SUN-584 Micrornas in Brown and White Adipocytes

Abstract Two types of adipose tissue exist: white (WAT) and brown (BAT). WAT stores energy while BAT consumes fatty acids and produces heat by non-shivering thermogenesis through Uncoupling Protein 1 (UCP1). BAT and WAT cooperate in maintaining energy homeostasis balance. Understanding their physiology is important for the development of treatments against diseases where this equilibrium is compromised, such as obesity and associated metabolic disorders. MicroRNAs (miRNAs) are potent gene regulators and an increasing body of evidence suggests their involvement in adipogenesis and adipose metabolism. MiRNAs can also be secreted into the extracellular environment and be taken up by distal cells, mediating cell-to-cell communication. However, very little is known about adipose tissue-derived circulating miRNAs. Through miRNA PCR array analysis we identified several miRNAs that are differentially secreted among undifferentiated and differentiated brown and white adipocytes, such as miR-196a, 378a-3p and miR-138-5p. Bioinformatics target prediction revealed that these miRNAs are potentially involved in important processes regulating the functioning of adipose tissue and its cross-talk with distal cells. Among the predicted targets of miR-196a, we identified ADAM10 (A Disintegrin And Metalloproteinase Domain-containing protein 10). This protein is responsible for the proteolytic release of several cell-surface proteins involved in numerous biological processes such as inflammation and its role could be of relevant importance in the physiopathology of the adipose tissues.

Download Full-text

Recent advances in our understanding of brown and beige adipose tissue: the good fat that keeps you healthy

F1000Research ◽

10.12688/f1000research.14585.1 ◽

2018 ◽

Vol 7 ◽

pp. 1129 ◽

Cited By ~ 12

Author(s):

Michael E. Symonds ◽

Peter Aldiss ◽

Mark Pope ◽

Helen Budge

Keyword(s):

Adipose Tissue ◽

Thermal Environment ◽

Uncoupling Protein ◽

White Adipocytes ◽

Brown Adipose ◽

Adult Humans ◽

Beige Fat ◽

Rapid Generation ◽

Beige Adipose Tissue ◽

Shivering Thermogenesis

Brown adipose tissue (BAT) possesses a unique uncoupling protein (UCP1) which, when activated, enables the rapid generation of heat and the oxidation of lipids or glucose or both. It is present in small amounts (~15–350 mL) in adult humans. UCP1 is rapidly activated at birth and is essential in preventing hypothermia in newborns, who rapidly generate large amounts of heat through non-shivering thermogenesis. Since the “re-discovery” of BAT in adult humans about 10 years ago, there has been an exceptional amount of research interest. This has been accompanied by the establishment of beige fat, characterised as discrete areas of UCP1-containing cells dispersed within white adipocytes. Typically, the amount of UCP1 in these depots is around 10% of the amount found in classic BAT. The abundance of brown/beige fat is reduced with obesity, and the challenge is to prevent its loss with ageing or to reactivate existing depots or both. This is difficult, as the current gold standard for assessing BAT function in humans measures radio-labelled glucose uptake in the fasted state and is usually dependent on cold exposure and the same subject can be found to exhibit both positive and negative scans with repeated scanning. Rodent studies have identified multiple pathways that may modulate brown/beige fat function, but their direct relevance to humans is constrained, as these studies typically are undertaken in cool-adapted animals. BAT remains a challenging organ to study in humans and is able to swiftly adapt to changes in the thermal environment and thus enable rapid changes in heat production and glucose oxidation.

Download Full-text

Irisin exerts dual effects on browning and adipogenesis of human white adipocytes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00094.2016 ◽

2016 ◽

Vol 311 (2) ◽

pp. E530-E541 ◽

Cited By ~ 64

Author(s):

Yuan Zhang ◽

Chao Xie ◽

Hai Wang ◽

Robin M. Foss ◽

Morgan Clare ◽

...

