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Biomedical subjects

P M Watson

Publications and source records attributed to P M Watson.

At least 19 recordsLinked to original sources
PubMed2001

Leptin selectively reduces white adipose tissue in mice via a UCP1-dependent mechanism in brown adipose tissue.

We tested the hypothesis that leptin, in addition to reducing body fat by restraining food intake, reduces body fat through a peripheral mechanism requiring uncoupling protein 1 (UCP1). Leptin was administered to wild-type (WT) mice and mice with a targeted disruption of the UCP1 gene (UCP1 deficient), while vehicle-injected control animals of each genotype were pair-fed to each leptin-treated group. Leptin reduced the size of white adipose tissue (WAT) depots in WT mice but not in UCP1-deficient animals. This was accompanied by a threefold increase in the amount of UCP1 protein and mRNA in the brown adipose tissue (BAT) of WT mice. Leptin also increased UCP2 mRNA in WAT of both WT and UCP1-deficient mice but increased UCP2 and UCP3 mRNA only in BAT from UCP1-deficient mice. These results indicate that leptin reduces WAT through a peripheral mechanism requiring the presence of UCP1, with little or no involvement of UCP2 or UCP3.

Adipose Tissue↗
PubMed2000

Central leptin regulates the UCP1 and ob genes in brown and white adipose tissue via different beta-adrenoceptor subtypes.

The three known subtypes of beta-adrenoreceptors (beta(1)-AR, beta(2)-AR, and beta(3)-AR) are differentially expressed in brown and white adipose tissue and mediate peripheral responses to central modulation of sympathetic outflow by leptin. To assess the relative roles of the beta-AR subtypes in mediating leptin's effects on adipocyte gene expression, mice with a targeted disruption of the beta(3)-adrenoreceptor gene (beta(3)-AR KO) were treated with vehicle or the beta(1)/beta(2)-AR selective antagonist, propranolol (20 microgram/g body weight/day) prior to intracerebroventricular (ICV) injections of leptin (0.1 microgram/g body weight/day). Leptin produced a 3-fold increase in UCP1 mRNA in brown adipose tissue of wild type (FVB/NJ) and beta(3)-AR KO mice. The response was unaltered by propranolol in wild type mice, but was completely blocked by this antagonist in beta(3)-AR KO mice. In contrast, ICV leptin had no effect on leptin mRNA in either epididymal or retroperitoneal white adipose tissue (WAT) from beta(3)-AR KOs. Moreover, propranolol did not block the ability of exogenous leptin to reduce leptin mRNA in either WAT depot site of wild type mice. These results demonstrate that the beta(3)-AR is required for leptin-mediated regulation of ob mRNA expression in WAT, but is interchangeable with the beta(1)/beta(2)-ARs in mediating leptin's effect on UCP1 mRNA expression in brown adipose tissue.

Adipose Tissue↗
PubMed2000

Differential regulation of leptin expression and function in A/J vs. C57BL/6J mice during diet-induced obesity.

Obesity-resistant (A/J) and obesity-prone (C57BL/6J) mice were weaned onto low-fat (LF) or high-fat (HF) diets and studied after 2, 10, and 16 wk. Despite consuming the same amount of food, A/J mice on the HF diet deposited less carcass lipid and gained less weight than C57BL/6J mice over the course of the study. Leptin mRNA was increased in white adipose tissue (WAT) in both strains on the HF diet but to significantly higher levels in A/J compared with C57BL/6J mice. Uncoupling protein 1 (UCP1) and UCP2 mRNA were induced by the HF diet in brown adipose tissue (BAT) and WAT of A/J mice, respectively, but not in C57BL/6J mice. UCP1 mRNA was also significantly higher in retroperitoneal WAT of A/J compared with C57BL/6J mice. The ability of A/J mice to resist diet-induced obesity is associated with a strain-specific increase in leptin, UCP1, and UCP2 expression in adipose tissue. The findings indicate that the HF diet does not compromise leptin-dependent regulation of adipocyte gene expression in A/J mice and suggest that maintenance of leptin responsiveness confers resistance to diet-induced obesity.

Adipose Tissue↗
PubMed1999

Induction of uncoupling protein expression in brown and white adipose tissue by leptin.

