Expression of uncoupling protein in skeletal muscle and white fat of obese mice treated with thermogenic beta 3-adrenergic agonist.

Nagase, Itsuro; Yoshida, Toshihide; Kumamoto, Kenzo; Umekawa, Tsunekazu; Sakane, Naoki; Nikami, Hideki; Kawada, Teruo; Saito, Masayuki

doi:10.1172/jci118748

Cited by 197 publications

(140 citation statements)

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“…The CL-treatment also resulted in about 3-fold increase in plasma free fatty acid level , and significant reduction of the plasma levels of glucose,insulin and T3 in obese mice. These effects of CL were essentially the same as those reported previously [17,24].…”

Section: Effects Of Cl-treatment On Tissue Weights and Blood Parameterssupporting

confidence: 90%

“…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].…”

mentioning

confidence: 99%

“…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.…”

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confidence: 99%

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

Nakamura

Nagase

Asano

et al. 2001

The Journal of Veterinary Medical Science

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ABSTRACT. Chronic stimulation of the β3-adrenergic receptor (AR) in obese animals resulted in a reduced adiposity associated with an increased expression of thermogenic uncoupling protein (UCP)1 in adipose tissues. In this study, the mRNA expression of newly cloned UCP isoforms (UCP2 and UCP3) were examined in obese yellow KK and C57BL control mice. UCP2 mRNA was found in all tissues examined, with higher levels in adipose tissues and skeletal muscle of the obese mice. UCP3 mRNA was expressed in skeletal muscle, heart and brown adipose tissue similarly in the two mouse strains. Daily injection of a selective β3-adrenergic agonist, CL316,243 (0.1 mg/kg), for 10 days resulted in a marked reduction of white fat pad weight and 1.8~4.8-fold increase in the mRNA levels of UCP2 and UCP3 in skeletal muscle of obese mice. No noticeable change in the UCP2 and 3 mRNA levels was found in brown and white adipose tissues. It was also found that CL316,243 injection produced a marked and sustained elevation of the plasma free fatty acid level. These results, together with our previous findings of the fatty acid-induced UCP expression in a myocyte cell line in vitro, suggest that the β3-AR agonist-induced UCP expression in skeletal muscle may be mediated through the elevated plasma free fatty acids. It was also suggested that anti-obesity effect of β3-AR agonists is attributable to increased thermogenesis not only by UCP1 but also by UCP2 and UCP3.KEY WORDS: adipose tissue, β3-adrenergic agonist, fatty acid, obese mouse, uncoupling protein.

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Section: Effects Of Cl-treatment On Tissue Weights and Blood Parameterssupporting

confidence: 90%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Nakamura

Nagase

Asano

et al. 2001

The Journal of Veterinary Medical Science

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“…The publications of two papers in 1996 prompted several laboratories to search for mitochondrial UCP and/or UCP homologues in skeletal muscle and other tissues, namely, (i) the report by Nagase et al [34] claiming that treatment with a h3 agonist led to weight loss associated with expression of an uncoupling protein detected in skeletal muscle and white adipose tissue by Northern and Western probing for the BAT-UCP, and (ii) the report of Rolfe and Brand [35] that the phenomenon of mitochondrial dproton leakT is not unique to BAT, as originally thought, but also exists in tissues other than BAT, and could contribute as much as 25-50% of the liver and skeletal muscle heat production at rest.…”

Section: Novel Duncouplingt Proteinsmentioning

confidence: 99%

Adaptive thermogenesis and uncoupling proteins: a reappraisal of their roles in fat metabolism and energy balance

