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Cannabidiol promotes browning in 3T3-L1 adipocytes

DOI:10.1007/s11010-016-2702-5
Authors:
Hilal Ahmad Parray at Daegu University
Hilal Ahmad Parray
Jong Won Yun at Daegu University
Jong Won Yun
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Abstract and Figures

Recruitment of the brown-like phenotype in white adipocytes (browning) and activation of existing brown adipocytes are currently being investigated as a means to combat obesity. Thus, a wide variety of dietary agents that contribute to browning of white adipocytes have been identified. The present study was designed to investigate the effects of cannabidiol (CBD), a major nonpsychotropic phytocannabinoid of Cannabis sativa, on induction of browning in 3T3-L1 adipocytes. CBD enhanced expression of a core set of brown fat-specific marker genes (Ucp1, Cited1, Tmem26, Prdm16, Cidea, Tbx1, Fgf21, and Pgc-1α) and proteins (UCP1, PRDM16, and PGC-1α). Increased expression of UCP1 and other brown fat-specific markers contributed to the browning of 3T3-L1 adipocytes possibly via activation of PPARγ and PI3K. In addition, CBD increased protein expression levels of CPT1, ACSL, SIRT1, and PLIN while down-regulating JNK2, SREBP1, and LPL. These data suggest possible roles for CBD in browning of white adipocytes, augmentation of lipolysis, thermogenesis, and reduction of lipogenesis. In conclusion, the current data suggest that CBD plays dual modulatory roles in the form of inducing the brown-like phenotype as well as promoting lipid metabolism. Thus, CBD may be explored as a potentially promising therapeutic agent for the prevention of obesity.
Chemical structure of cannabidiol (CBD) (a). Cytotoxicity in 3T3-L1 preadipocytes by MTT assay with CBD treatment for 72 h (b). Dose-dependent effect of CBD on expression of brown fat-specific marker proteins by Western blotting (c). 3T3-L1 cells were treated with different doses of CBD for 72 h, followed by quantification of protein expression by densitometric analysis. Data are presented as the mean ± S.D. and differences between groups were determined by One-way analysis of variance (ANOVA) using the Statistical Package of Social Science (SPSS, version 17.0; SPSS Inc., Chicago, IL, USA) program, followed by Turkey’s post hoc tests. Statistical significance between control and CBD-treated is shown as *p < 0.05 or **p < 0.01
Chemical structure of cannabidiol (CBD) (a). Cytotoxicity in 3T3-L1 preadipocytes by MTT assay with CBD treatment for 72 h (b). Dose-dependent effect of CBD on expression of brown fat-specific marker proteins by Western blotting (c). 3T3-L1 cells were treated with different doses of CBD for 72 h, followed by quantification of protein expression by densitometric analysis. Data are presented as the mean ± S.D. and differences between groups were determined by One-way analysis of variance (ANOVA) using the Statistical Package of Social Science (SPSS, version 17.0; SPSS Inc., Chicago, IL, USA) program, followed by Turkey’s post hoc tests. Statistical significance between control and CBD-treated is shown as *p < 0.05 or **p < 0.01
… 
CBD increases the expression of brown fat-specific proteins (a) and genes (b) in 3T3-L1 adipocytes. After 4–6 days of CBD treatment, cells were fixed with p-formaldehyde, subjected to staining with MitoTracker Red®, and then ICC staining for UCP1 (c) and PRDM16 (d). The representative confocal microscopic images show chances of mitochondrial membrane potential and statistics of fluorescence intensity. Immunofluorescent images were captured at 400X magnification and scale bars = 50 μm. Expression patterns of brown fat cell-specific genes were measured by real-time RT-PCR, whereas expression levels of proteins were measured by immunoblotting and quantified by densitometric analysis. Relative intensities (%) of proteins and mRNA were normalized with β-actin. All data are presented as the mean ± S.D., and differences between groups were determined by One-way Analysis of Variance (ANOVA). Statistical significance between control and CBD-treated group is shown as *p < 0.05 and **p < 0.01; control and cocktail-treated group depicted as †p < 0.05; cocktail and CBD-treated group is noted as #p < 0.05
