scholarly journals Proteome and Phosphoproteome Analysis of Brown Adipocytes Reveals That RICTOR Loss Dampens Global Insulin/AKT Signaling

2020 ◽  
Vol 19 (7) ◽  
pp. 1104-1119 ◽  
Author(s):  
Samuel W. Entwisle ◽  
Camila Martinez Calejman ◽  
Anthony S. Valente ◽  
Robert T. Lawrence ◽  
Chien-Min Hung ◽  
...  
Keyword(s):  
Time Course ◽  
Metabolic Diseases ◽  
De Novo ◽  
Brown Adipocytes ◽  
Droplet Dynamics ◽  
Bat Activity ◽  
Downstream Effectors ◽  
Brown Adipose ◽  
Perilipin 1 ◽  
Lipid Droplet Protein

Stimulating brown adipose tissue (BAT) activity represents a promising therapy for overcoming metabolic diseases. mTORC2 is important for regulating BAT metabolism, but its downstream targets have not been fully characterized. In this study, we apply proteomics and phosphoproteomics to investigate the downstream effectors of mTORC2 in brown adipocytes. We compare wild-type controls to isogenic cells with an induced knockout of the mTORC2 subunit RICTOR (Rictor-iKO) by stimulating each with insulin for a 30-min time course. In Rictor-iKO cells, we identify decreases to the abundance of glycolytic and de novo lipogenesis enzymes, and increases to mitochondrial proteins as well as a set of proteins known to increase upon interferon stimulation. We also observe significant differences to basal phosphorylation because of chronic RICTOR loss including decreased phosphorylation of the lipid droplet protein perilipin-1 in Rictor-iKO cells, suggesting that RICTOR could be involved with regulating basal lipolysis or droplet dynamics. Finally, we observe mild dampening of acute insulin signaling response in Rictor-iKO cells, and a subset of AKT substrates exhibiting statistically significant dependence on RICTOR.

scholarly journals Norepinephrine, tri-iodothyronine and insulin upregulate glyceraldehyde-3-phosphate dehydrogenase mRNA during Brown adipocyte differentiation

1999 ◽  
pp. 169-179 ◽  
Author(s):  
I Barroso ◽  
B Benito ◽  
C Garci-Jimenez ◽  
A Hernandez ◽  
MJ Obregon ◽  
...  
Keyword(s):  
De Novo ◽  
Precursor Cells ◽  
Brown Adipocyte ◽  
Mrna Levels ◽  
Brown Adipocytes ◽  
Gapdh Gene ◽  
Gapdh Mrna ◽  
Brown Adipose ◽  
Dose Dependent ◽  
De Novo Protein Synthesis

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene expression was studied in differentiating brown adipocytes. Northern blot analysis showed that GAPDH mRNA levels increased during differentiation of precursor cells into mature adipocytes, mainly in the initial stages of the differentiation process. Insulin, tri-iodothyronine (T(3)) and norepinephrine, the main regulators of brown adipose tissue function, upregulated GAPDH mRNA levels, whereas retinoic acid inhibited them. The effect of insulin was present on all culture days examined, was time- and dose-dependent, and was exerted through its own receptors, as demonstrated by comparing insulin and insulin-like growth factor (IGF)-I and -II potencies in this system. Using the transcriptional inhibitor, actinomycin D, we demonstrated that T(3), and to a lesser extent insulin, stabilized GAPDH mRNA. Experiments with cycloheximide indicated that both hormones require de novo protein synthesis to achieve their effects. Using cAMP analogs, we showed that the effect of norepinephrine is probably exerted through this second messenger. Co-operation was elucidated between norepinephrine- and insulin-mediated induction of GAPDH mRNA levels. In summary, we have demonstrated that GAPDH mRNA is subjected to multifactorial regulation in differentiating brown adipocytes that includes differentiation of precursor cells and the lipogenic/lipolytic regulators of the tissue.

