Brown fat is essential for cold-induced thermogenesis  but not for obesity resistance in aP2-<i>Ucp</i> mice

Stefl, B; Janovská, Alena; Hodný, Zdeněk; Rossmeisl, Martin; Horáková, Milada; Syrový, I; Bémová, Jaroslava; Bendlová, Běla; Kopecký, Jan

doi:10.1152/ajpendo.1998.274.3.e527

Cited by 54 publications

(75 citation statements)

References 31 publications

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“…The anti-obesity effect was very robust, observed even in 13-month-old A y /a mice (Kopecky et al 1995), and during the whole life in transgenic mice with C57BL/6 J background fed high-fat diet (S. Kopecky et al, unpublished), in spite of the decline in the content of ectopic UCP1 in WAT during aging (Rossmeisl et al 2002). Thus, obesity resistance represented a dominant feature induced by ectopic UCP1 in WAT (Kopecky et al 1995(Kopecky et al , 1996aStefl et al 1998). In mice with the transient adenoviral UCP1 expression in epididymal fat, no significant changes in body weight and the weight of epididymal fat were observed, but the diameter of UCP1-expressing adipocytes was significantly reduced (Yamada et al 2006).…”

Section: Body Composition and Obesitymentioning

confidence: 97%

“…That mitochondrial uncoupling in WAT could reduce obesity was found in 1995 by Kopecky et al (1995) using aP2-Ucp1 transgenic mice and explored systematically later on (Kopecky et al 1996a, b;Stefl et al 1998;Baumruk et al 1999;Rossmeisl et al 2000Rossmeisl et al , 2002Rossmeisl et al , 2005Flachs et al 2002;Matejkova et al 2004). In these mice, the fatspecific aP2 promoter was used to drive expression of UCP1 from the whole genomic DNA sequence, resulting in enhanced expression of UCP1 in both WAT and BAT of mice with C57BL/6 J background.…”

Section: White Adipose Tissuementioning

confidence: 99%

“…Only one line of the aP2-Ucp1 mice has been studied, mostly animals heterozygous for the transgene. These mice show atrophy of BAT, resulting presumably from excessive amounts of UCP1, which collapse energy metabolism in BAT cells, with the most pronounced phenotype in the homozygous transgenic mice (Stefl et al 1998). More transgenic UCP1 is detected in subcutaneous than in gonadal WAT, and the expression declines during aging (Rossmeisl et al 2002), suggesting a posttranscriptional control of the transgene expression or possibly an elimination of UCP1-expressing adipocytes with time.…”

Section: White Adipose Tissuementioning

confidence: 99%

“…However, transgenic mice were protected against both genetic obesity, as shown in a cross of aP2-Ucp1 mice with lethal yellow (A y /a) mice (Kopecky et al 1995), as well as against high-fat diet-induced obesity (Kopecky et al 1996a;Stefl et al 1998), independent of gender (Kopecky et al 1996a). The reduction in body weight gain of *50% of heterozygous aP2-Ucp1 transgenic mice under high-fat feeding was associated with a decreased adiposity but not with changes in lean body mass (Kopecky et al 1996a), although homozygous transgenic mice, which were almost completely resistant to obesity, tended to be smaller (Stefl et al 1998). Importantly, the weight of subcutaneous but not gonadal WAT of the transgenic mice was reduced, in accordance with the higher expression of the transgene in the subcutaneous fat (Kopecky et al 1995(Kopecky et al , 1996a, suggesting the importance of metabolic changes induced in situ by ectopic UCP1 for reduction of WAT mass.…”

Section: Body Composition and Obesitymentioning

confidence: 99%

“…Although obesity resistant, the aP2-Ucp1 mice exhibit BAT atrophy associated with decreased norepinephrineinduced respiration at the whole-body level, cold-sensitivity of homozygous (but not heterozygous) transgenic Energy intake Cumulative energy intake decreased or unchanged (Kopecky et al 1996a;Stefl et al 1998) Increased (Couplan et al 2002;Klaus et al 2005) Reduced per animal on HFD (Ishigaki et al 2005) Body temperature Reduced in homozygous mice (Stefl et al 1998) Increased (Gates et al 2007) Unchanged (Li et al 2000) Unchanged (Ishigaki et al 2005) Reduced in cold (Klaus et al 2005) High-fat diet-induced obesity…”

