PPARs in the Control of Uncoupling Proteins Gene Expression

Uncoupling proteins (UCPs) are mitochondrial membrane transporters involved in the control of energy conversion in mitochondria. Experimental and genetic evidence relate dysfunctions of UCPs with metabolic syndrome and obesity. The PPAR subtypes mediate to a large extent the transcriptional regulation of the UCP genes, with a distinct relevance depending on the UCP gene and the tissue in which it is expressed. UCP1 gene is under the dual control of PPARγand PPARαin relation to brown adipocyte differentiation and lipid oxidation, respectively. UCP3 gene is regulated by PPARαand PPARδin the muscle, heart, and adipose tissues. UCP2 gene is also under the control of PPARs even in tissues in which it is the predominantly expressed UCP (eg, the pancreas and liver). This review summarizes the current understanding of the role of PPARs in UCPs gene expression in normal conditions and also in the context of type-2 diabetes or obesity.

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Pref-1 in brown adipose tissue: specific involvement in brown adipocyte differentiation and regulatory role of C/EBPδ

Biochemical Journal ◽

10.1042/bj20111714 ◽

2012 ◽

Vol 443 (3) ◽

pp. 799-810 ◽

Cited By ~ 22

Author(s):

Jordi Armengol ◽

Josep A. Villena ◽

Elayne Hondares ◽

María C. Carmona ◽

Hei Sook Sul ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Adipocyte Differentiation ◽

Proximal Promoter ◽

Brown Adipocyte ◽

Specific Marker ◽

Brown Adipose ◽

Factor C

Pref-1 (pre-adipocyte factor-1) is known to play a central role in regulating white adipocyte differentiation, but the role of Pref-1 in BAT (brown adipose tissue) has not been analysed. In the present study we found that Pref-1 expression is high in fetal BAT and declines progressively after birth. However, Pref-1-null mice showed unaltered fetal development of BAT, but exhibited signs of over-activation of BAT thermogenesis in the post-natal period. In C/EBP (CCAAT/enhancer-binding protein) α-null mice, a rodent model of impaired fetal BAT differentiation, Pref-1 was dramatically overexpressed, in association with reduced expression of the Ucp1 (uncoupling protein 1) gene, a BAT-specific marker of thermogenic differentiation. In brown adipocyte cell culture models, Pref-1 was mostly expressed in pre-adipocytes and declined with brown adipocyte differentiation. The transcription factor C/EBPδ activated the Pref-1 gene transcription in brown adipocytes, through binding to the proximal promoter region. Accordingly, siRNA (small interfering RNA)-induced C/EBPδ knockdown led to reduced Pref-1 gene expression. This effect is consistent with the observed overexpression of C/EBPδ in C/EBPα-null BAT and high expression of C/EBPδ in brown pre-adipocytes. Dexamethasone treatment of brown pre-adipocytes suppressed Pref-1 down-regulation occurring throughout the brown adipocyte differentiation process, increased the expression of C/EBPδ and strongly impaired expression of the thermogenic markers UCP1 and PGC-1α [PPARγ (peroxisome-proliferator-activated receptor γ) co-activator-α]. However, it did not alter normal fat accumulation or expression of non-BAT-specific genes. Collectively, these results specifically implicate Pref-1 in controlling the thermogenic gene expression program in BAT, and identify C/EBPδ as a novel transcriptional regulator of Pref-1 gene expression that may be related to the specific role of glucocorticoids in BAT differentiation.

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Effects of BMP7 produced by group 2 innate lymphoid cells on adipogenesis

International Immunology ◽

10.1093/intimm/dxaa013 ◽

2020 ◽

Vol 32 (6) ◽

pp. 407-419 ◽

Cited By ~ 1

Author(s):

Yurina Miyajima ◽

Kafi N Ealey ◽

Yasutaka Motomura ◽

Miho Mochizuki ◽

Natsuki Takeno ◽

...

Keyword(s):

Lipid Accumulation ◽

Adipocyte Differentiation ◽

Allergic Inflammation ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Brown Adipocytes ◽

Morphogenetic Protein ◽

Group 2

Abstract Group 2 innate lymphoid cells (ILC2s) are type 2 cytokine-producing cells that have important roles in helminth infection and allergic inflammation. ILC2s are tissue-resident cells, and their phenotypes and roles are regulated by tissue-specific environmental factors. While the role of ILC2s in the lung, intestine and bone marrow has been elucidated in many studies, their role in adipose tissues is still unclear. Here, we report on the role of ILC2-derived bone morphogenetic protein 7 (BMP7) in adipocyte differentiation and lipid accumulation. Co-culture of fat-derived ILC2s with pluripotent mesenchymal C3H10T1/2 cells and committed white preadipocyte 3T3-L1 cells resulted in their differentiation to adipocytes and induced lipid accumulation. Co-culture experiments using BMP7-deficient ILC2s revealed that BMP7, produced by ILC2s, induces differentiation into brown adipocytes. Our results demonstrate that BMP7, produced by ILC2s, affects adipocyte differentiation, particularly in brown adipocytes.

