scholarly journals Genetic background and diet affect brown adipose gene coexpression networks associated with metabolic phenotypes

2020 ◽  
Vol 52 (6) ◽  
pp. 223-233 ◽  
Author(s):  
Caryn Carson ◽  
Heather A. Lawson
Keyword(s):  
Adipose Tissue ◽  
Cell Division ◽  
Brown Adipose Tissue ◽  
Genetic Background ◽  
Cytokine Response ◽  
Transcriptional Networks ◽  
Metabolic Phenotypes ◽  
Gene Coexpression ◽  
Obesity And Diabetes ◽  
Brown Adipose

Adipose is a dynamic endocrine organ that is critical for regulating metabolism and is highly responsive to nutritional environment. Brown adipose tissue is an exciting potential therapeutic target; however, there are no systematic studies of gene-by-environment interactions affecting function of this organ. We leveraged a weighted gene coexpression network analysis to identify transcriptional networks in brown adipose tissue from LG/J and SM/J inbred mice fed high- or low-fat diets and correlate these networks with metabolic phenotypes. We identified eight primary gene network modules associated with variation in obesity and diabetes-related traits. Four modules were enriched for metabolically relevant processes such as immune and cytokine response, cell division, peroxisome functions, and organic molecule metabolic processes. The relative expression of genes in these modules is highly dependent on both genetic background and dietary environment. Genes in the immune/cytokine response and cell division modules are particularly highly expressed in high fat-fed SM/J mice, which show unique brown adipose-dependent remission of diabetes. The interconnectivity of genes in these modules is also heavily dependent on diet and strain, with most genes showing both higher expression and coexpression under the same context. We highlight several genes of interest, Col28a1, Cyp26b1, Bmp8b, and Ngef, that have distinct expression patterns among strain-by-diet contexts and fall under metabolic quantitative trait loci previously mapped in an F16 generation of an advanced intercross between LG/J and SM/J. Each of these genes have some connection to obesity and diabetes-related traits, but have not been studied in brown adipose tissue. Our results provide important insights into the relationship between brown adipose and systemic metabolism by being the first gene-by-environment study of brown adipose transcriptional networks.

scholarly journals Genetic background and diet affect brown adipose gene co-expression – metabolic associations

2019 ◽  
Author(s):  
Caryn Carson ◽  
Heather A Lawson
Keyword(s):  
Adipose Tissue ◽  
Cell Division ◽  
Brown Adipose Tissue ◽  
Genetic Background ◽  
Organic Molecule ◽  
Expression Patterns ◽  
Transcriptional Networks ◽  
Obesity And Diabetes ◽  
Gene By Environment Interactions ◽  
Brown Adipose

AbstractAdipose is a dynamic endocrine organ that is critical for regulating metabolism and is highly responsive to nutritional environment. Brown adipose tissue is an exciting potential therapeutic target, however there are no systematic studies of gene-by-environment interactions affecting function of this organ. We leveraged a weighted gene co-expression network analysis to identify transcriptional networks in brown adipose tissue from LG/J and SM/J inbred mice fed high or low fat diets, and correlate these networks with metabolic phenotypes. We identified 8 primary gene network modules associated with variation in obesity and diabetes-related traits. Four modules were enriched for metabolically relevant processes such as immune and cytokine response, cell division, peroxisome functions, and organic molecule metabolic processes. The relative expression of genes in these modules is highly dependent on both genetic background and dietary environment. Genes in the immune/cytkine response and cell division modules are particularly highly expressed in high fat-fed SM/J mice, which show unique brown adipose-dependent remission of diabetes. The interconnectivity of genes in these modules is also heavily dependent on diet and strain, with most genes showing both higher expression and co-expression under the same context. We highlight 4 candidate genes, Col28a1, Cyp26b1, Bmp8b, and Kcnj14, that have distinct expression patterns among strain-by-diet contexts and fall under metabolic QTL previously mapped in an F16 generation of an advanced intercross between these two strains. Each of these genes have some connection to obesity and diabetes-related traits, but have not been studied in brown adipose tissue. In summary, our results provide important insights into the relationship between brown adipose and systemic metabolism by being the first gene-by-environment study of brown adipose transcriptional networks and introducing novel candidate genes for follow-up studies of biological mechanisms of action.Author SummaryResearch on brown adipose tissue is a promising new avenue for understanding and potentially treating metabolic dysfunction. However, we do not know how genetic background interacts with dietary environment to affect the brown adipose transcriptional response, and how this might affect systemic metabolism. Here we report the first investigation of gene-by-environment interactions on brown adipose gene expression networks associating with multiple obesity and diabetes-related traits. We identified 8 primary networks correlated with variation in these traits in mice, including networks enriched for immune and cytokine response, cell division, organic molecule metabolism, and peroxisome genes. Characterizing these networks and their distinct diet-by-strain expression and co-expression patterns is an important step towards understanding how brown adipose tissue responds to an obesogenic diet, how this response affects metabolism, and how this can be modified by genetic variation.

