β₃-Adrenergic agonist induces a functionally active uncoupling protein in fat and slow-twitch muscle fibers

Abstract

The mitochondrial uncoupling protein (UCP) has usually been found only in brown adipose tissue. We recently observed that a chronic administration of the β3-adrenergic agonist CL-316,243 (CL) induced the ectopic expression of UCP in white fat and skeletal muscle in genetic obese yellow KK mice. The aim of the present study was to examine whether UCP could be induced in nongenetic obese animals produced by neonatal injections of monosodiuml-glutamate (MSG). The daily subcutaneous injection of CL (0.1 mg/kg) to MSG-induced obese mice for 2 wk caused significant reductions of body weight (15%) and white fat pad weight (58%). Northern and Western blot analyses showed that CL induced significant expressions of UCP in the white fat and muscle, as well as in brown fat. Immunohistochemical observations revealed that the UCP stains in white fat were localized on multilocular cells and that those in muscle were localized on slow-twitch fibers rich in mitochondria. Immunoelectron microscopy confirmed the mitochondrial localization of UCP in the myocytes. The guanosine 5′-diphosphate (GDP) binding to mitochondria in brown fat doubled after the CL treatment. Moreover, significant GDP binding was detected in the white fat and muscle of the CL-treated mice, at about one-fourth and one-thirteenth the activity of brown fat, respectively, suggesting that ectopically expressed UCP is functionally active. We concluded that the β3-adrenergic agonist CL can induce functionally active UCP in white fat and slow-twitch muscle fibers of obese mice.

.BETA.3-Adrenergic Agonist Up-Regulates Uncoupling Proteins 2 and 3 in Skeletal Muscle of the Mouse.

“…These results, together with our previous findings of the CL-induced expression of UCP1 in the adipose tissues [17,20,25], suggest that antiobesity effect of β3-AR agonists is attributable to increased thermogenesis not only by UCP1 but also by UCP2 and UCP3.…”

“…The present study revealed that the daily injection of CL for 10 days resulted in a significant increase in the expression of both UCP2 and UCP3 mRNAs in skeletal muscle. We [17,25] demonstrated previously that a similar treatment with CL not only increased UCP1 expression in BAT but also elicited ectopic UCP1 expression in WAT and also even in skeletal muscle. In the present study, the stimulative effect of CL on UCP2 and UCP3 expression was not found in the adipose tissues.…”

“…Thus, it is most likely that free fatty acids released from CL-stimulated adipose tissues act on skeletal muscle to activate UCP2 and UCP3 expression. This may be also the case in the ectopic expression of UCP1 in myocyte reported previously [17,25]. Further studies are needed to understand the molecular mechanisms for the fatty-acid induced UCP expression, particularly on the possible regulation of UCP gene transcription by the peroxisome prolifertor-activated receptors which are activated by fatty acids.…”

“…UCP is originally known as a unique molecule exclusively present in brown adipose tissue (BAT), an organ for adaptive thermogenesis during cold exposure and spontaneous hyperphagia in rodents and some neonatal mammals including humans [9]. It has been demonstrated that chronic treatment of obese animals by agonist to the β3 adrenergic receptor (AR) resulted in a reduced adiposity associated with an increased expression of UCP [6,10,17,25]. Particularly interesting was that UCP was found in various fat pads usually considered as white adipose tissue (WAT) and even in skeletal muscle [6,17,25].…”

“…It has been demonstrated that chronic treatment of obese animals by agonist to the β3 adrenergic receptor (AR) resulted in a reduced adiposity associated with an increased expression of UCP [6,10,17,25]. Particularly interesting was that UCP was found in various fat pads usually considered as white adipose tissue (WAT) and even in skeletal muscle [6,17,25]. Such ectopic expression of UCP may contribute significantly to an increase in heat production (energy expenditure) and the reduction of adiposity.…”