CBD increases the expression of brown fat-specific proteins (a) and genes (b) in 3T3-L1 adipocytes. After 4–6 days of CBD treatment, cells were fixed with p-formaldehyde, subjected to staining with MitoTracker Red®, and then ICC staining for UCP1 (c) and PRDM16 (d). The representative confocal microscopic images show chances of mitochondrial membrane potential and statistics of fluorescence intensity. Immunofluorescent images were captured at 400X magnification and scale bars = 50 μm. Expression patterns of brown fat cell-specific genes were measured by real-time RT-PCR, whereas expression levels of proteins were measured by immunoblotting and quantified by densitometric analysis. Relative intensities (%) of proteins and mRNA were normalized with β-actin. All data are presented as the mean ± S.D., and differences between groups were determined by One-way Analysis of Variance (ANOVA). Statistical significance between control and CBD-treated group is shown as *p < 0.05 and **p < 0.01; control and cocktail-treated group depicted as †p < 0.05; cocktail and CBD-treated group is noted as #p < 0.05
… 
Effects of CBD on expression of marker proteins in 3T3-L1 adipocytes responsible for adipogenesis and lipolysis (a), and lipogenesis (b). Representative images of Oil Red O staining were taken at 200X and scale bars = 50 μm (c). Protein expression was measured by immunoblotting and quantified by densitometric analysis
Effects of CBD on expression of marker proteins in 3T3-L1 adipocytes responsible for adipogenesis and lipolysis (a), and lipogenesis (b). Representative images of Oil Red O staining were taken at 200X and scale bars = 50 μm (c). Protein expression was measured by immunoblotting and quantified by densitometric analysis
… 
Effects of a GW9662 (PPARγ inhibitor) and b Wortmannin (PI3K inhibitor) on expression levels of browning marker proteins. GW9662 (5 μM) and Wortmannin (1 μM) were treated to 3T3-L1 adipocytes, and expression levels of proteins were determined by immunoblotting. All data are presented as the mean ± S.D., and differences among groups were determined by One-way Analysis of Variance (ANOVA) using the Statistical Package of Social Science (SPSS, version 17.0; SPSS Inc., Chicago, IL, USA) Program, followed by Turkey’s post hoc tests. Statistical significance among different groups are shown as *p < 0.05 and **p < 0.01
Effects of a GW9662 (PPARγ inhibitor) and b Wortmannin (PI3K inhibitor) on expression levels of browning marker proteins. GW9662 (5 μM) and Wortmannin (1 μM) were treated to 3T3-L1 adipocytes, and expression levels of proteins were determined by immunoblotting. All data are presented as the mean ± S.D., and differences among groups were determined by One-way Analysis of Variance (ANOVA) using the Statistical Package of Social Science (SPSS, version 17.0; SPSS Inc., Chicago, IL, USA) Program, followed by Turkey’s post hoc tests. Statistical significance among different groups are shown as *p < 0.05 and **p < 0.01
… 
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Cannabidiol promotes browning in 3T3-L1 adipocytes
Hilal Ahmad Parray
1
•Jong Won Yun
1
Received: 11 February 2016 / Accepted: 6 April 2016 / Published online: 11 April 2016
ÓSpringer Science+Business Media New York 2016
Abstract Recruitment of the brown-like phenotype in
white adipocytes (browning) and activation of existing
brown adipocytes are currently being investigated as a
means to combat obesity. Thus, a wide variety of dietary
agents that contribute to browning of white adipocytes
have been identified. The present study was designed to
investigate the effects of cannabidiol (CBD), a major
nonpsychotropic phytocannabinoid of Cannabis sativa, on
induction of browning in 3T3-L1 adipocytes. CBD
enhanced expression of a core set of brown fat-specific
marker genes (Ucp1, Cited1, Tmem26, Prdm16, Cidea,
Tbx1, Fgf21, and Pgc-1a) and proteins (UCP1, PRDM16,
and PGC-1a). Increased expression of UCP1 and other
brown fat-specific markers contributed to the browning of
3T3-L1 adipocytes possibly via activation of PPARcand
PI3K. In addition, CBD increased protein expression levels
of CPT1, ACSL, SIRT1, and PLIN while down-regulating
JNK2, SREBP1, and LPL. These data suggest possible
roles for CBD in browning of white adipocytes, augmen-
tation of lipolysis, thermogenesis, and reduction of lipo-
genesis. In conclusion, the current data suggest that CBD
plays dual modulatory roles in the form of inducing the
brown-like phenotype as well as promoting lipid metabo-
lism. Thus, CBD may be explored as a potentially
promising therapeutic agent for the prevention of obesity.
