Brown and beige adipose tissue regulate systemic metabolism through a metabolite interorgan signaling axis

AbstractBrown 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 interorgan signaling network. Using metabolomics, we identify 3-methyl-2-oxovaleric acid, 5-oxoproline, and β-hydroxyisobutyric acid as small molecule metabokines synthesized in browning adipocytes and secreted via monocarboxylate transporters. 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid induce a brown adipocyte-specific phenotype in white adipocytes and mitochondrial oxidative energy metabolism in skeletal myocytes both in vitro and in vivo. 3-methyl-2-oxovaleric acid and 5-oxoproline signal through cAMP-PKA-p38 MAPK and β-hydroxyisobutyric acid via mTOR. In humans, plasma and adipose tissue 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid concentrations correlate with markers of adipose browning and inversely associate with body mass index. These metabolites reduce adiposity, increase energy expenditure and improve glucose and insulin homeostasis in mouse models of obesity and diabetes. Our findings identify beige adipose-brown adipose-muscle physiological metabokine crosstalk.

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

10.21203/rs.3.rs-38426/v1 ◽

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.

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

Scientific Reports ◽

10.1038/s41598-020-77143-6 ◽

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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ACE2 Pathway Regulates Thermogenesis and Energy Metabolism

10.1101/2021.08.10.455823 ◽

2021 ◽

Author(s):

Xi Cao ◽

Tingting Shi ◽

Chuanhai Zhang ◽

Wanzhu Jin ◽

Lini Song ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

Brown Adipose Tissue ◽

Knockout Mice ◽

Metabolic Disorders ◽

Energy Homeostasis ◽

Cold Stimulation ◽

Obesity And Diabetes ◽

Brown Adipose ◽

Pka Pathway

Identification of key regulators of energy homeostasis holds important therapeutic promise for metabolic disorders, such as obesity and diabetes. ACE2 cleaves angiotensin II (Ang II) to generate Ang-(1-7) which acts mainly through the Mas receptor. Here, we identify ACE2 pathway as a critical regulator in the maintenance of thermogenesis and energy expenditure. We found that ACE2 is highly expressed in brown adipose tissue (BAT) and that cold stimulation increases ACE2 and Ang-(1-7) levels in BAT and serum. ACE2 knockout mice (ACE2-/y), Mas knockout mice (Mas-/-), and the mice transplanted with brown adipose tissue from Mas-/- mice displayed impaired thermogenesis. In contrast, impaired thermogenesis of db/db obese diabetic mice and high-fat diet-induced obese mice were ameliorated by overexpression of ACE2 or continuous infusion of Ang-(1-7). Activation of ACE2 pathway was associated with improvement of metabolic parameters, including blood glucose, lipids and energy expenditure in multiple animal models. Consistently, ACE2 pathway remarkably enhanced the browning of white adipose tissue. Mechanistically, we showed that ACE2 pathway activated Akt/FoxO1 and PKA pathway, leading to induction of UCP1 and activation of mitochondrial function. Our data propose that adaptive thermogenesis requires regulation of ACE2 pathway and highlight novel therapeutic targets for the treatment of metabolic disorders.

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HOXA5 Participates in Brown Adipose Tissue and Epaxial Skeletal Muscle Patterning and in Brown Adipocyte Differentiation

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.632303 ◽

2021 ◽

Vol 9 ◽

Author(s):

Miriam A. Holzman ◽

Abigail Ryckman ◽

Tova M. Finkelstein ◽

Kim Landry-Truchon ◽

Kyra A. Schindler ◽

...

