The Dipeptidyl Peptidase-4 Inhibitor Des-Fluoro-Sitagliptin Regulates Brown Adipose Tissue Uncoupling Protein Levels in Mice with Diet-Induced Obesity

To investigate the mechanisms underlying long-term resistance of the A/J mouse strain to diet-induced obesity, we studied, over a period of 4 wk, the expression of uncoupling proteins in brown adipose tissue and the expression of hypothalamic neuropeptides known to regulate energy homeostasis and then used microarray analysis to identify other potentially important hypothalamic peptides. Despite increased caloric intake after 2 days of high-fat feeding, body weights of A/J mice remained stable. On and after 1 wk of high-fat feeding, A/J mice adjusted their food intake to consume the same amount of calories as mice fed a low-fat diet; thus their body weight and insulin, corticosterone, free fatty acid, and glucose levels remained unchanged for 4 wk. We found no changes in hypothalamic expression of several orexigenic and/or anorexigenic neuropeptides known to play an important role in energy homeostasis for the duration of the study. Uncoupling protein-2 mRNA expression in brown adipose tissue, however, was significantly upregulated after 2 days of high-fat feeding and tended to remain elevated for the duration of the 4-wk study. Gene array analysis revealed that several genes are up- or downregulated in response to 2 days and 1 wk of high-fat feeding. Real-time PCR analysis confirmed that expression of the hypothalamic IL-1 pathway (IL-1β, IL-1 type 1 and 2 receptors, and PPM1b/PP2C-β, a molecule that has been implicated in the inhibition of transforming growth factor-β-activated kinase-1-mediated IL-1 action) is altered after 2 days, but not 1 wk, of high-fat feeding. The role of additional molecules discovered by microarray analysis needs to be further explored in the future.

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The Effect of Hyperbaric Therapy on Brown Adipose Tissue in Rats

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18179165 ◽

2021 ◽

Vol 18 (17) ◽

pp. 9165

Author(s):

Chang-Hyung Lee ◽

Young-A Choi ◽

Sung-Jin Heo ◽

Parkyong Song

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Cold Exposure ◽

Therapeutic Potential ◽

Uncoupling Protein ◽

Peroxisome Proliferator ◽

Sprague Dawley ◽

Protein Levels ◽

Brown Adipose ◽

Ucp1 Expression

Brown adipose tissue (BAT) plays an important role in thermogenic regulation, which contributes to alleviating diet-induced obesity through uncoupling protein 1 (UCP1) expression. While cold exposure and physical exercise are known to increase BAT development and UCP1 expression, the contribution of hyperbaric oxygen (HBO) therapy to BAT maturation remains largely unknown. Here, we show that HBO treatment sufficiently increases BAT volumes and thermogenic protein levels in Sprague-Dawley rats. Through 18F-FDG PET/CT analysis, we found that exposure to high-pressure oxygen (1.5–2.5 ATA) for 7 consecutive days increased radiolabeled glucose uptake and BAT development to an extent comparable to cold exposure. Consistent with BAT maturation, thermogenic protein levels, such as those of UCP1 and peroxisome proliferator-activated receptor γ coactivator 1α (PGC−1α), were largely increased by HBO treatment. Taken together, we suggest HBO therapy as a novel method of inducing BAT development, considering its therapeutic potential for the treatment of metabolic disorders.

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Evaluation of Active Brown Adipose Tissue by the Use of Hyperpolarized [1-13C]Pyruvate MRI in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms19092597 ◽

2018 ◽

Vol 19 (9) ◽

pp. 2597 ◽

Cited By ~ 5

Author(s):

Mette Riis-Vestergaard ◽

Peter Breining ◽

Steen Pedersen ◽

Christoffer Laustsen ◽

Hans Stødkilde-Jørgensen ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Cold Exposure ◽