Keyword(s):

Adipose Tissue ◽

Uncoupling Protein ◽

Adipogenic Differentiation ◽

Mapk Signaling ◽

Cellular Energy ◽

Subcutaneous White Adipose Tissue ◽

Basal Expression ◽

White Adipocytes ◽

Ucp1 Expression

To better understand the role of irisin in humans, we examined the effects of irisin in human primary adipocytes and fresh human subcutaneous white adipose tissue (scWAT). Human primary adipocytes derived from 28 female donors' fresh scWAT were used to examine the effects of irisin on browning and mitochondrial respiration, and preadipocytes were used to examine the effects of irisin on adipogenesis and osteogenesis. Cultured fragments of scWAT and perirenal brown fat were used for investigating signal transduction pathways that mediate irisin's browning effect by Western blotting to detect phosphorylated forms of p38, ERK, and STAT3 as well as uncoupling protein 1 (UCP1). Individual responses to irisin in scWAT were correlated with basal expression levels of brown/beige genes. Irisin upregulated the expression of browning-associated genes and UCP1 protein in both cultured primary mature adipocytes and fresh adipose tissues. It also significantly increased thermogenesis at 5 nmol/l by elevating cellular energy metabolism (OCR and ECAR). Treating human scWAT with irisin increased UCP1 expression by activating the ERK and p38 MAPK signaling. Blocking either pathway with specific inhibitors abolished irisin-induced UCP1 upregulation. However, our results showed that UCP1 in human perirenal adipose tissue was insensitive to irisin. Basal levels of brown/beige and FNDC5 genes correlated positively with the browning response of scWAT to irisin. In addition, irisin significantly inhibited adipogenic differentiation but promoted osteogenic differentiation. We conclude that irisin promotes “browning” of mature white adipocytes by increasing cellular thermogenesis, whereas it inhibits adipogenesis and promotes osteogenesis during lineage-specific differentiation. Our findings provide a rationale for further exploring the therapeutic use of irisin in obesity and exercise-associated bone formation.

Download Full-text

Metformin induces oxidative stress in white adipocytes and raises uncoupling protein 2 levels

Journal of Endocrinology ◽

10.1677/joe-08-0278 ◽

2008 ◽

Vol 199 (1) ◽

pp. 33-40 ◽

Cited By ~ 56

Author(s):

Andrea Anedda ◽

Eduardo Rial ◽

M Mar González-Barroso

Keyword(s):

Oxidative Stress ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Uncoupling Protein ◽

Acid Oxidation ◽

Protein Levels ◽

White Adipocytes ◽

Epididymal White Adipose Tissue ◽

Amp Activated Protein Kinase

Metformin is a drug widely used to treat type 2 diabetes. It enhances insulin sensitivity by improving glucose utilization in tissues like liver or muscle. Metformin inhibits respiration, and the decrease in cellular energy activates the AMP-activated protein kinase that in turn switches on catabolic pathways. Moreover, metformin increases lipolysis and β-oxidation in white adipose tissue, thereby reducing the triglyceride stores. The uncoupling proteins (UCPs) are transporters that lower the efficiency of mitochondrial oxidative phosphorylation. UCP2 is thought to protect against oxidative stress although, alternatively, it could play an energy dissipation role. The aim of this work was to analyse the involvement of UCP2 on the effects of metformin in white adipocytes. We studied the effect of this drug in differentiating 3T3-L1 adipocytes and found that metformin causes oxidative stress since it increases the levels of reactive oxygen species (ROS) and lowers the aconitase activity. Variations in UCP2 protein levels parallel those of ROS. Metformin also increases lipolysis in these cells although only when the levels of ROS and UCP2 have decreased. Hence, UCP2 does not appear to be needed to facilitate fatty acid oxidation. Furthermore, treatment of C57BL/6 mice with metformin also augmented the levels of UCP2 in epididymal white adipose tissue. We conclude that metformin treatment leads to the overexpression of UCP2 in adipocytes to minimize the oxidative stress that is probably due to the inhibition of respiration caused by the drug.