Testosterone reduces metabolic brown fat activity in male mice

2021 ◽  
Author(s):  
Marta Lantero Rodriguez ◽  
Maaike Schilperoort ◽  
Inger Johansson ◽  
Elin Svedlund Eriksson ◽  
Vilborg Palsdottir ◽  
...  
Keyword(s):  
Body Temperature ◽  
Core Body Temperature ◽  
Negative Regulator ◽  
Acid Uptake ◽  
Male Mice ◽  
Brown Adipocytes ◽  
Bat Activity ◽  
Brown Adipose ◽  
Core Body

Brown adipose tissue (BAT) burns substantial amounts of mainly lipids to produce heat. Some studies indicate that BAT activity and core body temperature are lower in males than females. Here we investigated the role of testosterone and its receptor (the androgen receptor; AR) in metabolic BAT activity in male mice. Castration, which renders mice testosterone deficient, slightly promoted the expression of thermogenic markers in BAT, decreased BAT lipid content, and increased basal lipolysis in isolated brown adipocytes. Further, castration increased the core body temperature. Triglyceride-derived fatty acid uptake, a proxy for metabolic BAT activity in vivo, was strongly increased in BAT from castrated mice (4.5-fold increase vs. sham-castrated mice) and testosterone replacement reversed the castration-induced increase in metabolic BAT activity. BAT-specific AR deficiency did not mimic the castration effects in vivo and AR agonist treatment did not diminish the activity of cultured brown adipocytes in vitro, suggesting that androgens do not modulate BAT activity via a direct, AR-mediated pathway. In conclusion, testosterone is a negative regulator of metabolic BAT activity in male mice. Our findings provide new insight into the metabolic actions of testosterone.

scholarly journals Biomarkers of Browning in Cold Exposed Siberian Adults

Nutrients ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2162
Author(s):  
Agrafena Efremova ◽  
Georgia Colleluori ◽  
Mikhail Thomsky ◽  
Jessica Perugini ◽  
Marina Protasoni ◽  
...  
Keyword(s):  
Cold Exposure ◽  
Mononuclear Cells ◽  
Metabolic Diseases ◽  
Exposed Group ◽  
Anthropometric Parameters ◽  
Cold Temperatures ◽  
Bat Activity ◽  
Fat Depots ◽  
Brown Adipose ◽  
White Fat

Cold-exposure promotes energy expenditure by inducing brown adipose tissue (BAT) thermogenesis, which over time, is also sustained by browning, the appearance, or increase, of brown-like cells into white fat depots. Identification of circulating markers reflecting BAT activity and browning is crucial to study this phenomenon and its triggers, also holding possible implications for the therapy of obesity and metabolic diseases. Using RT-qPCR, we evaluated the peripheral blood mononuclear cells (PBMC) expression profile of regulators of BAT activity (CIDEA, PRDM16), white adipocytes browning (HOXC9 and SLC27A1), and fatty acid β-oxidation (CPT1A) in 150 Siberian healthy miners living at extremely cold temperatures compared to 29 healthy subjects living in thermoneutral conditions. Anthropometric parameters, glucose, and lipid profiles were also assessed. The cold-exposed group showed significantly lower weight, BMI, hip circumference, and PBMC expression of CIDEA, but higher expression of HOXC9 and higher circulating glucose compared to controls. Within the cold-exposed group, BMI, total cholesterol, and the atherogenic coefficient were lower in individuals exposed to low temperatures for a longer time. In conclusion, human PBMC expresses the brown adipocytes marker CIDEA and the browning marker HOXC9, which, varying according to cold-exposure, possibly reflect changes in BAT activation and white fat browning.

scholarly journals Does Adipose Tissue Thermogenesis Play a Role in Metabolic Health?

