Phytanic acid, a novel activator of uncoupling protein-1 gene transcription and brown adipocyte differentiation

Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a phytol-derived branched-chain fatty acid present in dietary products. Phytanic acid increased uncoupling protein-1 (UCP1) mRNA expression in brown adipocytes differentiated in culture. Phytanic acid induced the expression of the UCP1 gene promoter, which was enhanced by co-transfection with a retinoid X receptor (RXR) expression vector but not with other expression vectors driving peroxisome proliferator-activated receptor (PPAR) α, PPARγ or a form of RXR devoid of ligand-dependent sensitivity. The effect of phytanic acid on the UCP1 gene required the 5′ enhancer region of the gene and the effects of phytanic acid were mediated in an additive manner by three binding sites for RXR. Moreover, phytanic acid activates brown adipocyte differentiation: long-term exposure of brown preadipocytes to phytanic acid promoted the acquisition of the brown adipocyte morphology and caused a co-ordinate induction of the mRNAs for gene markers of brown adipocyte differentiation, such as UCP1, adipocyte lipid-binding protein aP2, lipoprotein lipase, the glucose transporter GLUT4 or subunit II of cytochrome c oxidase. In conclusion, phytanic acid is a natural product of phytol metabolism that activates brown adipocyte thermogenic function. It constitutes a potential nutritional signal linking dietary status to adaptive thermogenesis.

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Growth factor regulation of uncoupling protein-1 mRNA expression in brown adipocytes

AJP Cell Physiology ◽

10.1152/ajpcell.01396.2000 ◽

2002 ◽

Vol 282 (1) ◽

pp. C105-C112 ◽

Cited By ~ 22

Author(s):

Bibian García ◽

Maria-Jesús Obregón

Keyword(s):

Growth Factor ◽

Adipocyte Differentiation ◽

Uncoupling Protein ◽

Brown Adipocyte ◽

Mrna Levels ◽

Uncoupling Protein 1 ◽

Brown Adipocytes ◽

Proliferation And Differentiation ◽

Epidermal Growth ◽

Continuous Presence

To study the effect of the mitogens epidermal growth factor (EGF), acidic and basic fibroblast growth factors (aFGF and bFGF), and vasopressin on brown adipocyte differentiation, we analyzed the expression of uncoupling protein-1 (UCP-1) mRNA. Quiescent brown preadipocytes express high levels of UCP-1 mRNA in response to triiodothyronine (T3) and norepinephrine (NE). The addition of serum or the mitogenic condition aFGF + vasopressin + NE or EGF + vasopressin + NE decreases UCP-1 mRNA. A second addition of mitogens further decreases UCP-1 mRNA. Treatment with aFGF or bFGF alone increases UCP-1 mRNA, whereas the addition of EGF or vasopressin dramatically reduces UCP-1 mRNA levels. The continuous presence of T3 increases UCP-1 mRNA levels in cells treated with EGF, aFGF, or bFGF. The effect of T3 on the stimulation of DNA synthesis also was tested. T3 inhibits the mitogenic activity of aFGF and bFGF. In conclusion, mitogens like aFGF or bFGF allow brown adipocyte differentiation, whereas EGF and vasopressin inhibit the differentiation process. T3 behaves as an important hormone that regulates both brown adipocyte proliferation and differentiation.

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Dominant Negative Regulation by c-Jun of Transcription of the Uncoupling Protein-1 Gene through a Proximal cAMP-Regulatory Element: A Mechanism for Repressing Basal and Norepinephrine-Induced Expression of the Gene before Brown Adipocyte Differentiation

Molecular Endocrinology ◽

10.1210/mend.12.7.0137 ◽

1998 ◽

Vol 12 (7) ◽

pp. 1023-1037 ◽

Cited By ~ 35

Author(s):

Pilar Yubero ◽

MaJosé Barberá ◽

Rosa Alvarez ◽

Octavi Viñas ◽

Teresa Mampel ◽

...

Keyword(s):

Adipocyte Differentiation ◽

Uncoupling Protein ◽

Regulatory Element ◽

Negative Regulation ◽

Dominant Negative ◽

Brown Adipocyte ◽

Uncoupling Protein 1 ◽

Induced Expression

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SUN-587 IDH1-Dependent Alpha-KG Regulates Brown Fat Differentiation and Function by Modulating Histone Methylation

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1484 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Won Kon Kim ◽

Baek-Soo Han

Keyword(s):