Download Full-text

Dietary methionine restriction enhances metabolic flexibility and increases uncoupled respiration in both fed and fasted states

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00837.2009 ◽

2010 ◽

Vol 299 (3) ◽

pp. R728-R739 ◽

Cited By ~ 123

Author(s):

Barbara E. Hasek ◽

Laura K. Stewart ◽

Tara M. Henagan ◽

Anik Boudreau ◽

Natalie R. Lenard ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Homeostasis ◽

De Novo ◽

Uncoupling Protein ◽

Nutrient Sensing ◽

De Novo Lipogenesis ◽

Endocrine Function ◽

Fischer 344 ◽

Methionine Restriction ◽

Heat Increment

Dietary methionine restriction (MR) is a mimetic of chronic dietary restriction (DR) in the sense that MR increases rodent longevity, but without food restriction. We report here that MR also persistently increases total energy expenditure (EE) and limits fat deposition despite increasing weight-specific food consumption. In Fischer 344 (F344) rats consuming control or MR diets for 3, 9, and 20 mo, mean EE was 1.5-fold higher in MR vs. control rats, primarily due to higher EE during the night at all ages. The day-to-night transition produced a twofold higher heat increment of feeding (3.0°C vs. 1.5°C) in MR vs. controls and an exaggerated increase in respiratory quotient (RQ) to values greater than 1, indicative of the interconversion of glucose to lipid by de novo lipogenesis. The simultaneous inhibition of glucose utilization and shift to fat oxidation during the day was also more complete in MR (RQ ∼0.75) vs. controls (RQ ∼0.85). Dietary MR produced a rapid and persistent increase in uncoupling protein 1 expression in brown (BAT) and white adipose tissue (WAT) in conjunction with decreased leptin and increased adiponectin levels in serum, suggesting that remodeling of the metabolic and endocrine function of adipose tissue may have an important role in the overall increase in EE. We conclude that the hyperphagic response to dietary MR is matched to a coordinated increase in uncoupled respiration, suggesting the engagement of a nutrient-sensing mechanism, which compensates for limited methionine through integrated effects on energy homeostasis.

Download Full-text

Sesamol promotes browning of white adipocytes to ameliorate obesity by inducing mitochondrial biogenesis and inhibition mitophagy via β3-AR/PKA signaling pathway

Food & Nutrition Research ◽

10.29219/fnr.v65.7577 ◽

2021 ◽

Author(s):

Cui Lin ◽

Jihua Chen ◽

Minmin Hu ◽

Wenya Zheng ◽

Ziyu Song ◽

...

Keyword(s):