2013 ◽  
Vol 2013 ◽  
pp. 1-4
Author(s):  
Craig Porter ◽  
Elisabet Børsheim ◽  
Labros S. Sidossis
Keyword(s):  
Adipose Tissue ◽  
Energy Metabolism ◽  
Brown Adipose Tissue ◽  
Metabolic Diseases ◽  
Oxidative Capacity ◽  
Whole Body ◽  
Research Strategies ◽  
Brown Adipocytes ◽  
Brown Adipose

The function ascribed to brown adipose tissue in humans has long been confined to thermoregulation in neonates, where this thermogenic capacity was thought lost with maturation. Recently, brown adipose tissue depots have been identified in adult humans. The significant oxidative capacity of brown adipocytes and the ability of their mitochondria to respire independently of ATP production, has led to renewed interest in the role that these adipocytes play in human energy metabolism. In our view, there is a need for robust physiological studies determining the relationship between molecular signatures of brown adipose tissue, adipose tissue mitochondrial function, and whole body energy metabolism, in order to elucidate the significance of thermogenic adipose tissue in humans. Until such information is available, the role of thermogenic adipose tissue in human metabolism and the potential that these adipocytes may prevent or treat obesity and metabolic diseases in humans will remain unknown. In this article, we summarize the recent literature pertaining to brown adipose tissue function with the aims of drawing the readers’ attention to the lack of data concerning the role of brown adipocytes in human physiology, and to the potential limitations of current research strategies.

scholarly journals Relationship of brown adipose tissue perfusion and function: a study through β2-adrenoreceptor stimulation

2016 ◽  
Vol 120 (8) ◽  
pp. 825-832 ◽  
Author(s):  
Laura Ernande ◽  
Kristin I. Stanford ◽  
Robrecht Thoonen ◽  
Haihua Zhang ◽  
Maëva Clerte ◽  
...  
Keyword(s):  
Blood Flow ◽  
Adipose Tissue ◽  
Oxygen Consumption ◽  
Brown Adipose Tissue ◽  
Glucose Uptake ◽  
Direct Effect ◽  
Brown Adipocytes ◽  
Bat Activity ◽  
Brown Adipose

Brown adipose tissue (BAT) activation increases glucose and lipid consumption; as such, it is been considered as a potential therapy to decrease obesity. BAT is highly vascularized and its activation is associated with a necessary increase in blood flow. However, whether increasing BAT blood flow per se increases BAT activity is unknown. To examine this hypothesis, we investigated whether an isolated increase in BAT blood flow obtained by β2-adrenoreceptor (β2-AR) stimulation with salbutamol increased BAT activity. BAT blood flow was estimated in vivo in mice using contrast-enhanced ultrasound. The absence of direct effect of salbutamol on the function of isolated brown adipocytes was assessed by measuring oxygen consumption. The effect of salbutamol on BAT activity was investigated by measuring BAT glucose uptake in vivo. BAT blood flow increased by 2.3 ± 0.6-fold during β2-AR stimulation using salbutamol infusion in mice ( P = 0.003). β2-AR gene expression was detectable in BAT but was extremely low in isolated brown adipocytes. Oxygen consumption of isolated brown adipocytes did not change with salbutamol exposure, confirming the absence of a direct effect of β2-AR agonist on brown adipocytes. Finally, β2-AR stimulation by salbutamol increased BAT glucose uptake in vivo (991 ± 358 vs. 135 ± 49 ng glucose/mg tissue/45 min in salbutamol vs. saline injected mice, respectively, P = 0.046). In conclusion, an increase in BAT blood flow without direct stimulation of the brown adipocytes is associated with increased BAT metabolic activity. Increasing BAT blood flow might represent a new therapeutic target in obesity.

scholarly journals MECHANISMS IN ENDOCRINOLOGY: Brown adipose tissue in humans: regulation and metabolic significance

2016 ◽  
Vol 175 (1) ◽  
pp. R11-R25 ◽  
Author(s):  
Moe Thuzar ◽  
Ken K Y Ho
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Cold Exposure ◽  
Brown Adipocytes ◽  
Metabolic Hormones ◽  
Bat Activity ◽  
Adipose Tissue Depots ◽  
Brown Adipose ◽  
Adult Humans ◽  
Metabolic Significance