Histone Methylation ◽

Molecular Mechanisms ◽

Adipocyte Differentiation ◽

Uncoupling Protein ◽

Ectopic Expression ◽

Brown Adipocyte ◽

Brown Adipocytes ◽

Brown Adipose ◽

And Function ◽

Brown Adipogenesis

Abstract Brown adipocytes play important roles in the regulation of energy homeostasis by uncoupling protein 1-mediated non-shivering thermogenesis. Recent studies suggest that brown adipocytes as novel therapeutic targets for combating obesity and associated diseases, such as type II diabetes. However, the molecular mechanisms underlying brown adipocyte differentiation and function are not fully understood. We employed previous findings obtained through proteomic studies performed to assess proteins displaying altered levels during brown adipocyte differentiation. Here, we performed assays to determine the functional significance of their altered levels during brown adipogenesis and development. We identified isocitrate dehydrogenase 1 (IDH1) as upregulated during brown adipocyte differentiation, with subsequent investigations revealing that ectopic expression of IDH1 inhibited brown adipogenesis, whereas suppression of IDH1 levels promoted differentiation of brown adipocytes. Additionally, Idh1 overexpression resulted in increased levels of intracellular α-ketoglutarate (α-KG) and inhibited the expression of genes involved in brown adipogenesis. Exogenous treatment with α-KG reduced brown adipogenesis during the early phase of differentiation, and ChIP analysis revealed that IDH1-mediated α-KG reduced trimethylation of histone H3 lysine 4 in the promoters of genes associated with brown adipogenesis. Furthermore, administration of α-KG decreased adipogenic gene expression by modulating histone methylation in brown adipose tissues of mice. These results suggested that the IDH1–α-KG axis plays an important role in regulating brown adipocyte differentiation and might represent a therapeutic target for treating metabolic diseases.

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Structural models of mitochondrial uncoupling proteins obtained in DPC micelles are not physiologically relevant for their uncoupling activity

10.1101/2020.07.20.195602 ◽

2020 ◽

Author(s):

Mathilde S. Piel ◽

Sandrine Masscheleyn ◽

Frédéric Bouillaud ◽

Karine Moncoq ◽

Bruno Miroux

Keyword(s):

Uncoupling Protein ◽

Brown Adipocyte ◽

Acid Oxidation ◽

Long Chain Fatty Acids ◽

Proton Conductance ◽

Uncoupling Protein 1 ◽

Inner Mitochondrial Membrane ◽

Mitochondrial Uncoupling ◽

Mitochondrial Uncoupling Proteins

AbstractUncoupling protein 1 (UCP1) is found in the inner mitochondrial membrane of brown adipocyte. In the presence of long-chain fatty acids (LCFA), UCP1 increases the proton conductance, which, in turn, increases fatty acid oxidation and energy release as heat. Several atomic models of UCP1 and UCP2 have been obtained by NMR in dodecylphosphocholine (DPC), a detergent known to inactivate UCP1. Based on NMR titration experiment on UCP1 with LCFA, it has been proposed that K56 and K269 are crucial for LCFA binding and UCP1 activation. Given the numerous controversies on the use of DPC for structure-function analyses of membrane proteins, we revisited those UCP1 mutants in a more physiological context by expressing them in the mitochondria of S. cerevisiae. Mitochondrial respiration, assayed on permeabilized spheroplasts, enables the determination of UCP1 activation and inhibition. The K56S, K269S and K56S/K269S mutants did not display any default in activation, which shows that the NMR experiments in DPC detergent are not relevant to understand UCP1 function.

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Synergism between cAMP and PPARγSignalling in the Initiation of UCP1 Gene Expression in HIB1B Brown Adipocytes

PPAR Research ◽

10.1155/2013/476049 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 10

Author(s):

H. Y. Chen ◽

Q. Liu ◽

A. M. Salter ◽

M. A. Lomax

Keyword(s):

Tandem Repeats ◽

Uncoupling Protein ◽

Brown Adipocyte ◽

Specific Gene ◽

Uncoupling Protein 1 ◽

Brown Adipocytes ◽

Promoter Construct ◽

Ucp1 Expression ◽

Signalling Systems ◽

Antagonist Gw9662

Expression of the brown adipocyte-specific gene, uncoupling protein 1 (UCP1), is increased by both PPARγstimulation and cAMP activation through their ability to stimulate the expression of the PPAR coactivator PGC1α. In HIB1B brown preadipocytes, combination of the PPARγagonist, rosiglitazone, and the cAMP stimulator forskolin synergistically increased UCP1 mRNA expression, but PGC1αexpression was only increased additively by the two drugs. The PPARγantagonist, GW9662, and the PKA inhibitor, H89, both inhibited UCP1 expression stimulated by rosiglitazone and forskolin but PGC1αexpression was not altered to the same extent. Reporter studies demonstrated that combined rosiglitazone and forskolin synergistically activated transcription from a full length 3.1 kbp UCP1 luciferase promoter construct, but the response was only additive and much reduced when a minimal 260 bp proximal UCP1 promoter was examined. Rosiglitazone and forskolin in combination were able to synergistically stimulate promoters comprising of tandem repeats of either PPREs or CREs. We conclude that rosiglitazone and forskolin act together to synergistically activate the UCP1 promoter directly rather than by increasing PGC1αexpression and by a mechanism involving cross-talk between the signalling systems regulating the CRE and PPRE on the promoters.