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Adipocyte PU.1 knockout promotes insulin sensitivity in HFD-fed obese mice

Scientific Reports ◽

10.1038/s41598-019-51196-8 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Denise E. Lackey ◽

Felipe C. G. Reis ◽

Roi Isaac ◽

Rizaldy C. Zapata ◽

Dalila El Ouarrat ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Target Genes ◽

Obese Mice ◽

Tissue Macrophage

Abstract Insulin resistance is a key feature of obesity and type 2 diabetes. PU.1 is a master transcription factor predominantly expressed in macrophages but after HFD feeding PU.1 expression is also significantly increased in adipocytes. We generated adipocyte specific PU.1 knockout mice using adiponectin cre to investigate the role of PU.1 in adipocyte biology, insulin and glucose homeostasis. In HFD-fed obese mice systemic glucose tolerance and insulin sensitivity were improved in PU.1 AKO mice and clamp studies indicated improvements in both adipose and liver insulin sensitivity. At the level of adipose tissue, macrophage infiltration and inflammation was decreased and glucose uptake was increased in PU.1 AKO mice compared with controls. While PU.1 deletion in adipocytes did not affect the gene expression of PPARg itself, we observed increased expression of PPARg target genes in eWAT from HFD fed PU.1 AKO mice compared with controls. Furthermore, we observed decreased phosphorylation at serine 273 in PU.1 AKO mice compared with fl/fl controls, indicating that PPARg is more active when PU.1 expression is reduced in adipocytes. Therefore, in obesity the increased expression of PU.1 in adipocytes modifies the adipocyte PPARg cistrome resulting in impaired glucose tolerance and insulin sensitivity.

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257. Addition of glycine to vitrification solutions protects oocyte and embryo physiology and health

Reproduction Fertility and Development ◽

10.1071/srb05abs257 ◽

2005 ◽

Vol 17 (9) ◽

pp. 104

Author(s):

K. S. Cashman ◽

D. A. Froiland ◽

J. G. Thompson ◽

M. Lane

Keyword(s):

Gene Expression ◽

Membrane Potential ◽

Mitochondrial Membrane ◽

Multiple Comparisons ◽

Developmental Competence ◽

Rt Pcr ◽

Blastocyst Development ◽

Pixel Intensity ◽

Mitochondrial Distribution

Cryopreservation procedures for oocytes result in a significant reduction in viability. Although cryopreservation procedures cause dehydration and therefore osmotic stress, the role of osmolytes in solutions has not been considered and they have therefore not been included for routine use. The aim of this study was to assess the effects of the addition of the osmolyte glycine to vitrification solutions on the health and developmental competence of mouse oocytes. Oocytes were collected from F1 female mice and cryopreserved using cryoloop vitrification with or without glycine, with fresh oocytes examined as controls (n = 2086). Mitochondrial distribution and membrane potential as well as the morphology of the spindles and chromosomes were assessed. Oocytes were fertilised to assess their ability to develop into blastocysts, which were then assessed for their expression of Glut1, Glut3 and IGF2 by real-time RT-PCR. Statistical analysis was performed using a generalised linear model followed by multiple comparisons using an LSD test. Vitrification without glycine perturbed mitochondrial distribution (mean pixel intensity of outer region:inner region, 1.58±0.20, P<0.01) and mitochondrial membrane potential (mean pixel intensity 0.56±0.01, P<0.01) compared to control oocytes (2.34±0.24 and 0.52±0.01, respectively). The addition of glycine prevented these changes (1.97±0.16 and 0.53±0.01, respectively). Vitrification without glycine resulted in 52% of spindles and chromosomes appearing normal while this was increased to 69% with the addition of glycine, however in both treatments these abnormalities appeared to recover after culture for 2 h. Vitrification did not affect fertilisation and blastocyst development however expression of Glut3 was decreased 2.9 fold in blastocysts resulting from oocytes vitrified in the absence of glycine (P<0.01). The data presented suggests that the addition of glycine results in fewer perturbations in oocyte physiology and gene expression of the subsequent blastocysts and should therefore be considered for routine inclusion in solutions for the cryopreservation of oocytes.