Deposition of excess body fat occurs when energy intake chronically exceeds energy expenditure. In ob/ob mice, the absence of leptin affects both components of the energy balance equation, and the mice become morbidly obese after weaning. Treatment of ob/ob mice with exogenous leptin reduces body weight by decreasing food intake and stimulating energy utilization, but even when saline- and leptin-injected ob/ob mice are pair-fed, mice receiving leptin lose significantly more weight. Therefore, the purpose of the present study was to test the hypotheses that uncoupling protein-1 (UCP1) expression is reduced in adipose tissue from ob/ob mice and is restored by treatment with exogenous leptin. Lean and ob/ob mice (5-6 weeks old) were housed at 23 C and treated with leptin (20 microg/g BW x day) for 3 days before they were killed. Compared with levels in lean littermates, UCP1 messenger RNA (mRNA) and protein levels were lower in brown adipose tissue (BAT) and retroperitoneal white adipose tissue (WAT) from ob/ob mice. Treatment of ob/ob mice with leptin reduced body weight and produced a 4- to 5-fold increase in UCP1 mRNA levels in both interscapular BAT and retroperitoneal WAT. The increases in UCP1 mRNA were accompanied by comparable increases in UCP1 protein in mitochondrial preparations from each tissue. Given that the sole known function of UCP1 is to uncouple oxidative phosphorylation, the present results are consistent with the conclusion that leptin stimulates energy utilization in ob/ob mice by increasing thermogenic activity and capacity (UCP1). In addition, the present results suggest that decreased UCP1 expression in BAT and WAT of ob/ob mice is in part responsible for their increased metabolic efficiency and propensity to become obese.

Adipose Tissue↗
PubMed1999

Norepinephrine is required for leptin effects on gene expression in brown and white adipose tissue.

Exogenous leptin enhances energy utilization in ob/ob mice by binding its hypothalamic receptor and selectively increasing peripheral fat oxidation. Leptin also increases uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT), but the neurotransmitter that mediates this effect has not been established. The present experiments sought to determine whether leptin regulates UCP1 expression in BAT and its own expression in white adipose tissue (WAT) through the long or short forms of leptin receptor and modulation of norepinephrine release. Mice lacking dopamine beta-hydroxylase (Dbh-/-), the enzyme responsible for synthesizing norepinephrine and epinephrine from dopamine, were treated with leptin (20 microg/g body weight/day) for 3 days before they were euthanized. UCP1 messenger RNA (mRNA) and protein expression were 5-fold higher in BAT from control (Dbh+/-) compared with Dbh-/- mice. Leptin produced a 4-fold increase in UCP1 mRNA levels in Dbh+/- mice but had no effect on UCP1 expression in Dbh-/-. The beta3-adrenergic agonist, CL-316,243 increased UCP1 expression and established that BAT from both groups of mice was capable of responding to beta-adrenergic stimulation. Similarly, exogenous leptin reduced leptin mRNA in WAT from Dbh+/- but not Dbh-/- mice. In separate experiments, leptin produced comparable reductions in food intake in both Dbh+/- and Dbh-/- mice, illustrating that norepinephrine is not required for leptin's effect on food intake. Lastly, db/db mice lacking the long form of the leptin receptor failed to increase UCP1 mRNA in response to exogenous leptin but increased UCP1 mRNA in response to CL-316,243. These studies establish that norepinephrine is required for leptin to regulate its own expression in WAT and UCP1 expression in BAT and indicate that these effects are likely mediated through the centrally expressed long form of the leptin receptor.

Adipose Tissue↗
PubMed1997

RU-486 (Mifepristone) ameliorates diabetes but does not correct deficient beta-adrenergic signalling in adipocytes from mature C57BL/6J-ob/ob mice.

OBJECTIVE: To investigate the role of hypercorticism in the development of compromised beta-adrenergic signalling in adipocytes of mature C57BL/6J-ob/ob mice. DESIGN AND EXPERIMENTAL UNITS: Mature male ob/ob mice and their lean littermates were treated with vehicle or the specific glucocorticoid receptor (GR) antagonist, RU-486 (30 mg/kg bw/d) for 21 d. MEASUREMENTS: Blood glucose, serum insulin, adipocyte Glut-4 expression, adipocyte Gs alpha expression, adenylylcyclase activation by beta-adrenergic receptor (beta-AR) agonists in adipocyte membranes and mRNA levels for beta 1-, beta 2- and beta 3-adrenergic receptor subtypes in adipocytes. RESULTS: RU-486 reduced blood glucose levels in ob/ob mice to levels that were not different from lean mice. RU-486 also reduced serum insulin by approximately 50% in ob/ob mice, but failed to restore depressed Gs alpha or GLUT-4 expression in adipocytes of ob/ob mice. RU-486 produced a two-fold increase in beta 3-AR mRNA in ob/ob mice and a small but significant improvement in isoprenaline-mediated adenylylcyclase activation. CONCLUSIONS: The present results indicate that glucocorticoid antagonism ameliorates diabetic symptoms of the mature ob/ob mouse, but does not lessen their obesity or fully reverse deficient expression and function of components of the adipocyte beta-adrenergic signalling cascade.