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.

scholarly journals Multimodal Imaging for the Detection of Brown Adipose Tissue Activation in Women: A Pilot Study Using NIRS and Infrared Thermography

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Valentina Hartwig ◽  
Letizia Guiducci ◽  
Martina Marinelli ◽  
Laura Pistoia ◽  
Tommaso Minutoli Tegrimi ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Pilot Study ◽  
Brown Adipose Tissue ◽  
Infrared Thermography ◽  
Pharmacological Intervention ◽  
Oral Glucose ◽  
Cold Stimulation ◽  
Standard Clinical Practice ◽  
Obesity And Diabetes ◽  
Brown Adipose

Purpose. A clear link between obesity and brown adipose tissue (BAT) dysfunction has been recently demonstrated. The purpose of this pilot study is to determine if near-infrared spectroscopy (NIRS) 2D imaging together with infrared thermography (IRT) is capable of identifying thermal and vascular response in the supraclavicular (SCV) areas after the ingestion of an oral glucose load as a thermogenic stimulation. Method. We studied two groups of women (obese versus lean) for discerning their different responses. NIRS and IRT images were acquired on the neck in the left SCV region during a 3 h oral glucose tolerance test (OGTT) and immediately after a cold stimulation. Results. We detected a significant thermal response of BAT in SCV fossa in both groups. Both during OGTT and after cold stimulation, skin temperature was persistently higher in lean versus obese. This response was not coupled with changes in oxygen saturation of subcutaneous tissue in that area. Discussion and Conclusion. The results show that NIRS/IRT may be a novel, noninvasive, radiation-free, easy to use, and low-cost method for monitoring, during the standard clinical practice, the diet and pharmacological intervention which aims to stimulate BAT as a potential therapeutic target against obesity and diabetes.

scholarly journals Synthesis-free PET imaging of brown adipose tissue and TSPO via Combination of Disulfiram and 64CuCl2

2017 ◽  
Author(s):  
Jing Yang ◽  
Jian Yang ◽  
Lu Wang ◽  
Anna Moore ◽  
Steven H. Liang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Pet Imaging ◽  
Imaging Biomarker ◽  
Imaging Method ◽  
Steroid Synthesis ◽  
Pet Tracer ◽  
Obesity And Diabetes ◽  
Brown Adipose ◽  
First Time