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Unexpected Deposition of Brown Fat in Mammary Gland During Postnatal Development

Molecular Endocrinology ◽

10.1210/me.2001-0337 ◽

2002 ◽

Vol 16 (11) ◽

pp. 2618-2627 ◽

Cited By ~ 29

Author(s):

Valérie Gouon-Evans ◽

Jeffrey W. Pollard

Keyword(s):

Mammary Gland ◽

Postnatal Development ◽

Mammary Epithelial Cells ◽

Uncoupling Protein ◽

Systemic Effect ◽

Brown Adipocyte ◽

Uncoupling Protein 1 ◽

Early Postnatal Development ◽

Adult Mice ◽

Brown Adipose

Abstract Mammary fat tissue is crucial for mammary ductal morphogenesis in both fetal and adult mice. There are two kinds of adipocytes, the energy-storing white and the energy-dissipating brown adipocyte. The precise identity of the types of adipocyte in the mammary gland has never been investigated but was always assumed to be only white fat. In this study, we show that both white and brown adipocytes are present in the postnatal mammary gland. The amount of brown adipose tissue (BAT) examined by histology and electron microscopy correlates with the transcript levels of uncoupling protein 1, which is a mitochondrial carrier expressed exclusively in BAT. Uncoupling protein 1 mRNAs are the highest during prepuberty, decrease upon puberty, and are finally undetectable in the adult mammary gland. The analysis of a BAT-depleted mouse model showed that depletion of mammary BAT in early postnatal development induces epithelial differentiation. Alveolar structures were formed along all ducts and were functional since they produced β-casein. However, mammary transplantation experiments indicated that a systemic effect was responsible for epithelium differentiation. Our data suggest that BAT negatively regulates the differentiation of mammary epithelial cells in a systemic manner during prepubertal ductal outgrowth.

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Ubc9 Impairs Activation of the Brown Fat Energy Metabolism Program in Human White Adipocytes

Molecular Endocrinology ◽

10.1210/me.2015-1084 ◽

2015 ◽

Vol 29 (9) ◽

pp. 1320-1333 ◽

Cited By ~ 4

Author(s):

Sean M. Hartig ◽

David A. Bader ◽

Kathleen V. Abadie ◽

Massoud Motamed ◽

Mark P. Hamilton ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Energy Storage ◽

Energy Metabolism ◽

Uncoupling Protein ◽

Critical Role ◽

Brown Fat ◽

Negative Regulator ◽

Brown Adipocyte ◽

Uncoupling Protein 1

Abstract Insulin resistance and type 2 diabetes mellitus (T2DM) result from an inability to efficiently store and catabolize surplus energy in adipose tissue. Subcutaneous adipocytes protect against insulin resistance and T2DM by coupling differentiation with the induction of brown fat gene programs for efficient energy metabolism. Mechanisms that disrupt these programs in adipocytes are currently poorly defined, but represent therapeutic targets for the treatment of T2DM. To gain insight into these mechanisms, we performed a high-throughput microscopy screen that identified ubiquitin carrier protein 9 (Ubc9) as a negative regulator of energy storage in human sc adipocytes. Ubc9 depletion enhanced energy storage and induced the brown fat gene program in human sc adipocytes. Induction of adipocyte differentiation resulted in decreased Ubc9 expression commensurate with increased brown fat gene expression. Thiazolidinedione treatment reduced the interaction between Ubc9 and peroxisome proliferator-activated receptor (PPAR)γ, suggesting a mechanism by which Ubc9 represses PPARγ activity. In support of this hypothesis, Ubc9 overexpression remodeled energy metabolism in human sc adipocytes by selectively inhibiting brown adipocyte-specific function. Further, Ubc9 overexpression decreased uncoupling protein 1 expression by disrupting PPARγ binding at a critical uncoupling protein 1 enhancer region. Last, Ubc9 is significantly elevated in sc adipose tissue isolated from mouse models of insulin resistance as well as diabetic and insulin-resistant humans. Taken together, our findings demonstrate a critical role for Ubc9 in the regulation of sc adipocyte energy homeostasis.

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