beta-adrenoceptors in human white adipocytes and right atrial appendage has been investigated using CGP 12177 and novel phenylethanolamine and aryloxypropanolamine beta3-adrenoceptor (beta3AR) agonists with varying intrinsic activities and selectivities for human cloned betaAR subtypes. The ability to demonstrate beta1/2AR antagonist-insensitive (beta3 or other atypical betaAR-mediated) responses to CGP 12177 was critically dependent on the albumin batch used to prepare and incubate the adipocytes. Four aryloxypropanolamine selective beta3AR agonists (SB-226552, SB-229432, SB-236923, SB-246982) consistently elicited beta1/2AR antagonist-insensitive lipolysis. However, a phenylethanolamine (SB-220646) that was a selective full beta3AR agonist elicited full lipolytic and inotropic responses that were sensitive to beta1/2AR antagonism, despite it having very low efficacies at cloned beta1- and beta2ARs. A component of the response to another phenylethanolamine selective beta3AR agonist (SB-215691) was insensitive to beta1/2AR antagonism in some experiments. Because no [corrected] novel aryloxypropanolamine had a beta1/2AR antagonist-insensitive inotropic effect, these results establish more firmly that beta3ARs mediate lipolysis in human white adipocytes, and suggest that putative 'beta4ARs' mediate inotropic responses to CGP 12177. The results also illustrate the difficulty of predicting from studies on cloned betaARs which betaARs will mediate responses to agonists in tissues that have a high number of beta1- and beta2ARs or a low number of beta3ARs.

Functional genomics: going forwards from the databases.

Extrapolating systematically from gene sequence to function is undoubtedly the major challenge facing industry and academia alike as we approach the end of the millennium. Many electronic and laboratory approaches are being developed to meet this challenge but the rate of evolution of these is not keeping pace with the speed of sequence generation.

Synthesis of a selective alpha-2A adrenoceptor antagonist, BRL 48962, and its characterization at cloned human alpha-adrenoceptors.

The chiral synthesis of the potent and selective alpha-2A antagonist, BRL 48962, is described. Evaluation of BRL 48962 at cloned human alpha-adrenoceptors indicates that this antagonist has a selectivity in the order of 30-fold for the alpha-2A subtype.

Antidepressants and galactorrhoea.

Several antidepressants have been reported to produce hyperprolactinaemia, with or without galactorrhoea. We report a case of galactorrhoea associated with dothiepin and discuss the effects of a subsequent change in antidepressants.

Beta-adrenoceptor blocking drugs: adverse reactions and drug interactions.

Beta adrenoceptor blocking drugs are relatively well tolerated and adverse reactions to them are not common. The ones that do occur are reviewed in this paper under the following headings: Short term adverse reactions, drug interactions, long term adverse reactions, risks in pregnancy and hazards of abrupt withdrawal. Predictable short term effects may be caused either by the actions of these drugs on the beta 1- or beta 2-receptors. The beta 1 adverse effects are hypotension, bradycardia and cardiac failure; these are best avoided by not giving beta-adrenoceptor blocking drugs to susceptible patients with cardiac disease. The beta 2 adverse effects on the bronchi, the peripheral arteries and various metabolic functions may be reduced to some extent by using a relatively cardioselective drug. Unpredictable short term effects such as fatigue, sexual dysfunction and gastrointestinal symptoms may occur but are not common problems with this group of drugs. Similarly, serious drug interactions are infrequent. Under the heading of long term adverse effects the practolol problem and the risk of causing malignant disorders have been considered. There is no evidence that any of the currently available drugs will cause either a practolol syndrome or malignant disease in man. However, the need for careful appraisal by drug regulatory bodies and continued vigilance by all prescribers of beta-adrenoceptor blocking drugs remains. The possible adverse effects of treatment during pregnancy are also considered. It now appears that beta-adrenoceptor drugs can be used safely in pregnancy but since neonatal bradycardia and hypoglycemia may occur, care should be taken to look for these complications. A serious deterioration may occur when beta-adrenoceptor drugs, given to patients with significant ischemic heart disease, are suddenly stopped. This is a rare occurrence but prescribers should be aware of it.