Keywords Lipogenesis Cannabidiol Thermogenesis
Browning
Introduction
Obesity is the most common metabolic disease affecting
more than 1.4 billion people worldwide [1]. It has reached
global epidemic levels, leading to the development of
many common medical conditions such as diabetes, car-
diovascular diseases, and increased risk of cancer [2]. In
obesity development, energy intake exceeds energy
expenditure [3]. Any specific treatment for obesity must
either reduce energy intake or increase energy expenditure,
or promote both effects at the same time [4]. While
decreasing caloric intake is the baseline defense against
obesity, it is also critical to modify metabolic efficiency
and elevate energy expenditure through key metabolic
organs such as adipose tissues and skeletal muscle [5].
Recently, white and brown adipose tissues (WAT and
BAT) have been proposed as two specialized types of adi-
pose tissue in mammals with opposite functions. WAT and
BAT are morphologically and functionally different tissues,
with a unilocular structure in WAT and multilocular struc-
ture in BAT [6]. BAT plays a crucial role in the generation of
heat by oxidizing fatty acids produced by hydrolysis of
triglycerides [7]. In earlier studies, BAT was thought to
function basically in newborn babies and rodents as a
mechanism for easing adaptation to a cold environment [8].
However, recent studies have confirmed that adult humans
also have active BAT [9,10]. In response to various stimuli
mediated by different factors, UCP1-expressing multilocular
adipocytes with thermogenic capacity develop in WAT and
have been named beige or brite adipocytes [7]. Recruitment
of brite cells in WAT and activation of BAT are currently
being investigated as being potentially beneficial strategies
in the fight against obesity and related metabolic diseases
[11]. As beige adipocyte induction in WAT is associated
with protection against obesity in rodent models, it is
&Jong Won Yun
jwyun@daegu.ac.kr
1
Department of Biotechnology, Daegu University, Kyungsan,
Kyungbuk 712-714, Republic of Korea
123
Mol Cell Biochem (2016) 416:131–139
DOI 10.1007/s11010-016-2702-5
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Despite its reported anti-in ammatory and anti-seizure effects, the effects of CBD on parameters related to adiposity have not been fully elucidated. While in vitro experiments with 3T3-L1 cells, a wellestablished murine pre-adipocyte model, suggest that this phytocannabinoid exerts lipolytic effects (Silvestri et al., 2015), these effects seem to be related to the increase in genes related to adipocyte browning (Parray and Yun, 2016). Treatment of 3T3-L1 cells with CBD resulted in increased metabolic activity in these cells through an enhancement of lipolysis and thermogenesis, related to an elevation in expression of proteins involved in entry and oxidation of fatty acids in the mitochondria, including CPT1, ACSL, UCP1, and PGC-1a, and suggesting a browning of the adipocytes (Parray and Yun, 2016). ...
... While in vitro experiments with 3T3-L1 cells, a wellestablished murine pre-adipocyte model, suggest that this phytocannabinoid exerts lipolytic effects (Silvestri et al., 2015), these effects seem to be related to the increase in genes related to adipocyte browning (Parray and Yun, 2016). Treatment of 3T3-L1 cells with CBD resulted in increased metabolic activity in these cells through an enhancement of lipolysis and thermogenesis, related to an elevation in expression of proteins involved in entry and oxidation of fatty acids in the mitochondria, including CPT1, ACSL, UCP1, and PGC-1a, and suggesting a browning of the adipocytes (Parray and Yun, 2016). In humans, Cavalheiro et al. (2022) reported that an exhaustive review of literature yielded that cannabis users have a lower body mass index compared to non-users. ...
... Our results suggest that the transcriptional changes that result in the browning of adipocytes when exposed to CBD may also be driving the decrease in hypertrophy we observed when treating expanding pre-adipocytes with a low dose of CBD. A study on CBD's ability to promote browning of 3T3-L1 adipocytes described how this phytocannabinoid induced the brown fat phenotype through induction of brown fat-speci c genes and proteins with a concurrent increase in expression of PPAR-g and PI3K (Parray and Yun, 2016). Brown adipose tissue plays a major role in thermogenesis through the generation of heat that is associated with the oxidation of fatty acids mobilized from triacylglycerol stored in lipid droplets. ...
