Thermogenesis and mitochondrial GDP binding with age in response to the novel agonist CGP-12177A

Abstract

The ability to regulate body temperature diminishes with age in both humans and rodents. To investigate whether attenuation of sympathetically activated thermogenesis in brown adipose tissue (BAT) may account for the loss of thermoregulation with age, we assessed O2 consumption and body temperature in response to norepinephrine and the specific BAT beta-adrenergic agonist CGP-12177A in 6-, 18-, and 24-mo-old rats. In addition, the effects of this agonist on interscapular BAT mitochondrial GDP binding in young and senescent rats were determined. CGP-12177A rapidly induced an elevation in O2 consumption, which peaked at 25 min, followed by a decline over 4 h. The peak increase in O2 consumption over baseline and the cumulative 4-h response were decreased with age [P less than 0.02, analysis of variance (ANOVA)]. CGP-12177A induced an increase in body temperature that paralleled but appropriately lagged behind the increase in O2 consumption and that was decreased with age (P less than 0.02, ANOVA). The norepinephrine-induced increase in O2 consumption was also reduced with age but was not paralleled by a change in body temperature and was associated with a four- to fivefold increase in physical activity. In young rats CGP-12177A increased the number of available BAT mitochondrial GDP binding sites at 20 and 60 min post-injection, but in senescent rats GCP-12177A was unable to increase GDP binding. These data indicate that CGP-12177A is a novel agonist for BAT thermogenesis. With age there is a reduced capacity for thermogenesis that involves a failure to increase GDP binding, either due to a diminished amount of uncoupling protein with age or a failure to unmask reserve GDP binding sites.

Differential effects of retinoic acid on uncoupling protein-1 and leptin gene expression

“…Although RA increased UCP1 gene expression, there were no changes in either total protein or total DNA content in BAT over the short period of this experiment. However, the former observation raises the possibility that RA may be able to upregulate the capacity for thermogenesis in circumstances where BAT thermogenesis is impaired, such as in senescence (Scarpace et al 1992). Furthermore, RA may be able to upregulate the capacity for energy expenditure even in cases of normal thermogenesis, by influencing the recruitment process.…”

Unabated anorexic and enhanced thermogenic responses to melanotan II in diet-induced obese rats despite reduced melanocortin 3 and 4 receptor expression

“…Oxygen consumption was assessed in up to four rats simultaneously with an Oxyscan analyzer (OXS-4; Omnitech Electronics, Columbus, OH, USA) as described previously (Scarpace et al 1992). Flow rates were 2 liters/min with a 30-s sampling time at 5-min intervals.…”

The in vivo effects of beta-3-receptor agonist CGP-12177 on thyroxine deiodination in cold-exposed, sympathectomized rat brown fat

“…Other parameters of BAT thermogenesis, such as oxygen consumption (11) and GDP binding to BAT mitochondrial proteins (A Zaninovich) also showed that NE was moderately more effective. This could be the result of a complex mechanism for the in vivo activation of 5 H -DII, which would involve NE and more than one type of adrenergic receptor.…”

“…A selective, high af®nity beta-3-receptor blocker which would facilitate the analysis of the results has not yet been identi®ed. We used propranolol, whose af®nity for beta-3-receptors is far below (26) its af®nity for beta-1 and beta-2-receptors (11,21). Based on the sharp inhibition of CGP-12177 by propranolol and the fact that this adrenergic agonist interacts with receptors other than those with which NE interacts (27), one cannot rule out that beta-receptor subtypes other than beta-3 may have participated in the BAT response to CGP-12177.…”

“…The effects of NE on BAT uncoupling protein (UCP1) synthesis are mediated predominantly via beta-3-receptors (8), whereas alpha-1-receptors (7) and the synergism between alpha-1-and beta-receptors (9) have been reported to mediate the synthesis of 5 H -DII. The selective beta-3-adrenoreceptor agonist CGP-12177 activates BAT thermogenesis, as measured by GDP binding to UCP sites, UCP concentration or mitochondrial oxygen consumption (10,11). The effects of this agonist on BAT 5 H -DII activity in vivo are less known.…”