AbstractPET imaging is a widely applicable but a very expensive technology. Strategies that can significantly reduce the high cost of PET imaging are highly desirable both for research and commercialization. On-site synthesis is one important contributor to the high cost. In this report, we demonstrated the feasibility of a synthesis-free method for PET imaging of brown adipose tissue (BAT) and translocator protein 18kDa (TSPO) via a combination of Disulfiram, an FDA approved drug for alcoholism, and 64CuCl2 (termed 64Cu-Dis). Our blocking studies, Western blot, and tissue histological imaging suggested that the observed BAT contrast was due to 64Cu-Dis binding to TSPO, which was further confirmed as a specific biomarker for BAT imaging using [18F]-F-DPA, a TSPO-specific PET tracer. Our studies, for the first time, demonstrated that TSPO could serve as a potential imaging biomarker for BAT. Furthermore, since imaging contrast obtained with both 64Cu-Dis and [18F]-F-DPA was not dependent on BAT activation, these agents could be used for reliably imaging BAT mass. Additional value of our synthesis-free approach could be applied to imaging TSPO in other tissues as it is an established biomarker of neuro-inflammation in activated microglia and plays a role in immune response, steroid synthesis, and apoptosis. Although here we applied 64Cu-Dis for a synthesis-free PET imaging of BAT, we believe that our strategy could be extended to other targets while significantly reducing the cost of PET imaging.SignificanceBrown adipose tissue (BAT) has been considered as “good fat,” and large-scale analysis has undoubtedly validated its clinical significance. BAT tightly correlates with body-mass index (BMI), suggesting that BAT bears clear significance for metabolic disorders such as obesity and diabetes. BAT imaging with [18F]-FDG, the most used method for visualizing BAT, primarily reflects BAT activation, but not BAT mass. A convenient imaging method that can consistently reflect BAT mass is still lacking. In this report, we demonstrated that BAT mass can be reliably imaged with a synthesis-free method using the combination of Disulfiram and 64CuCl2 (64Cu-Dis) via TSPO binding. We further demonstrated for the first time that TSPO is a specific imaging biomarker for BAT.

scholarly journals ACE2 Pathway Regulates Thermogenesis and Energy Metabolism

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.

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

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.

scholarly journals Centrally Administered Resistin Enhances Sympathetic Nerve Activity to the Hindlimb but Attenuates the Activity to Brown Adipose Tissue

Endocrinology ◽  
2011 ◽  
Vol 152 (7) ◽  
pp. 2626-2633 ◽  
Author(s):  
S. Kosari ◽  
J. A. Rathner ◽  
F. Chen ◽  
S. Kosari ◽  
E. Badoer
Keyword(s):  
Cardiovascular Disease ◽  
Heart Rate ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Sympathetic Nerve ◽  
Energy Homeostasis ◽  
Sympathetic Nerve Activity ◽  
Nerve Activity ◽  
Obesity And Diabetes ◽  
Brown Adipose

Resistin, an adipokine, is believed to act in the brain to influence energy homeostasis. Plasma resistin levels are elevated in obesity and are associated with metabolic and cardiovascular disease. Increased muscle sympathetic nerve activity (SNA) is a characteristic of obesity, a risk factor for diabetes and cardiovascular disease. We hypothesized that resistin affects SNA, which contributes to metabolic and cardiovascular dysfunction. Here we investigated the effects of centrally administered resistin on SNA to muscle (lumbar) and brown adipose tissue (BAT), outputs that influence cardiovascular and energy homeostasis. Overnight-fasted rats were anesthetized, and resistin (7 μg) was administered into the lateral cerebral ventricle (intracerebroventricular). The lumbar sympathetic nerve trunk or sympathetic nerves supplying BAT were dissected free, and nerve activity was recorded. Arterial blood pressure, heart rate, body core temperature, and BAT temperature were also recorded. Responses to resistin or vehicle were monitored for 4 h after intracerebroventricular administration. Acutely administered resistin increased lumbar SNA but decreased BAT SNA. Mean arterial pressure and heart rate, however, were not significantly affected by resistin. BAT temperature was significantly reduced by resistin, and there was a concomitant fall in body temperature. The findings indicate that resistin has differential effects on SNA to tissues involved in metabolic and cardiovascular regulation. The decreased BAT SNA and the increased lumbar SNA elicited by resistin suggest that it may contribute to the increased muscle SNA and reduced energy expenditure observed in obesity and diabetes.

scholarly journals Brown Adipose Tissue: A New Target for Antiobesity Therapy

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

scholarly journals Novel Browning Agents, Mechanisms, and Therapeutic Potentials of Brown Adipose Tissue