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Muscle Development ◽

Lineage Tracing ◽

Brown Adipocyte ◽

Obesity And Diabetes ◽

Brown Adipose ◽

Droplet Morphology ◽

Epaxial Muscle

Brown adipose tissue (BAT) plays critical thermogenic, metabolic and endocrine roles in mammals, and aberrant BAT function is associated with metabolic disorders including obesity and diabetes. The major BAT depots are clustered at the neck and forelimb levels, and arise largely within the dermomyotome of somites, from a common progenitor with skeletal muscle. However, many aspects of BAT embryonic development are not well understood.Hoxa5patterns other tissues at the cervical and brachial levels, including skeletal, neural and respiratory structures. Here, we show thatHoxa5also positively regulates BAT development, while negatively regulating formation of epaxial skeletal muscle. HOXA5 protein is expressed in embryonic preadipocytes and adipocytes as early as embryonic day 12.5.Hoxa5null mutant embryos and rare, surviving adults show subtly reduced iBAT and sBAT formation, as well as aberrant marker expression, lower adipocyte density and altered lipid droplet morphology. Conversely, the epaxial muscles that arise from a common dermomyotome progenitor are expanded inHoxa5mutants. Conditional deletion ofHoxa5withMyf5/Crecan reproduce both BAT and epaxial muscle phenotypes, indicating that HOXA5 is necessary withinMyf5-positive cells for proper BAT and epaxial muscle development. However, recombinase-based lineage tracing shows thatHoxa5does not act cell-autonomously to repress skeletal muscle fate. Interestingly,Hoxa5-dependent regulation of adipose-associated transcripts is conserved in lung and diaphragm, suggesting a shared molecular role forHoxa5in multiple tissues. Together, these findings establish a role forHoxa5in embryonic BAT development.

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Chrysanthemum Leaf Ethanol Extract Prevents Obesity and Metabolic Disease in Diet-Induced Obese Mice via Lipid Mobilization in White Adipose Tissue

Nutrients ◽

10.3390/nu11061347 ◽

2019 ◽

Vol 11 (6) ◽

pp. 1347 ◽

Cited By ~ 3

Author(s):

Ri Ryu ◽

Eun-Young Kwon ◽

Ji-Young Choi ◽

Jong Cheol Shon ◽

Kwang-Hyeon Liu ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

White Adipose Tissue ◽

Ethanol Extract ◽

The Body ◽

Obese Mice ◽

Peripheral Tissues ◽

Lipid Mobilization ◽

Obesity And Diabetes ◽

Brown Adipose

This study aimed to elucidate the molecular mechanism of Chrysanthemum morifolium Ramat. against obesity and diabetes, by comparing the transcriptional changes in epididymal white adipose tissue (eWAT) with those of the bioactive compound in C. morifolium, luteolin (LU). Male C57BL/6J mice were fed a normal diet, high-fat diet (HFD), and HFD supplemented with 1.5% w/w chrysanthemum leaf ethanol extract (CLE) for 16 weeks. Supplementation with CLE and LU significantly decreased the body weight gain and eWAT weight by stimulating mRNA expressions for thermogenesis and energy expenditure in eWAT via lipid mobilization, which may be linked to the attenuation of dyslipidemia. Furthermore, CLE and LU increased uncoupling protein-1 protein expression in brown adipose tissue, leading to energy expenditure. Of note, CLE and LU supplements enhanced the balance between lipid storage and mobilization in white adipose tissue (WAT), in turn, inhibiting adipocyte inflammation and lipotoxicity of peripheral tissues. Moreover, CLE and LU attenuated hepatic steatosis by suppressing hepatic lipogenesis, thereby ameliorating insulin resistance and dyslipidemia. Our data suggest that CLE helps inhibit obesity and its comorbidities via the complex interplay between liver and WAT in diet-induced obese mice.

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

Genes ◽

10.3390/genes12050756 ◽

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.

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Orexin Restores Aging-Related Brown Adipose Tissue Dysfunction in Male Mice

Endocrinology ◽

10.1210/en.2013-1629 ◽

2014 ◽

Vol 155 (2) ◽

pp. 485-501 ◽

Cited By ~ 55

Author(s):

Dyan Sellayah ◽

Devanjan Sikder

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Fat Mass ◽

Core Body Temperature ◽

Brown Adipocyte ◽

Aged Mice ◽

Age Related ◽

Brown Adipose ◽

The Impact

The aging process causes an increase in percent body fat, but the mechanism remains unclear. In the present study we examined the impact of aging on brown adipose tissue (BAT) thermogenic activity as potential cause for the increase in adiposity. We show that aging is associated with interscapular BAT morphologic abnormalities and thermogenic dysfunction. In vitro experiments revealed that brown adipocyte differentiation is defective in aged mice. Interscapular brown tissue in aged mice is progressively populated by adipocytes bearing white morphologic characteristics. Aged mice fail to mobilize intracellular fuel reserves from brown adipocytes and exhibit deficiency in homeothermy. Our results suggest a role for orexin (OX) signaling in the regulation of thermogenesis during aging. Brown fat dysfunction and age-related assimilation of fat mass were accelerated in mice in which OX-producing neurons were ablated. Conversely, OX injections in old mice increased multilocular morphology, increased core body temperature, improved cold tolerance, and reduced adiposity. These results argue that BAT can be targeted for interventions to reverse age-associated increase in fat mass.