Cannabidiol treatment of proliferating 3T3-L1 pre-adipocytes affects mature cell size and expression of acyltransferases involved in lipid droplet synthesis
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Full-text available
  • Mar 2023
Background The phytocannabinoid cannabidiol (CBD) has been demonstrated to possess anti-inflammatory, anti-seizure, anti-oxidant, and proposed anti-obesity effects. Therapeutic modalities that improve the size of existing adipocytes through a reduction in hypertrophy, or result in increased hyperplasia (increased cell number) and decreased hypertrophy (enlarged cell size) during adipogenesis can result in smaller adipocytes that maintain insulin sensitivity, reducing the incidence of dysfunctional adipose tissue. The effect of timing CBD treatment to the proliferation (mitotic expansion) phase or the differentiation phase of pre-adipocytes on hyperplasia, hypertrophy, and expression of genes involved in triacylglycerol synthesis has not been investigated. We aimed to determine how exposing 3T3-L1 pre-adipocytes to CBD during the expansion or differentiation phase affected proliferation, cell size, and expression of enzymes involved in triacylglycerol synthesis. Methods Cells were treated with CBD at doses of 0.2 µM (low [CBD]) or 20 µM (high [CBD]) for measurement of cell viability and proliferation. Additionally, pre-adipocytes were exposed to CBD during proliferation and before stimulation of differentiation (expansion phase) or during the differentiation protocol (differentiation phase) and cell size, total lipid deposition and gene expression of acylglycerophosphate acyltransferase-2 (AGPAT2), diacylglycerol acyltransferase-2 (DGAT2), and glycerol-3-phosphate acyltransferase-3 (GPAT3) were quantified in the mature, lipid-storing adipocytes. Results The high CBD dose reduced cell viability and completely inhibited differentiation of pre-adipocytes into mature adipocytes when cells were treated during the differentiation period. Treatment of cells with the high CBD dose during the mitotic clonal expansion period significantly reduced but did not inhibit differentiation of the cells into the mature phenotype. The low CBD dose did not affect cell viability and resulted in increased proliferation and smaller mature adipocytes that did not differ from control cells with regards to lipid droplet deposition but that exhibited changes in gene expression of AGPAT and GPAT. Conclusions Our results suggest that a low (0.2 µM), physiologically achievable dose of CBD affects mature adipocyte cell size and gene expression of acyltransferases involved in triacylglycerol synthesis and that these effects are dependent on timing the CBD exposure to the cell’s mitotic clonal expansion phase.
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... The cells were treated with differential medium containing 10% fetal bovine serum (FBS, Gibco, Carlsbad, CA, USA), 5 µg/mL insulin, and maintained in 10% FBS DMEM containing insulin for another 5 days (day [3][4][5][6][7][8]. For induction of browning in 3T3-L1 adipocytes, they were treated with a medium containing 50 nM triiodothyronine (T3, sigma) (day 1-3), and maturation medium was supplemented with 50 nM triiodothyronine and 1 µM rosiglitazone (Rosi, Abcam, Cambridge, UK) (day [3][4][5][6][7][8], called browning media [11]. ML and MR were dissolved in the culture medium to prepare a stock solution. ...
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Mori Folium (Morus alba leaf, MF) and Mori Cortex Radicis (Morus alba root cortex, MR) have been studied for their anti-obesity effects by enhancing the browning process and inhibiting adipogenesis. However, important aspects of their protective mechanisms have not been thoroughly investigated, which could aid in developing functional food. Thus, this study aims to determine the synergistic effects of MF and MR against obesity and its associated mechanisms. In an in vitro cell culture model of brown adipocytes, a 1:1 mixture of MF and MR showed a synergistic effect on the expression of brown adipocyte-specific genes, including Ucp-1, Ppargc1a, Cbp/p300-interacting transactivator (Cited), Prdm16, Tbx1, and Fgf21 compared with either MF- or MR-treated conditions. Moreover, they demonstrated the involvement of cAMP and Ca2+ in induction of brown adipocyte-specific genes. In an in vivo model using HFD-fed mice, MF/MR significantly inhibited weight gain, plasma cholesterol, LDL, TG content, fat mass, and adipocyte size. Furthermore, MF/MR inhibited morphological alteration and the expressions of fatty acid synthesis genes such as Srebp1 and Fasn in the white adipose tissue. Thermogenesis genes were recovered in the brown adipose tissue with MF/MR supplementation, indicating that MF/MR regulated adipocytic dysmetabolism where AMPK signaling is involved. In conclusion, these results suggested that MF/MR regulates brown and beige adipocyte processes, providing one of the preventive functional food/herbal medicines against obesity and its associated metabolic diseases.
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... Momordica charantia extracts can activate the AMPK signalling pathway, reduce adipogenic gene expression and peroxisome proliferatoractivated receptor (PPAR) signalling in adipose tissue, and increase lipid oxidation in adipose tissue, thereby reducing obesity and insulin resistance [72,73]. In addition, cannabidiol can promote adipocyte browning for the treatment of metabolic diseases [74]. ...
