Beiging of white adipose tissue as a therapeutic strategy for weight loss in humans

2017 ◽  
Vol 31 (2) ◽  
Author(s):  
Baskaran Thyagarajan ◽  
Michelle T. Foster
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
White Adipose Tissue ◽  
Fat Utilization ◽  
Drug Molecules ◽  
Brown Adipose ◽  
And Storage

AbstractAn imbalance between energy intake and expenditure leads to obesity. Adiposity associated with obesity progressively causes inflammation, type 2 diabetes, hypertension, hyperlipidemia and cardiovascular disease. Excessive dietary intake of fat results in its accumulation and storage in the white adipose tissue (WAT), whereas energy expenditure by fat utilization and oxidation predominately occurs in the brown adipose tissue (BAT). Recently, the presence of a third type of fat, referred to as beige or brite (brown in white), has been recognized in certain kinds of WAT depots. It has been suggested that WAT can undergo the process of browning in response to stimuli that induce and enhance the expression of thermogenes characteristic of those typically associated with brown fat. The resultant beige or brite cells enhance energy expenditure by reducing lipids stored within adipose tissue. This has created significant excitement towards the development of a promising strategy to induce browning/beiging in WAT to combat the growing epidemic of obesity. This review systematically describes differential locations and functions of WAT and BAT, mechanisms of beiging of WAT and a concise analysis of drug molecules and natural products that activate the browning phenomenon in vitro and in vivo. This review also discusses potential approaches for targeting WAT with compounds for site-specific beiging induction. Overall, there are numerous mechanisms that govern browning of WAT. There are a variety of newly identified targets whereby potential molecules can promote beiging of WAT and thereby combat obesity.

Overexpression of a short human seipin/BSCL2 isoform in mouse adipose tissue results in mild lipodystrophy

2012 ◽  
Vol 302 (6) ◽  
pp. E705-E713 ◽  
Author(s):  
Xin Cui ◽  
Yuhui Wang ◽  
Lingjun Meng ◽  
Weihua Fei ◽  
Jingna Deng ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Transgenic Mice ◽  
White Adipose Tissue ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Triacylglycerol Content ◽  
Adipocyte Development

Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is a recessive disorder characterized by an almost complete loss of adipose tissue, insulin resistance, and fatty liver. BSCL2 is caused by loss-of-function mutations in the BSCL2/seipin gene, which encodes seipin. The essential role for seipin in adipogenesis has recently been established both in vitro and in vivo. However, seipin is highly upregulated at later stages of adipocyte development, and its role in mature adipocytes remains to be elucidated. We therefore generated transgenic mice overexpressing a short isoform of human BSCL2 gene (encoding 398 amino acids) using the adipocyte-specific aP2 promoter. The transgenic mice produced ∼150% more seipin than littermate controls in white adipose tissue. Surprisingly, the increased expression of seipin markedly reduced the mass of white adipose tissue and the size of adipocytes and lipid droplets. This may be due in part to elevated lipolysis rates in the transgenic mice. Moreover, there was a nearly 50% increase in the triacylglycerol content of transgenic liver. These results suggest that seipin promotes the differentiation of preadipocytes but may inhibit lipid storage in mature adipocytes.

scholarly journals The Role of Peptide Hormones Discovered in the 21st Century in the Regulation of Adipose Tissue Functions

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 756
Author(s):  
Paweł A. Kołodziejski ◽  
Ewa Pruszyńska-Oszmałek ◽  
Tatiana Wojciechowicz ◽  
Maciej Sassek ◽  
Natalia Leciejewska ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
21St Century ◽  
Energy Homeostasis ◽  
Peptide Hormones ◽  
Brown Adipose ◽  
Homeostasis Regulation

Peptide hormones play a prominent role in controlling energy homeostasis and metabolism. They have been implicated in controlling appetite, the function of the gastrointestinal and cardiovascular systems, energy expenditure, and reproduction. Furthermore, there is growing evidence indicating that peptide hormones and their receptors contribute to energy homeostasis regulation by interacting with white and brown adipose tissue. In this article, we review and discuss the literature addressing the role of selected peptide hormones discovered in the 21st century (adropin, apelin, elabela, irisin, kisspeptin, MOTS-c, phoenixin, spexin, and neuropeptides B and W) in controlling white and brown adipogenesis. Furthermore, we elaborate how these hormones control adipose tissue functions in vitro and in vivo.