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Essential roles of 11β-HSD1 in regulating brown adipocyte function

Journal of Molecular Endocrinology ◽

10.1530/jme-12-0099 ◽

2012 ◽

Vol 50 (1) ◽

pp. 103-113 ◽

Cited By ~ 28

Author(s):

Juan Liu ◽

Xiaocen Kong ◽

Long Wang ◽

Hanmei Qi ◽

Wenjuan Di ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Fat ◽

Brown Adipocyte ◽

Specific Gene ◽

Brown Adipocytes ◽

Expression Of Genes ◽

Brown Adipose ◽

Attractive Therapeutic Target ◽

And Function

Brown adipose tissue (BAT) increases energy expenditure and is an attractive therapeutic target for obesity. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1), an amplifier of local glucocorticoid activity, has been shown to modulate white adipose tissue (WAT) metabolism and function. In this study, we investigated the roles of 11β-HSD1 in regulating BAT function. We observed a significant increase in the expression of BAT-specific genes, including UCP1, Cidea, Cox7a1, and Cox8b, in BVT.2733 (a selective inhibitor of 11β-HSD1)-treated and 11β-HSD1-deficient primary brown adipocytes of mice. By contrast, a remarkable decrease in BAT-specific gene expression was detected in brown adipocytes when 11β-HSD1 was overexpressed, which effect was reversed by BVT.2733 treatment. Consistent with the in vitro results, expression of a range of genes related to brown fat function in high-fat diet-fed mice treated with BVT.2733. Our results indicate that 11β-HSD1 acts as a vital regulator that controls the expression of genes related to brown fat function and as such may become a potential target in preventing obesity.

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Brown Adipose Tissue: A New Target for Antiobesity Therapy

The Indonesian Biomedical Journal ◽

10.18585/inabj.v2i2.115 ◽

2010 ◽

Vol 2 (2) ◽

pp. 4

Author(s):

Anna Meiliana ◽

Andi Wijaya

Keyword(s):

Adipose Tissue ◽

Energy Balance ◽

Energy Expenditure ◽

Brown Adipose Tissue ◽

Positive Energy ◽

The Past ◽

Obesity And Diabetes ◽

Brown Adipose ◽

Adult Humans ◽

Thermogenic Capacity

BACKGROUND: Human fat consist of white and brown adipose tissue (WAT and BAT). Though most fat is energy-storing WAT, the thermogenic capacity of even small amounts of BAT makes it an attractive therapeutic target for inducing weight loss through energy expenditure.CONTENT: Over the past year, several independent research teams used a combination of positron-emission tomography and computed tomography (PET/CT) imaging, immunohistochemistry and gene and protein expression assays to prove conclusively that adult humans have functional BAT. BAT is important for thermogenesis and energy balance in small mammals and its induction in mice promotes energy expenditure, reduces adiposity and protects mice from diet-induced obesity. The thermogenic capacity of BAT is impressive. In humans, it has been estimated that as little as 50g of BAT could utilize up to 20% of basal caloric needs if maximally stimulated.SUMMARY: The obesity pandemic requires new and novel treatments. The past few years have witnessed multiple studies conclusively showing that adult humans have functional BAT, a tissue that has a tremendous capacity for obesity-reducing thermogenesis. Novel therapies targeting BAT thermogenesis may be available in the near future as therapeutic options for obesity and diabetes. Thermogenic ingredients may be considered as functional agents that could help in preventing a positive energy balance and obesity.KEYWORDS: brown adipose tissue, thermogenesis, energy expenditure, antiobesity therapy

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

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2017-0016 ◽

2017 ◽

Vol 31 (2) ◽

Cited By ~ 20

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.

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