Adipose Tissue ◽

Protein Kinase ◽

Total Cholesterol ◽

Protein Kinase A ◽

Mitochondrial Biogenesis ◽

Uncoupling Protein ◽

Obese Mice ◽

White Adipocytes ◽

Beige Adipocytes ◽

Kinase A

Background: Obesity is defined as an imbalance between energy intake and expenditure, and it is a serious risk factor of non-communicable diseases. Recently many studies have shown that promoting browning of white adipose tissue (WAT) to increase energy consumption has a great therapeutic potential for obesity. Sesamol, a lignan from sesame oil, had shown potential beneficial functions on obesity treatment. Objective: In this study, we used C57BL/6J mice and 3T3-L1 adipocytes to investigate the effects and the fundamental mechanisms of sesamol in enhancing the browning of white adipocytes to ameliorate obesity. Methods: Sixteen-week-old C57BL/6J male mice were fed high-fat diet (HFD) for 8 weeks to establish the obesity models. Half of the obese mice were administered with sesamol (100 mg/kg body weight [b.w.]/day [d] by gavage for another 8 weeks. Triacylglycerol (TG) and total cholesterol assay kits were used to quantify serum TG and total cholesterol (TC). Oil red O staining was used to detect lipid droplet in vitro. Mito-Tracker Green was used to detect the mitochondrial content. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the levels of beige-specific genes. Immunoblotting was used to detect the proteins involved in beige adipocytes formation. Results: Sesamol decreased the content of body fat and suppressed lipid accumulation in HFD-induced obese mice. In addition, sesamol significantly upregulated uncoupling protein-1 (UCP1) protein in adipose tissue. Further research found that sesamol also significantly activated the browning program in mature 3T3-L1 adipocytes, manifested by the increase in beige-specific genes and proteins. Moreover, sesamol greatly increased mitochondrial biogenesis, as proved by the upregulated protein levels of mitochondrial biogenesis, and the inhibition of the proteins associated with mitophagy. Furthermore, β3-adrenergic receptor (β3-AR), protein kinase A-C (PKA-C) and Phospho-protein kinase A (p-PKA) substrate were elevated by sesamol, and these effects were abolished by the pretreatment of antagonists β3-AR. Conclusion: Sesamol promoted browning of white adipocytes by inducing mitochondrial biogenesis and inhibiting mitophagy through the β3-AR/PKA pathway. This preclinical data promised the potential to consider sesamol as a metabolic modulator of HFD-induced obesity.

Download Full-text

Multifaceted Roles of Beige Fat in Energy Homeostasis Beyond UCP1

Endocrinology ◽

10.1210/en.2018-00371 ◽

2018 ◽

Vol 159 (7) ◽

pp. 2545-2553 ◽

Cited By ~ 9

Author(s):

Carlos Henrique Sponton ◽

Shingo Kajimura

Keyword(s):

Adipose Tissue ◽

Energy Homeostasis ◽

Uncoupling Protein ◽

Developmental Regulation ◽

Brown Adipocytes ◽

Adipose Tissue Depots ◽

Brown Adipose ◽

Beige Adipocytes ◽

Beige Fat ◽

Adipose Cells

Abstract Beige adipocytes are an inducible form of thermogenic adipose cells that emerge within the white adipose tissue in response to a variety of environmental stimuli, such as chronic cold acclimation. Similar to brown adipocytes that reside in brown adipose tissue depots, beige adipocytes are also thermogenic; however, beige adipocytes possess unique, distinguishing characteristics in their developmental regulation and biological function. This review highlights recent advances in our understanding of beige adipocytes, focusing on the diverse roles of beige fat in the regulation of energy homeostasis that are independent of the canonical thermogenic pathway via uncoupling protein 1.

Download Full-text

Corticotropin-Releasing Hormone-Mediated Pathway of Leptin to Regulate Feeding, Adiposity, and Uncoupling Protein Expression in Mice

Endocrinology ◽

10.1210/en.2003-0301 ◽

2003 ◽

Vol 144 (8) ◽

pp. 3547-3554 ◽

Cited By ~ 57

Author(s):

Takayuki Masaki ◽

Go Yoshimichi ◽

Seiichi Chiba ◽

Tohru Yasuda ◽

Hitoshi Noguchi ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Food Intake ◽

