Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity.

Kopecký, Jan; Clarke, George; Enerbäck, Sven; Spiegelman, Bruce M.; Kozak, Leslie P.

doi:10.1172/jci118363

Cited by 505 publications

(422 citation statements)

References 28 publications

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“…Previous studies found brown fat emergence in WAT coupled with enhanced whole-body energy expenditure, but these studies used non-dietary manipulations, including chronic exposure to cold, treatment with b3-adrenergic receptor agonists and forced WAT overexpression of key molecules of brown fat adipogenesis/function, such as PGC-1a, UCP1 or PRDM16. 12,14,18,20,[39][40][41][42] Brown fat adipogenesis has recently gained the interest of many research groups, as compelling evidence has been provided that brown fat exists not only in human neonates, as thought originally, but also in human adults where it likely protects against obesity, 2-8 through its superior capacity for burning fat (both stored and eaten) and energy dissipation. 9,43 Substantial progress in our understanding of brown fat adipogenesis has been made recently (Seale et al 43 ).…”

Section: Discussionmentioning

confidence: 99%

“…12,13 Importantly, the presence of these brownlike adipocytes in WAT, even in very small quantities, is associated with a significant reduction in whole-body adiposity. 14 Despite the recent advances in understanding brown fat adipogenesis, [15][16][17][18] the molecular mechanisms of brown fat emergence in traditional WAT have yet to be elucidated. A complex network of transcription factors that includes peroxisome proliferator-activated receptor-g coactivator1a (PGC-1a) controls brown fat adipogenesis.…”

Section: Introductionmentioning

confidence: 99%

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High-fat diet induces emergence of brown-like adipocytes in white adipose tissue of spontaneously hypertensive rats

et al. 2011

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Obesity has a profound adverse impact on health. In this study, we present evidence for high-fat diet (HFD)-induced emergence of brown-like adipocytes in white adipose tissue (WAT) of the spontaneously hypertensive rat (SHR). We studied adult males fed a HFD or normal diet (ND) for 12 weeks. At the end of the 12-week dietary intervention, HFD compared with ND rats showed significantly higher whole-body energy expenditure. HFD vs. ND rats also showed higher expression of genes involved in fatty acid oxidation, mitochondrial biogenesis and brown fat adipogenesis, as well as augmented mitochondrial mass in WAT but not in the liver or skeletal muscle. Consistent with the molecular changes, in HFD but not in ND rats, histological and immunohistochemistry-based analyses of WAT demonstrated the presence of small multilocular cells staining positively for uncoupling protein 1, indicating the emergence of brown-like adipocytes in WAT. Our results suggest that SHR may have the capacity to increase energy expenditure in response to a chronic HFD that may be linked to the emergence of brown-like adipocytes in WAT. Thus, the SHR may be an important genetic model to uncover novel mechanisms of resistance to dietary obesity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

High-fat diet induces emergence of brown-like adipocytes in white adipose tissue of spontaneously hypertensive rats

et al. 2011

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“…Ectopic UCP1 expression in WAT of aP2-Ucp1 transgenic mice did not affect body weight under basal conditions, that is, when the animals were fed a standard chow (Kopecky et al 1995(Kopecky et al , 1996a. 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).…”

Section: Body Composition and Obesitymentioning

confidence: 95%

“…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. About 2-10% of UCP1/membranous protein is present in WAT of heterozygous adult mice as compared with BAT of wild-type warm-acclimated mice (Kopecky et al 1995).…”

Section: White Adipose Tissuementioning

confidence: 99%

“…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%

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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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The Role of Energy Expenditure in the Regulation of Energy Balance

Ravussin

Kozak

2003

International Textbook of Diabetes Mellitus

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Throughout evolution, humans and animals have evolved redundant mechanisms promoting accumulation of fat (minimal energy expenditure and maximal food intake) during periods of feast to survive periods of famine. With the recent abrupt change in environmental conditions in which high fat food is constantly available and in which there is little need for physical activity (the current “pathoenvironment” or “toxic environment”), obesity has reached epidemic proportions in both industrialized countries and in urbanized populations around the world. Obesity results from a chronic imbalance between energy intake and energy expenditure. Hyperphagia, a low metabolic rate, low rates of fat oxidation, and an impaired sympathetic nervous activity characterize animal models of obesity. Similar metabolic factors have been found to characterize humans susceptible to weight gain. Despite the discovery of leptin more than 8 years ago and an unprecedented expansion of research efforts, our knowledge about the molecular mechanisms underlying obesity remains rudimentary. The cloning of genes corresponding to several mouse monogenic obesity syndromes and the subsequent characterization of the pathways involved have however shed some light, mostly on the regulation of food intake but much less on energy metabolism. This chapter will first state the premises of the regulation of energy balance, then review the variability of physiological mechanisms underlying the variability in energy balance, and finally summarize some of the important recent discoveries of the molecular mechanisms of energy expenditure.

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Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity.

Abstract: The brown fat-specific mitochondrial uncoupling protein (UCP) provides a mechanism for generating heat by uncoupling respiration and oxidative phosphorylation. It Invest. 1995Invest. . 96:2914Invest. -2923

Cited by 505 publications

References 28 publications

High-fat diet induces emergence of brown-like adipocytes in white adipose tissue of spontaneously hypertensive rats

High-fat diet induces emergence of brown-like adipocytes in white adipose tissue of spontaneously hypertensive rats

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

The Role of Energy Expenditure in the Regulation of Energy Balance

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