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Induction of Type 2 Iodothyronine Deiodinase in the Mediobasal Hypothalamus by Bacterial Lipopolysaccharide: Role of Corticosterone

Endocrinology ◽

10.1210/en.2007-1697 ◽

2008 ◽

Vol 149 (5) ◽

pp. 2484-2493 ◽

Cited By ~ 25

Author(s):

Edith Sánchez ◽

Praful S. Singru ◽

Csaba Fekete ◽

Ronald M. Lechan

Keyword(s):

Gene Expression ◽

Third Ventricle ◽

Significant Rise ◽

Bacterial Lipopolysaccharide ◽

Mediobasal Hypothalamus ◽

Sprague Dawley ◽

Iodothyronine Deiodinase ◽

Circulating Levels

To determine whether endotoxin-induced activation of type 2 iodothyronine deiodinase (D2) in the mediobasal hypothalamus is dependent on circulating levels of corticosterone, the effect of bacterial lipopolysaccharide (LPS) on D2 gene expression was studied in adrenalectomized, corticosterone-clamped adult, male, Sprague Dawley rats. In sham-adrenalectomized animals, LPS (250 μg/100 g body weight) increased circulating levels of corticosterone and IL-6, as well as tanycyte D2 mRNA in the mediobasal hypothalamus. Adrenalectomized, corticosterone-clamped animals showed no significant rise in corticosterone after LPS, compared with saline-treated controls but increased IL-6 levels and tanycyte D2 mRNA similar to LPS-treated sham controls. To further clarify the potential role of corticosterone in the regulation of D2 gene expression by LPS, animals were administered high doses of corticosterone to attain levels similar to that observed in the LPS-treated group. No significant increase in D2 mRNA was observed in the mediobasal hypothalamus with the exception of a small subpopulation of cells in the lateral walls of the third ventricle. These data indicate that the LPS-induced increase in D2 mRNA in the mediobasal hypothalamus is largely independent of circulating corticosterone and indicate that mechanisms other than adrenal activation are involved in the regulation of most tanycyte D2-expressing cells by endotoxin.

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Expression of GPR43 in Brown Adipogenesis Is Enhanced by Rosiglitazone and Controlled by PPARγ/RXR Heterodimerization

PPAR Research ◽

10.1155/2018/1051074 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Jiamiao Hu ◽

Arong Zhou ◽

Peter C. K. Cheung ◽

Baodong Zheng ◽

Shaoxiao Zeng ◽

...

Keyword(s):

Adipocyte Differentiation ◽

Late Phase ◽

Short Chain Fatty Acids ◽

Brown Adipocyte ◽

Biological Functions ◽

Brown Adipocytes ◽

White Adipocytes ◽

G Protein Coupled ◽

Brown Adipogenesis

GPR43, a G-protein coupled receptor recognizing short-chain fatty acids, has been reported to participate in many biological functions of white adipocytes, such as adipogenesis and lipolysis. However, the functional role of GPR43 in brown adipocytes is still not clear. In this study, we investigated the effects of the PPARγ agonist rosiglitazone on GPR43 expression in brown adipogenesis. The results demonstrated that GPR43 was expressed during the late phase of brown adipocyte differentiation, which could be further augmented by adipogenic agent rosiglitazone treatment. The PPARγ/RXR heterodimerization was found to be the key transcription factor for this enhancing effect of rosiglitazone on GPR43 expression. Taken together, these results suggested GPR43 levels might be regulated by PPARγ-activated events during brown adipocytes differentiation and reflect the adipogenesis status of brown adipocytes.

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Role of Ubiquilins for Brown Adipocyte Proteostasis and Thermogenesis

Frontiers in Endocrinology ◽

10.3389/fendo.2021.739021 ◽

2021 ◽

Vol 12 ◽

Author(s):

Carolin Muley ◽

Stefan Kotschi ◽

Alexander Bartelt

Keyword(s):