The recent discovery that functional brown adipose tissue (BAT) persists in adult humans has enkindled a renaissance in metabolic research, with a view of harnessing its thermogenic capacity to combat obesity. This review focuses on the advances in the regulation and the metabolic significance of BAT in humans. BAT activity in humans is stimulated by cold exposure and by several factors such as diet and metabolic hormones. BAT function is regulated at two levels: an acute process involving the stimulation of the intrinsic thermogenic activity of brown adipocytes and a chronic process of growth involving the proliferation of pre-existing brown adipocytes or differentiation to brown adipocytes of adipocytes from specific white adipose tissue depots. BAT activity is reduced in the obese, and its stimulation by cold exposure increases insulin sensitivity and reduces body fat. These observations provide strong evidence that BAT plays a significant role in energy balance in humans and has the potential to be harnessed as a therapeutic target for the management of obesity.

scholarly journals Elucidating the Regulatory Role of Melatonin in Brown, White, and Beige Adipocytes

2019 ◽  
Author(s):  
Ziye Xu ◽  
Wenjing You ◽  
Jiaqi Liu ◽  
Yizhen Wang ◽  
Tizhong Shan
Keyword(s):  
Adipose Tissue ◽  
Energy Metabolism ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Body Weight Gain ◽  
Tissue Mass ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Beige Adipocytes

AbstractThe high prevalence of obesity and its associated metabolic diseases has heightened the importance of understanding control of adipose tissue development and energy metabolism. In mammals, 3 types of adipocytes with different characteristics and origins have been identified: white, brown, and beige. Beige and brown adipocytes contain numerous mitochondria and have the capability to burn energy and counteract obesity, while white adipocytes store energy and are closely associated with metabolic disorders and obesity. Thus, regulation of the development and function of different adipocytes is important for controlling energy balance and combating obesity and related metabolic disorders. Melatonin is a neurohormone, which plays multiple roles in regulating inflammation, blood pressure, insulin actions, and energy metabolism. This article summarizes and discusses the role of melatonin in white, beige, and brown adipocytes, especially in affecting adipogenesis, inducing beige formation or white adipose tissue browning, enhancing brown adipose tissue mass and activities, improving anti-inflammatory and antioxidative effects, regulating adipokine secretion, and preventing body weight gain. Based on the current findings, melatonin is a potential therapeutic agent to control energy metabolism, adipogenesis, fat deposition, adiposity, and related metabolic diseases.

scholarly journals Cold-Induced Thermogenesis Increases Acetylation on the Brown Fat Proteome and Metabolome

2018 ◽  
Author(s):  
Samuel W. Entwisle ◽  
Joan Sanchez-Gurmaches ◽  
Robert T. Lawrence ◽  
David J. Pedersen ◽  
Su Myung Jung ◽  
...  
Keyword(s):  
Cold Acclimation ◽  
Metabolic Diseases ◽  
De Novo ◽  
Protein Abundance ◽  
Protein Acetylation ◽  
Acetyl Coa ◽  
Brown Adipose ◽  
Acetyl Coa Synthesis ◽  
Metabolic Properties ◽  
Functional Relevance

ABSTRACTStimulating brown adipose tissue (BAT) energy expenditure could be a therapy for obesity and related metabolic diseases. Achieving this requires a systems-level understanding of the biochemical underpinnings of thermogenesis. To identify novel metabolic features of active BAT, we measured protein abundance, protein acetylation, and metabolite levels in BAT isolated from mice living in their thermoneutral zone or in colder environments. We find that the enzymes which synthesize lipids from cytosolic acetyl-coA are among the most robustly increased proteins after cold acclimation, consistent with recent studies highlighting the importance of anabolic de novo lipogenesis in BAT. In addition, many mitochondrial proteins are hyperacetylated by cold acclimation, including several sites on UCP1, which may have functional relevance. Metabolomics analysis further reveals cold-dependent increases to acetylated carnitine and several amino acids. This BAT multi-omics resource highlights widespread proteomic and metabolic changes linked to acetyl-CoA synthesis and utilization that may be useful in unraveling the remarkable metabolic properties of active BAT.