Mrna Expression ◽

White Adipose Tissue ◽

Energy Homeostasis ◽

Uncoupling Protein ◽

Hypothalamic Nucleus ◽

Fat Cell ◽

Brown Adipose

Abstract To examine the functional role of CRH in the regulation of energy homeostasis by leptin, we measured the effects of the CRH antagonist, α-helical CRH 8–41 (αCRH) on a number of factors affected by leptin activity. These included food intake, body weight, hypothalamic c-fos-like immunoreactivity (c-FLI), weight and histological characterization of white adipose tissue, and mRNA expressions of uncoupling protein (UCP) in brown adipose tissue (BAT) in C57Bl/6 mice. Central infusion of leptin into the lateral cerebroventricle (icv) caused significant induction of c-FLI in the paraventricular nucleus (PVN), ventromedial hypothalamic nucleus (VMH), dorsomedial hypothalamic nucleus, and arcuate nucleus. In all these nuclei, the effect of leptin on expression of cFLI in the PVN and VMH was decreased by treatment with αCRH. Administration of leptin markedly decreased cumulative food intake and body weight with this effect being attenuated by pretreatment with αCRH. In peripheral tissue, leptin up-regulated BAT UCP1 mRNA expression and reduced fat depositions in this tissue. Those changes in BAT were also decreased by treatment with αCRH. As a consequence of the effects on food intake or energy expenditure, treatment with αCRH attenuated the leptin-induced reduction of body adiposity, fat cell size, triglyceride contents, and ob mRNA expression in white adipose tissue. Taken together, these results indicate that CRH neurons in the PVN and VMH may be an important mediator for leptin that contribute to regulation of feeding, adiposity, and UCP expression.

Download Full-text

Short-term resistance to diet-induced obesity in A/J mice is not associated with regulation of hypothalamic neuropeptides

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00114.2004 ◽

2004 ◽

Vol 287 (4) ◽

pp. E662-E670 ◽

Cited By ~ 13

Author(s):

John W. Bullen ◽

Mary Ziotopoulou ◽

Linda Ungsunan ◽

Jatin Misra ◽

Ilias Alevizos ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Microarray Analysis ◽

Energy Homeostasis ◽

Uncoupling Protein ◽

High Fat ◽

Diet Induced Obesity ◽

Brown Adipose ◽

Hypothalamic Neuropeptides ◽

Fat Feeding

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.

Download Full-text

Orally Induced Hyperthyroidism Regulates Hypothalamic AMP-Activated Protein Kinase

Nutrients ◽

10.3390/nu13124204 ◽

2021 ◽

Vol 13 (12) ◽

pp. 4204

Author(s):

Valentina Capelli ◽

Carmen Grijota-Martínez ◽

Nathalia R. V. Dragano ◽

Eval Rial-Pensado ◽

Johan Fernø ◽

...

Keyword(s):

Adipose Tissue ◽

Protein Kinase ◽

Energy Homeostasis ◽

Uncoupling Protein ◽

Core Body Temperature ◽

Metabolic Effects ◽

Central Administration ◽

Treatment Protocols ◽

Brown Adipose ◽

Amp Activated Protein Kinase

Besides their direct effects on peripheral metabolic tissues, thyroid hormones (TH) act on the hypothalamus to modulate energy homeostasis. However, since most of the hypothalamic actions of TH have been addressed in studies with direct central administration, the estimation of the relative contribution of the central vs. peripheral effects in physiologic conditions of peripheral release (or administration) of TH remains unclear. In this study we used two different models of peripherally induced hyperthyroidism (i.e., T4 and T3 oral administration) to assess and compare the serum and hypothalamic TH status and relate them to the metabolic effects of the treatment. Peripheral TH treatment affected feeding behavior, overall growth, core body temperature, body composition, brown adipose tissue (BAT) morphology and uncoupling protein 1 (UCP1) levels and metabolic activity, white adipose tissue (WAT) browning and liver metabolism. This resulted in an increased overall uncoupling capacity and a shift of the lipid metabolism from WAT accumulation to BAT fueling. Both peripheral treatment protocols induced significant changes in TH concentrations within the hypothalamus, with T3 eliciting a downregulation of hypothalamic AMP-activated protein kinase (AMPK), supporting the existence of a central action of peripheral TH. Altogether, these data suggest that peripherally administered TH modulate energy balance by various mechanisms; they also provide a unifying vision of the centrally mediated and the direct local metabolic effect of TH in the context of hyperthyroidism.

Download Full-text

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

BioMed Research International ◽

10.1155/2016/2365609 ◽

2016 ◽

Vol 2016 ◽

pp. 1-15 ◽

Cited By ~ 32

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.

Download Full-text