Mitochondrial biogenesis in brown adipose tissue is associated with differential expression of transcription regulatory factors

Introduction: In addition to its roles as a vascular signaling molecule, nitric oxide (NO) plays roles in metabolism. Mice deficient in eNOS are overweight and develop insulin resistance. It is not known whether the metabolic effects are due to primary roles of NO, or to increased visceral adiposity, leading to secondary metabolic changes. Hypothesis: We hypothesized that NO plays distinct and separable primary roles in white and brown adipogenesis, which underlie the effects on adiposity, energy metabolism, and expression of thermogenic genes. Methods: We exposed wild-type and mice carrying specific gain of function and loss of function eNOS mutations to cold at 4C for 48 hours and assessed expression of thermogenic gene programs in white and brown adipose tissue. To study cell autonomous effects, we differentiated adipocyte precursors from brown and white fat in the presence of NOS inhibitors and NO donors, as well as with siRNA to knockdown eNOS expression. Results: Cold exposure resulted in upregulation of the thermogenic gene program in brown adipose tissue. Animals carrying a gain of function mutation in eNOS showed increased UCP1 expression even without cold exposure. Induction of thermogenic genes was more pronounced in the animals with gain of function eNOS mutation. Differentiation of adipocyte precursors showed effects of eNOS on adipogenesis. Cells treated with the pharmacologic blockade (L-NAME and L-NA) as well as genetic knockdown (siRNA) showed dose-dependent inhibition of adipocyte differentiation. MitoTracker Red CMXRos staining showed that treatment with the NO donor SNAP increases mitochondrial biogenesis, while L-NAME decreases mitochondrial biogenesis. Conclusions: We show that eNOS-derived NO plays distinct and separable roles in white and brown adipogenesis. In brown adipocytes, eNOS regulates the expression of the thermogenic gene program, with upregulation of expression even without cold exposure, and greater increase in response to cold. In white adipocytes, eNOS-derived NO is required for adipocyte differentiation and mitochondrial biogenesis.

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Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet

The FASEB Journal ◽

10.1096/fj.11-200410 ◽

2012 ◽

Vol 26 (6) ◽

pp. 2351-2362 ◽

Cited By ~ 63

Author(s):

Shireesh Srivastava ◽

Yoshihiro Kashiwaya ◽

M. Todd King ◽

Ulrich Baxa ◽

Joseph Tam ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Mitochondrial Biogenesis ◽

Uncoupling Protein ◽

Uncoupling Protein 1 ◽

Brown Adipose ◽

Ketone Ester

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Reduction of body weight by rutin is associated with an increase of brown adipose tissue mitochondrial biogenesis in high‐fat diet induced obese rat (LB430)

The FASEB Journal ◽

10.1096/fasebj.28.1_supplement.lb430 ◽

2014 ◽

Vol 28 (S1) ◽

Author(s):

Sangjin Seo ◽

Soojung Oh ◽

Yoonjin Shin ◽

Sunyoon Jung ◽

Yangha Kim

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Mitochondrial Biogenesis ◽

High Fat Diet ◽

High Fat ◽

Brown Adipose

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Regulation of mitochondrial biogenesis in brown adipose tissue: nuclear respiratory factor-2/GA-binding protein is responsible for the transcriptional regulation of the gene for the mitochondrial ATP synthase β subunit

Biochemical Journal ◽

10.1042/bj3310121 ◽

1998 ◽

Vol 331 (1) ◽

pp. 121-127 ◽

Cited By ~ 39

Author(s):

Josep A. VILLENA ◽

Octavi VIÑAS ◽

Teresa MAMPEL ◽

Roser IGLESIAS ◽

Marta GIRALT ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Mitochondrial Biogenesis ◽

Adipocyte Differentiation ◽

Brown Adipocyte ◽

Brown Adipocytes ◽

Nuclear Respiratory Factor ◽

Brown Adipose ◽

Nuclear Respiratory Factor 2 ◽

Ga Binding Protein

The regulation of transcription of the gene for the β subunit of the FoF1 ATP synthase (ATPsynβ) in brown adipose tissue has been studied as a model to determine the molecular mechanisms for mitochondrial biogenesis associated with brown adipocyte differentiation. The expression of the ATPsynβ mRNA is induced during the brown adipocyte differentiation that occurs during murine prenatal development or when brown adipocytes differentiate in culture. This induction occurs in parallel with enhanced gene expression for other nuclear and mitochondrially-encoded components of the respiratory chain/oxidative phosphorylation system (OXPHOS). Transient transfection assays indicated that the expression of the ATPsynβ gene promoter is higher in differentiated HIB-1B brown adipocytes than in non-differentiated HIB-1B cells. A major transcriptional regulatory site was identified between nt -306 and -266 in the ATPsynβ promoter. This element has a higher enhancer capacity in differentiated brown adipocyte HIB-1B cells than in non-differentiated cells. Electrophoretic shift analysis indicated that Sp1and nuclear respiratory factor-2/GA-binding protein (NRF2/GABP) were the main nuclear proteins present in brown adipose tissue that bind this site. Double-point mutant analysis indicated a major role for the NRF2/GABP site in the enhancer capacity of this element in brown fat cells. It is proposed that NRF2/GABP plays a pivotal role in the co-ordinated enhancement of OXPHOS gene expression associated with mitochondrial biogenesis in brown adipocyte differentiation.