Brown and white adipose tissue metabolism in cold-exposed rats

1964 ◽  
Vol 207 (4) ◽  
pp. 840-844 ◽  
Author(s):  
G. Steiner ◽  
G. F. Cahill
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
White Adipose Tissue ◽  
Neutral Lipids ◽  
Adipose Tissue Metabolism ◽  
Epididymal Fat ◽  
Brown Adipose ◽  
Fat Pads

Brown and white adipose tissue from rats exposed to 5 C for 9 days has been studied with reference to its composition and handling of glucose-U-C14 in vivo and in vitro. Brown adipose tissue from cold-exposed rats demonstrated a decreased lipid content per milligram nitrogen, due mainly to decreased amounts of neutral lipid with little change in phospholipid. The incorporation of glucose into neutral lipids, glyceride glycerol, and fatty acids was increased in vivo and in vitro. There was increased incorporation into CO2 in vitro and there was no change in glucose conversion to phospholipid in vivo. No changes in any of these were noted in epididymal fat pads. These findings suggest that cold exposure leads to alterations in carbohydrate metabolism and lipogenesis in brown adipose tissue but not in epididymal fat pads. The possible role in thermogenesis is discussed.

scholarly journals Characterization of Viral Insulin-Like Peptides Reveals Unique White Adipose Tissue Specific Characteristics

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A437-A438
Author(s):  
Martina Chrudinova ◽  
Moreau Francois ◽  
Hye Lim Noh ◽  
Terezie Panikova ◽  
Lenka Zakova ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Uptake ◽  
Human Insulin ◽  
White Adipose Tissue ◽  
Glucose Transporter ◽  
Single Chain ◽  
Insulin Superfamily ◽  
Brown Adipose

Abstract The members of the insulin superfamily are well conserved across the evolution tree. We recently showed that four viruses in the Iridoviridae family possess genes that share high similarity with human insulin and IGF-1. By chemically synthesizing single chain (sc, IGF-1 like) forms of these viral insulin/IGF-1 like peptides (VILPs), we previously showed that sc VILPs have insulin/IGF properties in vitro and in vivo. However, characteristics of double chain (dc, insulin-like) VILPs remain unknown. In this study, we characterized dc forms of VILPs for Grouper iridovirus (GIV), Singapore grouper iridovirus (SGIV) and Lymphocystis disease virus-1 (LCDV-1). We showed that GIV and SGIV dcVILPs bind to both isoforms of human insulin receptor (IR-A, IR-B) and they bind to IGF-1R with a higher affinity than human insulin. These dcVILPs stimulate receptor phosphorylation and post-receptor signaling in vitro and in vivo. LCDV-1 dcVILP stimulated a weak response in in vitro signaling experiments, although we could not determine binding competition. Both GIV and SGIV dcVILPs stimulated glucose uptake in mice. In vivo infusion experiments in awake mice revealed that while insulin (2.5 mU/kg/min) and GIV dcVILP (125 mU/kg/min) stimulate a comparable glucose uptake in heart, skeletal muscle and brown adipose tissue, GIV dcVILP stimulates ~2 fold higher glucose uptake in white adipose tissue (WAT) compared to insulin. This is due to increased Akt phosphorylation and glucose transporter type 4 (GLUT4) expression compared to insulin specifically in WAT. Taken together, these results show that dc GIV and SGIV dcVILPs are active members of the insulin superfamily with unique characteristics. This observation evokes questions about their potential roles in human disease including diabetes and cancer. Elucidating the mechanism of tissue specificity for GIV dcVILP will help us to better understand insulin action and design new analogues that specifically target the tissues.

scholarly journals Characterization of Viral Insulins Reveals White Adipose Tissue Specific Effects in Mice

2020 ◽  
Author(s):  
Martina Chrudinová ◽  
Francois Moreau ◽  
Hye Lim Noh ◽  
Terezie Páníková ◽  
Lenka Žáková ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Uptake ◽  
Human Insulin ◽  
White Adipose Tissue ◽  
Glucose Transporter ◽  
Single Chain ◽  
Lymphocystis Disease Virus ◽  
Brown Adipose