Fdg Pet ◽

Metabolic Diseases ◽

Uncoupling Protein ◽

Protein Levels ◽

Positron Emission ◽

Brown Adipose

The capacity to increase energy expenditure makes brown adipose tissue (BAT) a putative target for treatment of metabolic diseases such as obesity. Presently, investigation of BAT in vivo is mainly performed by fluoro-d-glucose positron emission tomography (FDG PET)/CT. However, non-radioactive methods that add information on, for example, substrate metabolism are warranted. Thus, the aim of this study was to evaluate the potential of hyperpolarized [1-13C]pyruvate Magnetic Resonance Imaging (HP-MRI) to determine BAT activity in mice following chronic cold exposure. Cold (6 °C) and thermo-neutral (30 °C) acclimated mice were scanned with HP-MRI for assessment of the interscapular BAT (iBAT) activity. Comparable mice were scanned with the conventional method FDG PET/MRI. Finally, iBAT was evaluated for gene expression and protein levels of the specific thermogenic marker, uncoupling protein 1 (UCP1). Cold exposure increased the thermogenic capacity 3–4 fold (p < 0.05) as measured by UCP1 gene and protein analysis. Furthermore, cold exposure as compared with thermo-neutrality increased iBAT pyruvate metabolism by 5.5-fold determined by HP-MRI which is in good agreement with the 5-fold increment in FDG uptake (p < 0.05) measured by FDG PET/MRI. iBAT activity is detectable in mice using HP-MRI in which potential changes in intracellular metabolism may add useful information to the conventional FDG PET studies. HP-MRI may also be a promising radiation-free tool for repetitive BAT studies in humans.

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ACE2 exerts anti-obesity effect via stimulating brown adipose tissue and induction of browning in white adipose tissue

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00311.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. E1140-E1149 ◽

Cited By ~ 13

Author(s):

Yasuhiro Kawabe ◽

Jun Mori ◽

Hidechika Morimoto ◽

Mihoko Yamaguchi ◽

Satoshi Miyagaki ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

White Adipose Tissue ◽

Uncoupling Protein ◽

Ang Ii ◽

Angiotensin Converting Enzyme 2 ◽

Histone Deacetylase 3 ◽

Subcutaneous White Adipose Tissue ◽

Protein Levels ◽

Brown Adipose

The angiotensin II (ANG II)-ANG II type 1 receptor (AT1R) axis is a key player in the pathophysiology of obesity. Angiotensin-converting enzyme 2 (ACE2) counteracts the ANG II/AT1R axis via converting ANG II to angiotensin 1–7 (Ang 1–7), which is known to have an anti-obesity effect. In this study, we hypothesized that ACE2 exerts a strong anti-obesity effect by increasing Ang 1–7 levels. We injected intraperitoneally recombinant human ACE2 (rhACE2, 2.0 mg·kg−1·day−1) for 28 days to high-fat diet (HFD)-induced obesity mice. rhACE2 treatment decreased body weight and improved glucose metabolism. Furthermore, rhACE2 increased oxygen consumption and upregulated thermogenesis in HFD-fed mice. In the rhACE2 treatment group, brown adipose tissue (BAT) mass increased, accompanied with ameliorated insulin signaling and increased protein levels of uncoupling protein-1 (UCP-1) and PRD1-BF1-RIZ1 homologous domain containing 16. Importantly, subcutaneous white adipose tissue (sWAT) mass decreased, concomitant with browning, which was established by the increase of UCP-1 expression. The browning is the result of increased H3K27 acetylation via the downregulation of histone deacetylase 3 and increased H3K9 acetylation via upregulation of GCN5 and P300/CBP-associated factor. These results suggest that rhACE2 exerts anti-obesity effects by stimulating BAT and inducing browning in sWAT. ACE2 and the Ang 1–7 axis represent a potential therapeutic approach to prevent the development of obesity.

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Proglucagon-Derived Peptides, Glucose-Dependent Insulinotropic Polypeptide, and Dipeptidyl Peptidase-4-Mechanisms of Action in Adipose Tissue

Endocrinology ◽

10.1210/endocr/bqz029 ◽

2019 ◽

Vol 161 (1) ◽

Cited By ~ 1

Author(s):

Jacqueline L Beaudry ◽

Daniel J Drucker

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Energy Homeostasis ◽

Hormone Secretion ◽

Intestinal Failure ◽

Dipeptidyl Peptidase ◽

Receptor Expression ◽

Dipeptidyl Peptidase 4 ◽

Adipose Tissue Depots ◽

Brown Adipose

Abstract Proglucagon-derived peptides (PGDPs) and related gut hormones exemplified by glucose-dependent insulinotropic polypeptide (GIP) regulate energy disposal and storage through actions on metabolically sensitive organs, including adipose tissue. The actions of glucagon, glucagon-like peptide (GLP)-1, GLP-2, GIP, and their rate-limiting enzyme dipeptidyl peptidase-4, include direct and indirect regulation of islet hormone secretion, food intake, body weight, all contributing to control of white and brown adipose tissue activity. Moreover, agents mimicking actions of these peptides are in use for the therapy of metabolic disorders with disordered energy homeostasis such as diabetes, obesity, and intestinal failure. Here we highlight current concepts and mechanisms for direct and indirect actions of these peptides on adipose tissue depots. The available data highlight the importance of indirect peptide actions for control of adipose tissue biology, consistent with the very low level of endogenous peptide receptor expression within white and brown adipose tissue depots. Finally, we discuss limitations and challenges for the interpretation of available experimental observations, coupled to identification of enduring concepts supported by more robust evidence.