scholarly journals Association of circulating exosomal miR-122 levels with BAT activity in healthy humans

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yuko Okamatsu-Ogura ◽  
Mami Matsushita ◽  
Jussiaea Valente Bariuan ◽  
Kazuki Nagaya ◽  
Ayumi Tsubota ◽  
...  
Keyword(s):  
Body Fat ◽  
Metabolic Diseases ◽  
Standardized Uptake Value ◽  
Hdl Cholesterol ◽  
Serum Levels ◽  
Multivariate Regression Analysis ◽  
Bat Activity ◽  
Activity Group ◽  
Healthy Humans ◽  
Brown Adipose

Abstract Brown adipose tissue (BAT) plays an important role in body fat accumulation and the regulation of energy expenditure. Since the role of miRNAs in the pathogenesis of obesity and related metabolic diseases is contentious, we analyzed exosomal miRNAs in serum of healthy subjects with special references to BAT activity and body fat level. Forty male volunteers aged 20–30 years were recruited. Their BAT activity was assessed by fluorodeoxyglucose positron emission tomography and computed tomography after 2 h of cold exposure and expressed as a maximal standardized uptake value (SUVmax). Exosomal miRNA levels was analyzed using microarray and real-time PCR analyses. The miR-122-5p level in the high BAT activity group (SUV ≧ 3) was 53% lower than in the low BAT activity group (SUVmax <3). Pearson’s correlation analysis revealed that the serum miR-122-5p level correlated negatively with BAT activity and the serum HDL-cholesterol, and it correlated positively with age, BMI, body fat mass, and total cholesterol and triglyceride serum levels. Multivariate regression analysis revealed that BAT activity was associated with the serum miR-122-5p level independently of the other parameters. These results reveal the serum exosomal miR-122-5p level is negatively associated with BAT activity independently of obesity.

scholarly journals Vascular smooth muscle-derived TRPV1-expressing progenitors are a new source of cold-induced thermogenic adipocytes

2020 ◽  
Author(s):  
Farnaz Shamsi ◽  
Matthew D. Lynes ◽  
Mary Piper ◽  
Li-Lun Ho ◽  
Tian Lian Huang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Energy Expenditure ◽  
Vascular Smooth Muscle ◽  
Single Cell ◽  
Transient Receptor Potential ◽  
De Novo ◽  
Lineage Tracing ◽  
Brown Adipocytes ◽  
Cellular Origin ◽  
Brown Adipose

AbstractBrown adipose tissue (BAT) functions in energy expenditure in part due its role in thermoregulation. The prominent capacity of BAT to enhance fuel utilization and energy expenditure makes it an attractive target for treating obesity and metabolic disorders. Prolonged cold exposure induces de novo recruitment of brown adipocytes and activates their thermogenic activity. However, the exact source of cold-induced brown adipocytes is not completely understood. In this study, we sought to investigate the cellular origin of cold-induced brown adipocytes using single-cell RNA sequencing. We identified two distinct types of adipocyte progenitors that contribute to de novo recruitment of brown adipocytes in response to cold challenge. One is the previously known Pdgfra-expressing mesenchymal progenitors and the other is a vascular smooth muscle-derived adipocyte progenitor (VSM-APC) population, which expresses the temperature-sensitive ion channel transient receptor potential cation channel subfamily V member 1 (Trpv1). Using flow cytometry and lineage tracing, we demonstrated that the Trpv1pos VSM-APCs were indeed distinct from the Pdgfrapos progenitors and could contribute to brown adipocytes with greater thermogenic potential. Together, these findings illustrate a landscape of thermogenic adipose niche at the single cell resolution and identify a new cellular origin for the development of brown adipocytes.

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