Dulloo

Seydoux

Jacquet

2004

Physiology & Behavior

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After decades of controversies about the quantitative importance of autoregulatory adjustments in energy expenditure in weight regulation, there is now increasing recognition that even subtle variations in thermogenesis could, in dynamic systems and over the long term, be important in determining weight maintenance in some and obesity in others. The main challenge nowadays is to provide a mechanistic explanation for the role of adaptive thermogenesis in attenuating and correcting deviations of body weight and body composition, and in the identification of molecular mechanisms that constitute its effector systems. This workshop paper reconsiders what constitutes adaptive changes in thermogenesis and reassesses the role of the sympathetic nervous system (SNS) and uncoupling proteins (UCP1, UCP2, UCP3, UCP5/BMCP1) as the efferent and effector components of the classical one-control system for adaptive thermogenesis and fat oxidation. It then reviews the evidence suggesting that there are in fact two distinct control systems for adaptive thermogenesis, the biological significance of which is to satisfy-in a lifestyle of famine-and-feast-the needs to suppress thermogenesis for energy conservation during weight loss and weight recovery even under environmental stresses (e.g., cold, infection, nutrient imbalance) when sympathetic activation of thermogenesis has equally important survival value.Keywords: Obesity; Diabetes; Cachexia; Catecholamines; UCP Resistance to obesity in an obesigenic environmentOne of the greatest challenges towards understanding the aetiology of human obesity is to explain how in environments that promote overeating of high-fat foods and discourage physical activity, there is always a section of the population who, apparently without conscious effort, do not become obese. How do they resist obesity? How is constancy of body weight achieved over decades in these individuals? In addressing the issue of human susceptibility to leanness and fatness, there are three cardinal features of body weight regulation that need to be underlined: (i) Humans cannot escape the laws of thermodynamics.Whatever theory is put forward to explain body weight and body composition regulation, it is undeniable that changes in body energy stores (and ultimately body weight) cannot occur unless there is a difference between energy intake and energy expenditure. (ii) Subtle perturbations in energy balance can lead to obesity. To put it another way, long-term constancy of body weight can only be achieved if the matching between energy intake and energy expenditure is extremely precise, since an error of only 1% between input and output of energy, if persistent, will lead to a gain or loss of 1 kg per year or some 40 kg between the age of 20 to 60 years. Yet, a difference of 5% between energy intake and energy expenditure is hardly measurable with available techniques. (iii) Body weight is a fluctuating and oscillatory phenomenon. Even in individuals that maintain a relatively stable lean body weight over decades, the...

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“…UCP-1 is specifically produced in BAT; this protein uncouples oxidative phosphorylation from electron transport, resulting in the dissipation of energy as heat [24,25]. The emergence of these ectopic cells in the WAT of rats [26] and of mice [27] was found to be induced by cold acclimatisation or by the administration of selective β3-AR agonists [27,28]. Interestingly, the emergence of brown fat cells in white fat depots was associated with a lean phenotype in several transgenic mouse models, including β1-AR transgenic mice [22], FOXC2 transgenic mice [29] and Tif2 −/− (also known as Ncoa2 −/− ) mice [30].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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Aims/hypothesis Proinflammatory cytokines, including IL-1, exert pleiotropic effects on the neuro-immuno-endocrine system. Previously, we showed that mice with knockout of the gene encoding IL-1 receptor antagonist (Il1ra −/− , also known as Il1rn −/− ) have a lean phenotype. The present study was designed to analyse the mechanisms leading to this lean phenotype.Methods Il1ra −/− mice were fed a high-fat diet following weaning. Energy expenditure, body temperature, heart rate, blood parameters, urinary catecholamines and adipose tissue were analysed. Results Il1ra −/− mice exhibited resistance to obesity induced by a high-fat diet; this resistance was associated with increased energy expenditure and a decreased respiratory quotient, indicating that the ratio of fat:carbohydrate metabolism in Il1ra −/− mice is greater than in controls. Activity level in Il1ra −/− mice was significantly decreased and body temperature was significantly increased, compared with wild-type (WT) mice. Inguinal white adipose tissues in Il1ra −/− mice express increased levels of Ucp1 and mitochondrial respiratory chain genes compared with WT mice. Histological analysis of adipose tissue in Il1ra −/− mice revealed that brown adipose tissue is hyperactive and inguinal white adipose tissue contains smaller cells, which exhibit the distinctive multilocular appearance of brown adipocytes. Urinary epinephrine and norepinephrine excretion in Il1ra −/− mice was significantly increased compared with WT mice, suggesting that Il1ra −/− mice have increased sympathetic tone. Consistent with this, heart rate in Il1ra −/− mice was also significantly increased. Conclusions/interpretation Our results show that Il1ra −/− mice have increased energy expenditure, fat:carbohydrate oxidation ratio, body temperature, heart rate and catecholamine production. All of these observations are consistent with an enhanced sympathetic tone.

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Expression of uncoupling protein in skeletal muscle and white fat of obese mice treated with thermogenic beta 3-adrenergic agonist.

Cited by 197 publications

References 23 publications

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

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

Adaptive thermogenesis and uncoupling proteins: a reappraisal of their roles in fat metabolism and energy balance

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

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