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Obesity is often accompanied by metabolic disorder and insulin resistance, resulting in type 2 diabetes. Based on previous findings, FYGL, a natural hyperbranched proteoglycan extracted from the G. lucidum fruiting body, can decrease blood glucose and reduce body weight in diabetic mice. In this article, the underlying mechanism of FYGL in ameliorating obesity-induced diabetes was further investigated both in vivo and in vitro. FYGL upregulated expression of metabolic genes related to fatty acid biosynthesis, fatty acid β-oxidation and thermogenesis; downregulated the expression of insulin resistance-related genes; and significantly increased the number of beige adipocytes in db/db mice. In addition, FYGL inhibited preadipocyte differentiation of 3T3-L1 cells by increasing the expression of FABP-4. FYGL not only promoted fatty acid synthesis but also more significantly promoted triglyceride degradation and metabolism by activating the AMPK signalling pathway, therefore preventing fat accumulation, balancing adipocyte production and lipid metabolism, and regulating metabolic disorders and unhealthy obesity. FYGL could be used as a promising pharmacological agent for the treatment of metabolic disorder-related obesity.
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... It is unknown whether long-term CBD use influences anaerobic performance without a muscle damaging protocol or alters other aspects of health and fitness. Some studies suggest that CBD may play a role in body composition through glucose metabolization in adipocytes [20] and brown adipose tissue [21], but one study suggests that oral CBD (30 mg) has no effect on body composition in those with overweight or obesity [22]. One RCT observed that acute CBD ingestion (300 mg) increased maximal oxygen consumption (VO 2 max) without altering other cardiovascular parameters [23], but there are no other studies to confirm this aerobic enhancement effect. ...
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Background: There is a lack of research on the effects of cannabidiol (CBD) on health-related fitness, physical activity, cognitive health, psychological wellbeing, and concentrations of C-reactive protein (CRP) in healthy individuals. CBD has potential anti-inflammatory and neuroprotective effects. Methods: This study aimed to investigate the effects of 8 weeks of CBD on the above-mentioned measures in healthy individuals. Forty-eight participants were randomized into two groups receiving either oral capsules of 50 mg of CBD or a calorie-matched placebo daily. Participants completed pre- and post-intervention assessments, including blood draws, body composition, fitness, physical activity, and self-reported surveys. Results: There were no significant differences between groups regarding body composition, aerobic fitness, muscular strength, physical activity, cognitive health, psychological wellbeing, and resting CRP concentrations. However, the placebo group experienced a decline in mean peak power and relative peak power compared to the CBD group. Conclusions: The results suggest that 8 weeks of CBD supplementation may prevent declines in anaerobic fitness over time. However, long-term CBD supplementation may not be beneficial for altering measures of health-related fitness, mental health, and inflammation in healthy individuals.
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... browning (41)(42)(43)(44)(45)(46)(47). To our knowledge, this is the first report that NAR, a dietary bioactive compound, enhances ISO-stimulated thermogenic activation (Ucp1 expression and mitochondrial uncoupling) in 3T3-L1 adipocytes at 10 µM, a level that is achievable through dietary consumption in human subjects (38). ...
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Identifying functional brown adipose tissue (BAT) has provided new hope for obesity treatment and prevention. Functional BAT includes classical BAT and brown-like adipose tissue converted from white adipose tissue. By promoting thermogenesis (i.e., heat production) via uncoupling protein 1 (UCP1), functional BAT can increase energy expenditure and aid obesity treatment and prevention. Naringenin (NAR) is a flavanone primarily found in citrus fruits. NAR has been reported to decrease body weight, increase energy expenditure in treated mice, and promote browning in human adipocytes. Here, we examined the effects of NAR on 3T3-L1 adipocytes’ browning and β-adrenergic agonist isoproterenol (ISO)-stimulated thermogenic activation and classical murine brown adipogenesis. In addition, we demonstrated the signaling pathways and involvement of peroxisome proliferator-activated receptor gamma (PPARγ) in the process. We found that NAR did not increase Ucp1 mRNA expression at the basal (i.e., non-ISO stimulated) condition. Instead, it enhanced Ucp1 and Pgc-1 α up-regulation and thermogenesis under ISO-stimulated conditions in 3T3-L1 adipocytes. NAR promoted protein kinase A (PKA) activation and phosphorylation of p38 MAPK downstream of ISO stimulation and activated PPARγ. Pharmacological inhibition of either PKA or p38 and PPARγ knockdown attenuated Ucp1 up-regulation by NAR. Moreover, NAR promoted brown adipogenesis by increasing lipid accumulation, brown marker expression, and thermogenesis in murine brown adipocytes, which was also attenuated by PPARγ knockdown. Together, our results suggest that NAR may promote the development of functional BAT in part through PPARγ activation. NAR’s role in combating human obesity warrants further investigation.