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Umesh D. Wankhade ◽  
Michael Shen ◽  
Hariom Yadav ◽  
Keshari M. Thakali
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Energy Homeostasis ◽  
Therapeutic Potential ◽  
Uncoupling Protein ◽  
Brown Adipocytes ◽  
Atp Production ◽  
Obesity And Diabetes ◽  
Brown Adipose ◽  
Beige Adipocytes

Nonshivering thermogenesis is the process of biological heat production in mammals and is primarily mediated by brown adipose tissue (BAT). Through ubiquitous expression of uncoupling protein 1 (Ucp1) on the mitochondrial inner membrane, BAT displays uncoupling of fuel combustion and ATP production in order to dissipate energy as heat. Because of its crucial role in regulating energy homeostasis, ongoing exploration of BAT has emphasized its therapeutic potential in addressing the global epidemics of obesity and diabetes. The recent appreciation that adult humans possess functional BAT strengthens this prospect. Furthermore, it has been identified that there are both classical brown adipocytes residing in dedicated BAT depots and “beige” adipocytes residing in white adipose tissue depots that can acquire BAT-like characteristics in response to environmental cues. This review aims to provide a brief overview of BAT research and summarize recent findings concerning the physiological, cellular, and developmental characteristics of brown adipocytes. In addition, some key genetic, molecular, and pharmacologic targets of BAT/Beige cells that have been reported to have therapeutic potential to combat obesity will be discussed.

scholarly journals Comprehensive Analysis of the Characteristics and Differences in Adult and Newborn Brown Adipose Tissue (BAT): Newborn BAT Is a More Active/Dynamic BAT

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 201 ◽  
Author(s):  
Junyu Liu ◽  
Chuanhai Zhang ◽  
Boyang Zhang ◽  
Yao Sheng ◽  
Wentao Xu ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Transcription Factor ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Lipid Droplets ◽  
Uncoupling Protein ◽  
Differentially Methylated Region ◽  
Expression Levels ◽  
Obesity And Diabetes ◽  
Brown Adipose

Brown adipose tissue (BAT) plays an essential role in maintaining body temperature and in treating obesity and diabetes. The adult BAT (aBAT) and neonatal BAT (neBAT) vary greatly in capacity, but the characteristics and differences between them on the molecular level, as well as the related features of BAT as it develops post-delivery, have not yet been fully determined. In this study, we examined the morphological features of aBAT and neBAT of mice by using hematoxylin-eosin (H&E) staining, transmission electron microscopy (TEM), and scanning electron microscopy (SEM). We found that neBAT contains a smaller number and size of lipid droplets, as well as more abundant mitochondria, compared with aBAT. The dynamic morphological changes revealed that the number and size of lipid droplets increase, but the number of mitochondria gradually decrease during the post-delivery development, which consisted of some differences in RNA or protein expression levels, such as gradually decreased uncoupling protein 1 (UCP1) expression levels and mitochondrial genes, such as mitochondrial transcription factor A (Tfam). The adipocyte differentiation-related genes, such as transcription factor CCAAT enhancer-binding protein β (CEBPβ), were also continuously upregulated. Additionally, the different features of aBAT and neBAT were analyzed from the global transcription (RNA-Seq) level, which included messenger RNA (mRNA), microRNA, long non-coding RNA (lncRNA), circRNA, and DNA methylation, as well as proteins (proteomics). Differentially methylated region (DMR) analysis identified 383 hyper- and 503 hypo-methylated genes, as well as 1221 new circRNA in ne-BAT and 1991 new circRNA in a-BAT, with significantly higher expression of circRNA in aBAT compared with neBAT. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that mitochondrial activity, protein synthesis, and cell life activity levels were higher in neBAT, and pathways related to ribosomes, spliceosomes, and metabolism were significantly activated in neBAT compared to aBAT. Collectively, this study describes the dynamic changes occurring throughout post-delivery development from the morphological, molecular and omics perspectives. Our study provides information that may be utilized in improving BAT functional activity through gene regulation and/or epigenetic regulation.

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