Indispensable role of mitochondrial UCP1 for antiobesity effect of β₃-adrenergic stimulation

Abstract

. Indispensable role of mitochondrial UCP1 for antiobesity effect of ␤ 3-adrenergic stimulation. Am J Physiol Endocrinol Metab 290: E1014 -E1021, 2006. First published December 20, 2005 doi:10.1152/ajpendo.00105.2005.-Mitochondrial uncoupling protein-1 (UCP1) has been thought to be a key molecule for thermogenesis during cold exposure and spontaneous hyperphagia and thereby in the autonomic regulation of energy expenditure and adiposity. However, UCP1 knockout (KO) mice were reported to be cold intolerant but unexpectedly did not get obese even after hyperphagia, implying that UCP1 may not be involved in the regulation of adiposity. Treatment of obese animals with ␤ 3-adrenergic agonists is known to increase lipid mobilization, induce UCP1, and, finally, reduce body fat content. To obtain direct evidence for the role of UCP1 in the anti-obesity effect of ␤ 3-adrenergic stimulation, in the present study, UCP1-KO and wild-type (WT) mice were fed on cafeteria diets for 8 wk and then given a ␤ 3-adrenergic agonist, CL-316,243 (CL), or saline for 2 wk. A single injection of CL increased whole body oxygen consumption and brown fat temperature in WT mice but not in KO mice, and it elicited almost the same plasma free fatty acid response in WT and KO mice. WT and KO mice increased similarly their body and white fat pad weights on cafeteria diets compared with those on laboratory chow. Daily treatment with CL resulted in a marked reduction of white fat pad weight and the size of adipocytes in WT mice, but not in KO mice. Compared with WT mice, KO mice expressed increased levels of UCP2 in brown fat but decreased levels in white fat and comparable levels of UCP3. It was concluded that the anti-obesity effect of ␤ 3-adrenergic stimulation is largely attributable to UCP1, but less to UCP2 and UCP3, and thereby to UCP1-dependent degradation of fatty acids released from white adipose tissue.uncoupling protein-1; adiposity; CL-316,243; energy expenditure; hyperphagia UNCOUPLING PROTEIN (UCP) IS A MOLECULE, as its name suggests, that uncouples mitochondrial oxidative phosphorylation by bypassing the electrochemical gradient across the inner membrane from the F1-ATPase and thereby dissipates energy as heat. Among several isoforms of the UCP family so far reported in mammals, UCP1 is the only one whose physiological importance has been firmly established; that is, UCP1 is present exclusively in brown adipose tissue (BAT), an organ specified for nonshivering thermogenesis during cold acclimation, arousal from hibernation, and recovery from anesthetic hypothermia (2). UCP1 has also been proposed to be involved in diet-induced thermogenesis, as well as cold-induced nonshivering thermogenesis, and play a significant role in the control of energy expenditure and whole body energy balance. This is supported by the observations, for example, that spontaneous overfeeding of highly palatable diets and/or high-fat diets gives rise to increased energy expenditure (oxygen consumption) in association with BAT hyperplasia and increased UCP1 c...

Role of β-adrenergic receptors in the anti-obesity and anti-diabetic effects of zinc-α2-glycoprotien (ZAG)

“…Using knock-out mice the antiobesity effect of 3-AR stimulation has been shown to be through the UCP-1 dependent degradation of fatty acids released from WAT (33,34). Until recently BAT was considered to be restricted to rodents and neonatal humans.…”

Structure–effect relation of C18 long-chain fatty acids in the reduction of body weight in rats

“…27,28 Although one might speculate that these two physiological responses to b-adrenergic stimulation are independent of each other, a recent study has demonstrated that the b 3 -adrenergic agonist, CL-316,243, could reduce white-fat pad size and the size of adipocytes only in wildtype but not in UCP1 knockout mice. 29 A DNA microarray study of WAT from obese (fa/fa) Zucker rats treated with the b 3 -adrenoceptor agonist KTO-7924 revealed specifically enhanced mRNA expressions not only of UCP1 but also of COX8H, 30 which is the terminal enzyme of the mitochondrial respiratory chain 31 and likewise highly expressed in BAT. 32 In line with these data, COX8H expression was also drastically increased in 2-OHOA-treated rats.…”

Increased fat:carbohydrate oxidation ratio in Il1ra −/− mice on a high-fat diet is associated with increased sympathetic tone

“…Mice lacking BAT due to the production of diphtheria toxin in this tissue are obese and insulin-resistant [17], indicating the importance of BAT in the control of body weight. Administration of β-adrenergic receptor (AR) agonists increases the metabolic rate [18][19][20], and mice lacking all three β-AR genes become markedly obese when reared on a HFD [21]. In contrast, transgenic overexpression of human β1-AR (also known as ADRB1) in WAT resulted in lean mice and an abundance of brown adipocytes in WAT [22].…”