Impaired Adipose Tissue Adrenergic Signaling in Obesity

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It was known for many years that obese C57BL/6J Lepob and C57KsJ LepRdb mice exhibited a marked inability to effectively mobilize triglycerides from white adipose tissue.46-49 These animals are also unable to recruit brown adipose tissue for thermogenesis in response to cold temperature-induced adr-energic stimulation,4950 indicating that adrenergic mechanisms regulating metabolism in both white and brown fat are affected in obesity. While defects in sympathetic outflow have been shown to be associated with obesity,51-53 other experiments also clearly indicated that there was impaired P-adrener-gic receptor (PAR) function at the level of the adipocyte itself, independent of the availability of catecholamines.48

Because activation of adenylyl cyclase by catecholamines and the expected elevation in intracellular cAMP are depressed in C57BL/6J Lepob animals, in the late 1970s and early 1980s several investigators tried to determine the nature of the molecular defect in adipocytes from obese animals. The components of the adrenergic signal transduction pathway (at least those which were known at the time, which did not include P3AR) were examined, and were not different between lean and obese animals despite a severe blunting of the P-adrenergic response, adenylyl cyclase itself, and other downstream effectors of the lipolytic process.48,54,55 Collectively, these results led to the conclusion that the signal transduction mechanism of the P-adrenergic receptor(s) must be defective. It is now apparent that earlier PAR radioligand-binding results in adipose tissue were misleading because the classical PAR radioligands such as cyanopindolol exhibit a 20- to 50-fold weaker affinity for the P3AR than for P1AR and P2AR.3156 Therefore, P3AR levels were essentially undetected, and estimates of P1AR and P2AR were distorted. In 1989/1990 the first P3AR clone was isolated from a human genomic DNA library.57

Figure 12.3 shows the impaired ability of white adipose tissue from genetically obese (C57BL/6J Lepob) mice to stimulate adenylyl cyclase activity in response to P-agonist stimulation, and the dramatic decrease in expression of the newly discovered P3AR, as well as of the P1AR. Although these ade-nylyl cyclase data are similar to many previous reports (e.g., Reference 46), a unique aspect of our method of analysis was the use of epinephrine and the very large number of data points. This allowed us to perform complex nonlinear curve-fitting routines58 to dissect the contributions of the individual PAR subtypes to the adenylyl cyclase response. In normal lean animals, the high- and low-affinity populations correspond to {P1AR + P2AR} and P3AR, respectively. By contrast, there is only one population of sites in the C57BL/6J Lepob mouse, and this corresponds to the high-affinity population. Through a series of pharmacologic analyses we showed that these reductions in PAR expression (Fig. 12.3) correspond functionally to the impaired stimulation of cAMP production, and appear to be largely responsible for the defects in catecholamine-stimulated lipolysis observed in the C57BL/6J Lepob mouse.33 Similar findings of depressed P3AR mRNA levels in the Zucker fatty (fa/fa) rat were reported by Muzzin et al.,59 but the relationship to changes in the function of the receptor was not examined in that study. We have now extended our original findings to several other mouse models of obesity. We find significant deficits in the expression and function

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