Overexpression of UCP-3 in Skeletal Muscle of Mice Results in Increased Expression of Mitochondrial Thioesterase mRNA

Moore, Gary B.T.; Himms‐Hagen, Jean; Harper, Mary‐Ellen; Clapham, John C.

doi:10.1006/bbrc.2001.4848

Cited by 67 publications

(58 citation statements)

References 19 publications

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“…Abundant expression of this gene correlates with preferential lipid utilization, and increased energy expenditure. The role of uncoupling proteins in regulating energy balance have been extensively investigated through transgenic mice and cell culture studies (41)(42)(43). Repression of UCP3 mRNA also correlates with the decreased expression of genes involved in lipid absorption and utilization, in concordance with the observations derived from this study.…”

Section: Figsupporting

confidence: 86%

Rev-erbβ Regulates the Expression of Genes Involved in Lipid Absorption in Skeletal Muscle Cells

Ramakrishnan

Lau

Burke

et al. 2005

Journal of Biological Chemistry

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Rev-erb␤ is an orphan nuclear receptor that selectively blocks trans-activation mediated by the retinoic acid-related orphan receptor-␣ (ROR␣). ROR␣ has been implicated in the regulation of high density lipoprotein cholesterol, lipid homeostasis, and inflammation. Reverb␤ and ROR␣ are expressed in similar tissues, including skeletal muscle; however, the pathophysiological function of Rev-erb␤ has remained obscure. We hypothesize from the similar expression patterns, target genes, and overlapping cognate sequences of these nuclear receptors that Rev-erb␤ regulates lipid metabolism in skeletal muscle. This lean tissue accounts for >30% of total body weight and 50% of energy expenditure. Moreover, this metabolically demanding tissue is a primary site of glucose disposal, fatty acid oxidation, and cholesterol efflux. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. We utilize ectopic expression in skeletal muscle cells to understand the regulatory role of Rev-erb␤ in this major mass peripheral tissue. Exogenous expression of a dominant negative version of mouse Rev-erb␤ decreases the expression of many genes involved in fatty acid/lipid absorption (including Cd36, and Fabp-3 and -4). Interestingly, we observed a robust induction (>15-fold) in mRNA expression of interleukin-6, an "exerciseinduced myokine" that regulates energy expenditure and inflammation. Furthermore, we observed the dramatic repression (>20-fold) of myostatin mRNA, another myokine that is a negative regulator of muscle hypertrophy and hyperplasia that impacts on body fat accumulation. This study implicates Rev-erb␤ in the control of lipid and energy homoeostasis in skeletal muscle. In conclusion, we speculate that selective modulators of Rev-erb␤ may have therapeutic utility in the treatment of dyslipidemia and regulation of muscle growth. Members of the nuclear receptor (NR)1 superfamily bind to specific DNA elements and function as transcriptional regulators (1, 2). In addition to the ligand-activated NRs, many members within this superfamily have no known ligand, and are referred to as "orphan NRs" (3). The orphan receptor Rev-erb␤ (NR1D2, also known as Rev-erb␣-related receptor, RVR) belongs to the family of "Reverbs" that also contain Rev-erb␣ (4, 5). The primary structure of these two receptors together with retinoic acid-related orphan receptor-␣ (ROR␣) and the Drosophila orphan receptor, E75A, is very similar especially in the DNA-binding domain and the putative ligand-binding domain (6).Two Rev-erb␤ genes have been identified; Rev-erb␤1 and Rev-erb␤2, which are alternatively spliced products of the Reverb␤ gene (7). The mRNA expression data shows that Rev-erb␤ is abundantly expressed in most tissues, although higher levels of expression are observed in skeletal muscle, brain, kidney, and liver (Refs. 4 and 8 and references therein).Rev-erb␣, Rev-erb␤, and ROR bind as monomers to the nuclear receptor half-site motif, PuGGTCA flanked 5Ј by an ATrich sequence ((A/T) 6 PuGGTCA). Although...