ABSTRACTMembers of the insulin/IGF superfamily are well conserved across the evolutionary tree. We recently showed that four viruses in the Iridoviridae family possess genes that encode proteins highly homologous to human insulin/IGF-1. Using chemically synthesized single chain (sc), i.e. IGF-1-like, forms of the viral insulin/IGF-1 like peptides (VILPs), we previously showed that they can stimulate human receptors. Because these peptides possess potential cleavage sites to form double chain (dc), i.e. more insulin-like, VILPs, in this study, we have characterized dc forms of VILPs for Grouper iridovirus (GIV), Singapore grouper iridovirus (SGIV) and Lymphocystis disease virus-1 (LCDV-1). GIV and SGIV dcVILPs bind to both isoforms of human insulin receptor (IR-A, IR-B) and to the IGF1R, and for the latter show higher affinity than human insulin. These dcVILPs stimulate IR and IGF1R phosphorylation and post-receptor signaling in vitro and in vivo. Both GIV and SGIV dcVILPs stimulate glucose uptake in mice. In vivo infusion experiments in awake mice revealed that while insulin (0.015 nmol/kg/min) and GIV dcVILP (0.75nmol/kg/min) stimulated a comparable glucose uptake in heart, skeletal muscle and brown adipose tissue, GIV dcVILP stimulated ~2 fold higher glucose uptake in white adipose tissue (WAT) compared to insulin. This was associated with increased Akt phosphorylation and glucose transporter type 4 (GLUT4) gene expression compared to insulin. Taken together, these results show that GIV and SGIV dcVILPs are active members of the insulin superfamily with unique characteristics. Elucidating the mechanism of tissue specificity for GIV dcVILP will help us to better understand insulin action, design new analogues that specifically target the tissues, and provide new insights into their potential role in disease.

scholarly journals Androgens modulate glucocorticoid receptor activity in adipose tissue and liver

2019 ◽  
Vol 240 (1) ◽  
pp. 51-63 ◽  
Author(s):  
Dieuwertje C E Spaanderman ◽  
Mark Nixon ◽  
Jacobus C Buurstede ◽  
Hetty H C M Sips ◽  
Maaike Schilperoort ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Glucocorticoid Receptors ◽  
Transcriptional Response ◽  
Tissue Expression ◽  
Brown Adipocytes ◽  
Glucocorticoid Signaling ◽  
Brown Adipose

Glucocorticoid signaling is context dependent, and in certain scenarios, glucocorticoid receptors (GRs) are able to engage with other members of the nuclear receptor subfamily. Glucocorticoid signaling can exert sexually dimorphic effects, suggesting a possible interaction with androgen sex hormones. We therefore set out to determine the crosstalk between glucocorticoids and androgens in metabolic tissues including white adipose tissue, liver and brown adipose tissue. Thereto we exposed male C57BL/6J mice to elevated levels of corticosterone in combination with an androgen receptor (AR) agonist or an AR antagonist. Systemic and local glucocorticoid levels were determined by mass spectrometry, and tissue expression of glucocorticoid-responsive genes and protein was measured by RT-qPCR and Western blot, respectively. To evaluate crosstalk in vitro, cultured white and brown adipocytes were exposed to a combination of corticosterone and an AR agonist. We found that AR agonism potentiated transcriptional response to GR in vitro in white and brown adipocytes and in vivo in white and brown adipose tissues. Conversely, AR antagonism substantially attenuated glucocorticoid signaling in white adipose tissue and liver. In white adipose tissue, this effect could partially be attributed to decreased 11B-hydroxysteroid dehydrogenase type 1-mediated glucocorticoid regeneration upon AR antagonism. In liver, attenuated GR activity was independent of active glucocorticoid ligand levels. We conclude that androgen signaling modulates GR transcriptional output in a tissue-specific manner.

scholarly journals Brown and beige adipose tissue regulate systemic metabolism to resist diet-induced obesity through metabolite signals in an inter-organ signaling axis

2020 ◽  
Author(s):  
Anna Whitehead ◽  
Fynn Krause ◽  
Amy Moran ◽  
Jason Scragg ◽  
Ben McNally ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Brown Adipocyte ◽  
Oxidative Energy Metabolism ◽  
Obesity And Diabetes ◽  
Brown Adipose ◽  
Endocrine Organs ◽  
Beige Adipose Tissue