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Thyroid hormone (T3) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy

Autophagy ◽

10.1080/15548627.2018.1511263 ◽

2018 ◽

Vol 15 (1) ◽

pp. 131-150 ◽

Cited By ~ 29

Author(s):

Winifred W. Yau ◽

Brijesh K. Singh ◽

Ronny Lesmana ◽

Jin Zhou ◽

Rohit A. Sinha ◽

...

Keyword(s):

Adipose Tissue ◽

Thyroid Hormone ◽

Brown Adipose Tissue ◽

Mitochondrial Biogenesis ◽

Brown Adipose

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Modulation of aquaporin gene expression by n-3 long-chain PUFA lipid structures in white and brown adipose tissue from hamsters

British Journal Of Nutrition ◽

10.1017/s0007114518002519 ◽

2018 ◽

Vol 120 (10) ◽

pp. 1098-1106 ◽

Cited By ~ 3

Author(s):

Paula A. Lopes ◽

Rute Martins ◽

Inês Vieira da Silva ◽

Marta S. Madeira ◽

José A. M. Prates ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Differential Expression ◽

Mrna Levels ◽

Chain Pufa ◽

Epa And Dha ◽

Brown Adipose ◽

Long Chain ◽

Lipid Structures

AbstractEPA (20 : 5n-3) and DHA (22 : 6n-3) fatty acids have weight-reducing properties with physiological activity depending on their molecular structure – that is, as TAG or ethyl esters (EE). Aquaporins (AQP) are membrane protein channels recognised as important players in fat metabolism, but their differential expression in white adipose tissue (WAT) and brown adipose tissue (BAT), as well as their modulation by dietary n-3 long-chain PUFA (LCPUFA) such as EPA and DHA, has never been investigated. In this study, the transcriptional profiles of AQP3, AQP5, AQP7 and selected lipid markers of WAT (subcutaneous and visceral) and BAT (interscapular) from hamsters fed diets containing n-3 LCPUFA in different lipid structures such as fish oil (FO, rich in EPA and DHA in the TAG form) and FO-EE (rich in EPA and DHA in the EE form) were used and compared with linseed oil (LSO) as the reference group. A clear effect of fat depot was observed for AQP3 and leptin (LEP), with the lowest values of mRNA found in BAT relative to WAT. The opposite occurred for PPARα. AQP7 was affected by diet, with FO-fed hamsters having higher mRNA levels compared with LSO-fed hamsters. The relative gene expression of AQP5, adiponectin (ADIPO), GLUT4 and PPARγ was influenced by both fat tissue and diet. Taken together, our results revealed a differential expression profile of AQP and some markers of lipid metabolism in both WAT and BAT in response to feeding n-3 LCPUFA in two different structural formats: TAG v. EE.

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TRPV1 Activation Stimulates Brown Adipose Tissue Activation and Enhances Mitochondrial Biogenesis to Counteract Diet-Induced Obesity

Biophysical Journal ◽

10.1016/j.bpj.2016.11.2209 ◽

2017 ◽

Vol 112 (3) ◽

pp. 408a

Author(s):

Padmamalini Baskaran ◽

Zhaojie Zhang ◽

Baskaran Thyagarajan

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Mitochondrial Biogenesis ◽

Diet Induced Obesity ◽

Brown Adipose

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Triiodothyronine induces UCP-1 expression and mitochondrial biogenesis in human adipocytes

AJP Cell Physiology ◽

10.1152/ajpcell.00010.2011 ◽

2012 ◽

Vol 302 (2) ◽

pp. C463-C472 ◽

Cited By ~ 93

Author(s):

Joo-Young Lee ◽

Nobuyuki Takahashi ◽

Midori Yasubuchi ◽

Young-Il Kim ◽

Hikari Hashizaki ◽

...

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Mitochondrial Biogenesis ◽

Uncoupling Protein ◽

Human Adipose Tissue ◽

Energy Utilization ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Brown Adipose

Uncoupling protein (UCP)-1 expressed in brown adipose tissue plays an important role in thermogenesis. Recent data suggest that brown-like adipocytes in white adipose tissue (WAT) and skeletal muscle play a crucial role in the regulation of body weight. Understanding of the mechanism underlying the increase in UCP-1 expression level in these organs should, therefore, provide an approach to managing obesity. The thyroid hormone (TH) has profound effects on mitochondrial biogenesis and promotes the mRNA expression of UCP in skeletal muscle and brown adipose tissue. However, the action of TH on the induction of brown-like adipocytes in WAT has not been elucidated. Thus we investigate whether TH could regulate UCP-1 expression in WAT using multipotent cells isolated from human adipose tissue. In this study, triiodothyronine (T3) treatment induced UCP-1 expression and mitochondrial biogenesis, accompanied by the induction of the CCAAT/enhancer binding protein, peroxisome proliferator-activated receptor-γ coactivator-1α, and nuclear respiratory factor-1 in differentiated human multipotent adipose-derived stem cells. The effects of T3 on UCP-1 induction were dependent on TH receptor-β. Moreover, T3 treatment increased oxygen consumption rate. These findings indicate that T3 is an active modulator, which induces energy utilization in white adipocytes through the regulation of UCP-1 expression and mitochondrial biogenesis. Our findings provide evidence that T3 serves as a bipotential mediator of mitochondrial biogenesis.

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