Gene Expression ◽

Quality Control ◽

Adipose Tissue ◽

Cold Exposure ◽

Protein Quality ◽

Brown Adipocyte ◽

Brown Adipocytes ◽

Brown Adipose ◽

Shivering Thermogenesis

The acclimatization of brown adipose tissue (BAT) to sustained cold exposure requires an adaptive increase in proteasomal protein quality control. Ubiquilins represent a recently identified family of shuttle proteins with versatile functions in protein degradation, such as facilitating substrate targeting and proteasomal degradation. However, whether ubiquilins participate in brown adipocyte function has not been investigated so far. Here, we determine the role of ubiquilins for proteostasis and non-shivering thermogenesis in brown adipocytes. We found that Ubqln1, 2 and 4 are highly expressed in BAT and their expression was induced by cold and proteasomal inhibition. Surprisingly, silencing of ubiquilin gene expression (one or multiple in combinations) did not lead to aggravated ER stress or inflammation. Moreover, ubiquitin level and proteasomal activity under basal conditions were not impacted by loss of ubiquilins. Also, non-shivering thermogenesis measured by norepinephrine-induced respiration remained intact after loss of ubiquilins. In conclusion, ubiquilin proteins are highly abundant in BAT and regulated by cold, but they are dispensable for brown adipocyte proteostasis and thermogenesis.

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Genetic variants of uncoupling proteins-2 and -3 in relation to maximal oxygen uptake in different sports.

Acta Biochimica Polonica ◽

10.18388/abp.2013_1953 ◽

2013 ◽

Vol 60 (1) ◽

Cited By ~ 3

Author(s):

Joanna Holdys ◽

Piotr Gronek ◽

Jakub Kryściak ◽

Daniel Stanisławski

Keyword(s):

Oxygen Uptake ◽

Maximal Oxygen Uptake ◽

Genetic Variants ◽

Untranslated Region ◽

Heat Energy ◽

Uncoupling Proteins ◽

Atp Production ◽

Ucp3 Gene ◽

Ucp2 Gene ◽

The University

Uncoupling proteins 2 and 3 (UCP2 and UCP3) as mitochondrial electron transporters are involved in regulation of ATP production and energy dissipation as heat. Energy efficiency plays an important role in physical performance, especially in aerobic fitness. The aim of this study was to examine the association between maximal oxygen uptake and genetic variants of the UCP2 and UCP3 genes. The studies were carried out in a group of 154 men and 85 women, professional athletes representing various sports and fitness levels and students of the University of Physical Education in Poznań. Physiological and molecular procedures were used, i.e. direct measurement of maximum oxygen uptake (VO₂max) and analysis of an insertion/deletion (I/D) polymorphism in the 3'untranslated region of exon 8 of the UCP2 gene and a C>T substitution in exon 5 (Y210Y) of the UCP3 gene. No statistically significant associations were found, only certain trends. Insertion allele (I) of the I/D UCP2 and the T allele of the UCP3 gene were favourable in obtaining higher VO₂max level and might be considered as endurance-related alleles.

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Synaptosomal Protein of 25 kDa (Snap25) Polymorphisms Associated with Glycemic Parameters in Type 2 Diabetes Patients

Journal of Diabetes Research ◽

10.1155/2016/8943092 ◽

2016 ◽

Vol 2016 ◽

pp. 1-4 ◽

Cited By ~ 5

Author(s):

Nasser M. Al-Daghri ◽

Andrea S. Costa ◽

Majed S. Alokail ◽

Milena Zanzottera ◽

Amal M. Alenad ◽

...

Keyword(s):

Gene Expression ◽

Type 2 Diabetes ◽

Genomic Dna ◽

Fasting Glucose ◽

Glucose Levels ◽

Intron 1 ◽

Hba1c Levels

A possible role ofSnap25polymorphisms in type 2 diabetes mellitus (T2DM) was evaluated by analyzing three SNPs within intron 1 in a region known to affect the gene expression in vitro. Genomic DNA from 1019 Saudi individuals (489 confirmed T2DM and 530 controls) was genotyped for SNPs rs363039, rs363043, and rs363050 inSnap25using the TaqMan Genotyping Assay. Significantly higher levels of fasting glucose and HbA1c were detected in T2DM patients carrying the rs363050 (AG/GG) genotypes compared to the (AA) genotype (f=4.41,df=1, andp=0.03andf=5.31,df=1, andp=0.03, resp.). In these same patients, insulin levels were significantly decreased compared to the (AA) individuals (f=7.29,df=1, andp=0.009). Significant associations were detected between rs363050 (AG/GG) genotypes and increasing fasting glucose levels (p=0.01and OR: 1.05), HbA1c levels (OR: 5.06 andp=0.02), and lower insulinemia (p=0.03and OR: 0.95) in T2DM patients. The minorSnap25rs363050 (G) allele, which results in a reduced expression ofSnap25, is associated with altered glycemic parameters in T2DM possibly because of reduced functionality in the exocytotic machinery leading to suboptimal release of insulin.

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