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Section: Figsupporting

confidence: 86%

Rev-erbβ Regulates the Expression of Genes Involved in Lipid Absorption in Skeletal Muscle Cells

Ramakrishnan

Lau

Burke

et al. 2005

Journal of Biological Chemistry

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“…The relationship of this Nur77-dependent subgroup of genes is consistent with the phenotype of the obese ␤-AR less null mice. A number of studies have investigated ectopic and muscle-specific overexpression of UCP3 in transgenic mice and in cell culture (45)(46)(47). These investigations have reported (i) increased rates of energy expenditure, (ii) preferential lipid utilization and lipolysis, (iii) resistance to high fat diet-induced weight gain and obesity in the context of FIG.…”

Section: Nur77 Regulates Lipolysis In Skeletal Muscle 12581mentioning

confidence: 99%

“…LPL and CPT-1). However, this is not surprising as increased or decreased flux of fatty acids through the oxidation pathway does not necessarily require marked changes in genes involved in fat catabolism (45).…”

Section: Figmentioning

confidence: 99%

Nur77 Regulates Lipolysis in Skeletal Muscle Cells

Maxwell

Cleasby

Harding

et al. 2005

Journal of Biological Chemistry

146

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Skeletal muscle is a major mass peripheral tissue that accounts for ϳ40% of total body weight and 50% of energy expenditure and is a primary site of glucose disposal and fatty acid oxidation. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. Excessive caloric intake is sensed by the brain and induces ␤-adrenergic receptor (␤-AR)-mediated adaptive thermogenesis. ␤-AR null mice develop severe obesity on a high fat diet. However, the target gene(s), target tissues(s), and molecular mechanism involved remain obscure. We observed that 30 -60 min of ␤-AR agonist (isoprenaline) treatment of C2C12 skeletal muscle cells strikingly activated (>100-fold) the expression of the mRNA encoding the nuclear hormone receptor, Nur77. In contrast, the expression of other nuclear receptors that regulate lipid and carbohydrate metabolism was not induced. Stable transfection of Nur77-specific small interfering RNAs (siNur77) into skeletal muscle cells repressed endogenous Nur77 mRNA expression. Moreover, we observed attenuation of gene and protein expression associated with the regulation of energy expenditure and lipid homeostasis, for example AMP-activated protein kinase ␥3, UCP3, CD36, adiponectin receptor 2, GLUT4, and caveolin-3. Attenuation of Nur77 expression resulted in decreased lipolysis. Finally, in concordance with the cell culture model, injection and electrotransfer of siNur77 into mouse tibialis cranialis muscle resulted in the repression of UCP3 mRNA expression. This study demonstrates regulatory cross-talk between the nuclear hormone receptor and ␤-AR signaling pathways. Moreover, it suggests Nur77 modulates the expression of genes that are key regulators of skeletal muscle lipid and energy homeostasis. In conclusion, we speculate that Nur77 agonists would stimulate lipolysis and increase energy expenditure in skeletal muscle and suggest selective activators of Nur77 may have therapeutic utility in the treatment of obesity.Obesity and fat deposition are primarily controlled by food intake and energy expenditure. Obesity has been linked to the development of heart disease, cancer, and stroke, the top three causes of death in the United States, and has recently been recognized by the World Health Organization as one of the top 10 global health problems. Moreover, obesity leads to metabolic syndrome X, a disorder that includes elevated levels of triglycerides and low density lipoprotein (bad) cholesterol, low levels of high density lipoprotein (good) cholesterol, impaired fasting glucose, and hypertension (2). These are cardiovascular risk factors for diseases such as atherosclerosis and type II diabetes. More than 65% of United States adults are overweight, and Ͼ30% of adults (greater than 61 million people) are clinically obese (1, 2).Diet, lifestyle, metabolism, and genetics are the most significant factors in controlling weight. Current obesity therapies perform modestly and are aimed at central appetite suppression and reduced fat absorption. Recent research su...

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“…The export of fatty acid anion thus permits continued rapid fatty acid oxidation in the face of an oversupply, while at the same time eliminating from the mitochondrion a potentially deleterious substrate, FFA, that it is unable to metabolize. Support for this hypothesis is drawn from the observation that thioesterase expression is increased in mice overexpressing UCP3 [80], and that there is a good correlation between thioesterase and UCP3 gene expression [81]. However, the various components of this model remain speculatory, and convincing evidence that a potential source of fatty acid anions in the mitochondrial matrix derived from the hydrolysis of acyl-CoA by an acyl-CoA thioesterase has not been reported.…”

Section: Ucp1-homologues: a Link With Regulation Of Lipids As Fuel Sumentioning

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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Overexpression of UCP-3 in Skeletal Muscle of Mice Results in Increased Expression of Mitochondrial Thioesterase mRNA

Cited by 67 publications

References 19 publications

Rev-erbβ Regulates the Expression of Genes Involved in Lipid Absorption in Skeletal Muscle Cells

Rev-erbβ Regulates the Expression of Genes Involved in Lipid Absorption in Skeletal Muscle Cells

Nur77 Regulates Lipolysis in Skeletal Muscle Cells

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

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