Section: Energy Metabolismmentioning

confidence: 99%

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Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

et al. 2011

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Strategies to prevent and treat obesity aim to decrease energy intake and/or increase energy expenditure. Regarding the increase of energy expenditure, two key intracellular targets may be considered (1) mitochondrial oxidative phosphorylation, the major site of ATP production, and (2) AMP-activated protein kinase (AMPK), the master regulator of cellular energy homeostasis. Experiments performed mainly in transgenic mice revealed a possibility to ameliorate obesity and associated disorders by mitochondrial uncoupling in metabolically relevant tissues, especially in white adipose tissue (WAT), skeletal muscle (SM), and liver. Thus, ectopic expression of brown fat-specific mitochondrial uncoupling protein 1 (UCP1) elicited major metabolic effects both at the cellular/tissue level and at the whole-body level. In addition to expected increases in energy expenditure, surprisingly complex phenotypic effects were detected. The consequences of mitochondrial uncoupling in WAT and SM are not identical, showing robust and stable obesity resistance accompanied by improvement of lipid metabolism in the case of ectopic UCP1 in WAT, while preservation of insulin sensitivity in the context of high-fat feeding represents the major outcome of muscle UCP1 expression. These complex responses could be largely explained by tissue-specific activation of AMPK, triggered by a depression of cellular energy charge. Experimental data support the idea that (1) while being always activated in response to mitochondrial uncoupling and compromised intracellular energy status in general, AMPK could augment energy expenditure and mediate local as well as whole-body effects; and (2) activation of AMPK alone does not lead to induction of energy expenditure and weight reduction.

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Section: Body Composition and Obesitymentioning

confidence: 97%

Section: White Adipose Tissuementioning

confidence: 99%

Section: White Adipose Tissuementioning

confidence: 99%

Section: Body Composition and Obesitymentioning

confidence: 99%

Section: Energy Metabolismmentioning

confidence: 99%

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Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

et al. 2011

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A new mouse model for noninvasive fluorescence‐based monitoring of mitochondrial UCP1 expression

et al. 2019

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Mitochondrial uncoupling protein 1 (UCP1) is well known for its thermogenic function in brown adipose tissue (BAT). Since UCP1 expends energy on thermogenesis, UCP1 activation has been considered an approach to ameliorate obesity. As a tool for uncovering yet unknown mechanisms of UCP1 activation, we generated a transgenic mouse model in which UCP1 expression levels are reflected in fluorescence derived from monomeric red fluorescent protein 1 (mRFP1). In these UCP1‐mRFP1 BAC transgenic mice, fluorescence intensity mimics the change in UCP1 expression levels evoked through physiological or pharmacological stimulation. This transgenic mouse model will be useful in the search for bioactive compounds with the ability to induce UCP1 and for revealing undiscovered mechanisms of BAT activation.

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Diversity of Thermogenic Capacity Predicts Divergent Obesity Susceptibility in a Wild Rodent

Zhang

Shen

Liu

et al. 2017

Obesity

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Objective: The objective of the present study was to examine whether wild rodents exhibit diverse obesity susceptibility and what factors predispose subjects to this divergence in response to a high-fat diet (HFD). Methods: Sixty male and female Brandt's voles (Lasiopodomys brandtii) were fed an HFD for 8 weeks, and the upper (obesity prone [OP]) and lower (obesity resistant [OR]) one-third for mass gain were selected. Energy budgets and pathologic changes were measured. Another 30 males were fed a low-fat control diet (LFD) for 10 weeks and then fed an HFD for 12 weeks. The energetic parameters of the rodents on an LFD were analyzed for the correlation with body mass of the rodents on an HFD. Results: OP voles had higher energy intakes, higher levels of noradrenaline-induced nonshivering thermogenesis, and a greater impairment of insulin tolerance than OR voles. Unlike laboratory rodents, there were no differences in physical activity or resting metabolic rate between these groups of voles. The thermogenic capacity during LFD feeding was the strongest predictor for mass gain during HFD feeding. Conclusions: This study suggests that a wild rodent species of Brandt's voles exhibits diverse obesity susceptibility in reaction to an HFD, providing a natural model to give insight into the mechanisms for divergent obesity susceptibility. This study also indicates that maximum thermogenic capacity has a predictive power for the development of obesity when an HFD was available.

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Brown fat is essential for cold-induced thermogenesis but not for obesity resistance in aP2-Ucp mice

Cited by 54 publications

References 31 publications

Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

A new mouse model for noninvasive fluorescence‐based monitoring of mitochondrial UCP1 expression

Diversity of Thermogenic Capacity Predicts Divergent Obesity Susceptibility in a Wild Rodent

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