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Effects of stem cells from inducible brown adipose tissue on diet-induced obesity in mice

Scientific Reports ◽

10.1038/s41598-021-93224-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Enrique Calvo ◽

Noelia Keiran ◽

Catalina Núñez-Roa ◽

Elsa Maymó-Masip ◽

Miriam Ejarque ◽

...

Keyword(s):

Stem Cells ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Therapeutic Option ◽

Metabolic Activation ◽

Diet Induced Obesity ◽

Brown Adipose ◽

Obesity In Mice ◽

Treatment Of Obesity ◽

Visceral Adipose

AbstractAdipose-derived mesenchymal stem cells (ASCs) are a promising option for the treatment of obesity and its metabolic co-morbidities. Despite the recent identification of brown adipose tissue (BAT) as a potential target in the management of obesity, the use of ASCs isolated from BAT as a therapy for patients with obesity has not yet been explored. Metabolic activation of BAT has been shown to have not only thermogenic effects, but it also triggers the secretion of factors that confer protection against obesity. Herein, we isolated and characterized ASCs from the visceral adipose tissue surrounding a pheochromocytoma (IB-hASCs), a model of inducible BAT in humans. We then compared the anti-obesity properties of IB-hASCs and human ASCs isolated from visceral white adipose tissue (W-hASCs) in a murine model of diet-induced obesity. We found that both ASC therapies mitigated the metabolic abnormalities of obesity to a similar extent, including reducing weight gain and improving glucose tolerance. However, infusion of IB-hASCs was superior to W-hASCs in suppressing lipogenic and inflammatory markers, as well as preserving insulin secretion. Our findings provide evidence for the metabolic benefits of visceral ASC infusion and support further studies on IB-hASCs as a therapeutic option for obesity-related comorbidities.

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Expression of uncoupling protein mRNA in thermogenic or weakly thermogenic brown adipose tissue. Evidence for a rapid beta-adrenoreceptor-mediated and transcriptionally regulated step during activation of thermogenesis.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)66957-1 ◽

1986 ◽

Vol 261 (30) ◽

pp. 13905-13910

Author(s):

D Ricquier ◽

F Bouillaud ◽

P Toumelin ◽

G Mory ◽

R Bazin ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Uncoupling Protein ◽

Brown Adipose ◽

Uncoupling Protein Mrna

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A single mutation in uncoupling protein of rat brown adipose tissue mitochondria abolishes GDP sensitivity of H+ transport.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)37304-0 ◽

1994 ◽

Vol 269 (10) ◽

pp. 7435-7438

Author(s):

D.L. Murdza-Inglis ◽

M. Modriansky ◽

H.V. Patel ◽

G. Woldegiorgis ◽

K.B. Freeman ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Uncoupling Protein ◽

Single Mutation ◽

Brown Adipose

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TAF7L modulates brown adipose tissue formation

eLife ◽

10.7554/elife.02811 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 12

Author(s):

Haiying Zhou ◽

Bo Wan ◽

Ivan Grubisic ◽

Tommy Kaplan ◽

Robert Tjian

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Core Promoter ◽

Uncoupling Protein ◽

Dna Looping ◽

Chromatin Interactions ◽

Brown Adipose ◽

Important Regulator

Brown adipose tissue (BAT) plays an essential role in metabolic homeostasis by dissipating energy via thermogenesis through uncoupling protein 1 (UCP1). Previously, we reported that the TATA-binding protein associated factor 7L (TAF7L) is an important regulator of white adipose tissue (WAT) differentiation. In this study, we show that TAF7L also serves as a molecular switch between brown fat and muscle lineages in vivo and in vitro. In adipose tissue, TAF7L-containing TFIID complexes associate with PPARγ to mediate DNA looping between distal enhancers and core promoter elements. Our findings suggest that the presence of the tissue-specific TAF7L subunit in TFIID functions to promote long-range chromatin interactions during BAT lineage specification.

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