Abstract Brown and beige adipose tissue are emerging as distinct endocrine organs. These tissues are functionally associated with skeletal muscle, adipose tissue metabolism and systemic energy expenditure, suggesting an inter-organ signaling network. Using a metabolomic approach we identified 3-methyl-2-oxovaleric acid (MOVA), 5-oxoproline (5OP), and β-hydroxyisobutyric acid (BHIBA) as small molecule metabokines synthesized in browning adipocytes and secreted via monocarboxylate transporters. MOVA, 5OP and BHIBA induce a brown adipocyte-specific phenotype in white adipocytes and mitochondrial oxidative energy metabolism in skeletal myocytes both in vitro and in vivo. MOVA and 5OP signal through cAMP-PKA-p38 MAPK and BHIBA via mTOR. These metabolites reduce adiposity, increase energy expenditure and improve glucose and insulin homeostasis in mouse models of obesity and diabetes. In humans, plasma and adipose tissue MOVA, 5OP and BHIBA concentrations are correlated with markers of adipose browning and inversely associated with BMI. Our findings identify beige adipose-brown adipose-muscle physiological metabokine crosstalk.

scholarly journals TAF7L modulates brown adipose tissue formation

eLife ◽  
2014 ◽  
Vol 3 ◽  
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.

scholarly journals JAZF1 heterozygous knockout mice show altered adipose development and metabolism

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jain Jeong ◽  
Soyoung Jang ◽  
Song Park ◽  
Wookbong Kwon ◽  
Si-Yong Kim ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Knockout Mice ◽  
Metabolic Disorders ◽  
Adipocyte Differentiation ◽  
Zinc Finger Protein ◽  
Tissue Mass ◽  
In Vivo Models ◽  
Brown Adipose

Abstract Background Juxtaposed with another zinc finger protein 1 (JAZF1) is associated with metabolic disorders, including type 2 diabetes mellitus (T2DM). Several studies showed that JAZF1 and body fat mass are closely related. We attempted to elucidate the JAZF1 functions on adipose development and related metabolism using in vitro and in vivo models. Results The JAZF1 expression was precisely regulated during adipocyte differentiation of 3T3-L1 preadipocyte and mouse embryonic fibroblasts (MEFs). Homozygous JAZF1 deletion (JAZF1-KO) resulted in impaired adipocyte differentiation in MEF. The JAZF1 role in adipocyte differentiation was demonstrated by the regulation of PPARγ—a key regulator of adipocyte differentiation. Heterozygous JAZF1 deletion (JAZF1-Het) mice fed a normal diet (ND) or a high-fat diet (HFD) had less adipose tissue mass and impaired glucose homeostasis than the control (JAZF1-Cont) mice. However, other metabolic organs, such as brown adipose tissue and liver, were negligible effect on JAZF1 deficiency. Conclusion Our findings emphasized the JAZF1 role in adipocyte differentiation and related metabolism through the heterozygous knockout mice. This study provides new insights into the JAZF1 function in adipose development and metabolism, informing strategies for treating obesity and related metabolic disorders.

scholarly journals Dopamine receptor D1- and D2-agonists do not spark brown adipose tissue thermogenesis in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Francesca-Maria Raffaelli ◽  
Julia Resch ◽  
Rebecca Oelkrug ◽  
K. Alexander Iwen ◽  
Jens Mittag
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Dopamine Receptor ◽  
Ex Vivo ◽  
Potential Target ◽  
D2 Agonist ◽  
Obesity And Diabetes ◽  
Brown Adipose

AbstractBrown adipose tissue (BAT) thermogenesis is considered a potential target for treatment of obesity and diabetes. In vitro data suggest dopamine receptor signaling as a promising approach; however, the biological relevance of dopamine receptors in the direct activation of BAT thermogenesis in vivo remains unclear. We investigated BAT thermogenesis in vivo in mice using peripheral administration of D1-agonist SKF38393 or D2-agonist Sumanirole, infrared thermography, and in-depth molecular analyses of potential target tissues; and ex vivo in BAT explants to identify direct effects on key thermogenic markers. Acute in vivo treatment with the D1- or D2-agonist caused a short spike or brief decrease in BAT temperature, respectively. However, repeated daily administration did not induce lasting effects on BAT thermogenesis. Likewise, neither agonist directly affected Ucp1 or Dio2 mRNA expression in BAT explants. Taken together, the investigated agonists do not seem to exert lasting and physiologically relevant effects on BAT thermogenesis after peripheral administration, demonstrating that D1- and D2-receptors in iBAT are unlikely to constitute targets for obesity treatment via BAT activation.

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