Adenylyl Cyclases↗
PubMed1997

Adrenalectomy after weaning restores beta3-adrenergic receptor expression in white adipocytes from C57BL/6J-ob/ob mice.

The role of hypercorticism in the development of compromised beta-adrenergic signaling in adipose tissue was assessed in ob/ob mice adrenalectomized at 4 weeks of age and studied 1 and 3 weeks thereafter. Adrenalectomy prevented the rapid increase in body weight and fat deposition between 4 and 5 weeks of age in ob/ob mice and produced a phenotype indistinguishable from that of lean mice. However, adrenalectomized ob/ob mice became intermediate between lean and ob/ob mice by 7 weeks of age. Adipocyte beta3-adrenergic receptor (AR) messenger RNA levels were similar between lean and adrenalectomized ob/ob mice at both time points and were 4- to 8-fold higher than messenger RNA levels in ob/ob mice. As judged by maximal activation of adenylyl cyclase by a beta3-AR-selective agonist, adrenalectomy also restored functional activity of the beta3-AR to levels above or equivalent to those seen in lean mice at both time points. The present results suggest that development of hypercorticism at or before weaning in ob/ob mice represses expression of the beta3-AR and prevents the normal postweaning development of this signaling system in the adipocyte.

Adipocytes↗
PubMed1996

The beta 3-adrenergic receptor inhibits insulin-stimulated leptin secretion from isolated rat adipocytes.

Various model systems have been used to study the expression of the recently cloned ob gene, leptin. Here we report that freshly isolated rat white adipocytes incubated with insulin release leptin in a rapid and concentration-dependent manner (EC50 of 0.221 +/- .075 nM). Insulin-stimulated leptin release could be detected as early as 30 min and a maximal 2-3 fold effect was produced by 10 nM insulin. The effect of insulin was completely blocked by simultaneous activation of cAMP-dependent protein kinase. Using the activation of lipolysis as an index of cAMP-dependent protein kinase activity, we show that inhibition of leptin release by norepinephrine or the selective beta 3-adrenergic receptor agonist, CL316,243, occurred in parallel to activation of cAMP-dependent protein kinase. In addition, beta 1- and beta 2-adrenergic receptor antagonists did not impair the ability of norepinephrine or CL316,243 to inhibit leptin release from the adipocytes. These findings suggest that the beta 3-adrenergic receptor plays a central role in regulating the release of leptin from the adipocyte.

Adipocytes↗
PubMed1991

The tight-junction-specific protein ZO-1 is a component of the human and rat blood-brain barriers.

Continuous tight junctions between vascular endothelial cells, the principal anatomical basis for the blood-brain barrier, have been investigated functionally and morphologically but their molecular components have not been defined. This communication reports that the protein ZO-1, a specific constituent of epithelial tight junctions, is found in human and rat brain vasculature. ZO-1-positive immunocytochemical staining forms a tightly banded pattern outlining individual endothelial cells in blood vessels of the human cerebral cortex. Rat brain exhibits a similar staining of blood vessels as well as ZO-1-positive staining around individual epithelial cells of the choroid plexus. The antiserum used for immunocytochemistry recognizes a protein of about 200 kDa in rat brain microvessels by Western blot. These findings indicate that ZO-1 is located at the interendothelial junctions of brain vasculature, implicating its importance as a component of the blood-brain barrier.

Animals↗
PubMed1988

Finding the productivity standard in your acuity system.

What is a realistic patient workload for nurses to handle on a given shift? Should the workload vary from shift-to-shift and nurse-to-nurse? This article describes how (1) the authors identified the standard inherent in their patient classification system; (2) the system is used to establish department workload standards; (3) managers comply with the established standard; and (4) nursing costs are affected when compliance with the standard is not achieved.

Efficiency↗