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... In addition to the CB 1 -mediated anorexigenic effect mentioned above, the anti-obesity effect of CBD was mentioned to be CB 2 -mediated [32] or dependent on the induction of β-adrenergic receptors [38]. Moreover, some preclinical animal and in vitro data using cell cultures have identified some mechanisms of action that may contribute to these effects of CBD, including an increase in lipolysis [39,40], an increase in thermogenesis, a decrease in lipogenesis and an increase in browning of white adipocytes [41], and an increase in insulin secretion [42]. In this context, in one of the trials included in this review, CBD at a dose of 100 mg (taken twice a day) rendered a significant increase in the plasma level of gastric inhibitory polypeptide while reducing the levels of plasma resistin in a population of patients with type 2 diabetes. ...
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... Specific members of the gut microbiota, including Lactobacillus sp., have also been associated with BAT activation (Moreno-Navarrete and Fernandez-Real, 2019;Yoon et al., 2020;Kang et al., 2022). In vitro CBD treatment was shown to induce browning of cultured 3T3-L1 adipocytes by increasing their expression of BAT-specific marker genes (Parray and Yun, 2016). Brown adipocytes also take up glucose from circulation for de novo synthesis of free fatty acids to fuel NST ) therefore a CBDinduced increase in brown adipocyte activity or quantity may also provide explanation for the observed improvement in OGT ( Figure 1B). ...
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Browning of white adipocyte tissue (WAT) has received considerable attention due to its potential implication in preventing obesity and related comorbidities. Ginsenoside Rb1 is reported to improve glycolipid metabolism and reduce body weight in obese animals. However whether the body reducing effect mediates by browning effect remains unclear. For this purpose, 3T3-L1 adipocytes were used to study the effect of ginsenoside Rb1 on browning adipocytes specific genes and oxygen consumptions. The results demonstrate that 10 μM of ginsenoside Rb1 increases basal glucose uptake and promoted browning evidenced by significant increases in mRNA expressions of UCP-1, PGC-1α and PRDM16 in 3T3-L1 mature adipocytes. Further, ginsenoside Rb1 also increases PPARγ activity. And the browning effect is abrogated by GW9692, a PPARγ antagonist. In addition, ginsenoside Rb1 increases basal respiration rate, ATP production and uncoupling capacity in 3T3-L1 adipocytes. Those effects are also blunted by GW9692. The results suggest that ginsenoside Rb1 promote browning of 3T3-L1 adipocytes through induction of PPARγ. Our finding offer a new source to discover browning agonists and also useful to understand and extend the applications of ginseng and its constituents.
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Metabolic syndrome: A closer look at the growing epidemic and its associated pathologies
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Obesity is reaching epidemic proportions with recent worldwide figures estimated at 1.4 billion and rising year-on-year. Obesity affects all socioeconomic backgrounds and ethnicities and is a pre-requisite for metabolic syndrome. Metabolic syndrome is a clustering of risk factors, such as central obesity, insulin resistance, dyslipidaemia and hypertension that together culminate in the increased risk of type 2 diabetes mellitus and cardiovascular disease. As these conditions are among the leading causes of deaths worldwide and metabolic syndrome increases the risk of type 2 diabetes mellitus fivefold and cardiovascular disease threefold, it is of critical importance that a precise definition is agreed upon by all interested parties. Also of particular interest is the relationship between metabolic syndrome and cancer. Metabolic syndrome has been associated with a plethora of cancers including breast, pancreatic, colon and liver cancer. Furthermore, each individual risk factor for metabolic syndrome has also an association with cancer. Our review collates internationally generated information on metabolic syndrome, its many definitions and its associations with life-threatening conditions including type 2 diabetes mellitus, cardiovascular disease and cancer, providing a foundation for future advancements on this topic.
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SIRT1 Positively Regulates Autophagy and Mitochondria Function in Embryonic Stem Cells Under Oxidative Stress
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SIRT1, an NAD-dependent deacetylase, plays a role in regulation of autophagy. SIRT1 increases mitochondrial function and reduces oxidative stress, and has been linked to age-related reactive oxygen species (ROS) generation, which is highly dependent on mitochondrial metabolism. H2 O2 induces oxidative stress and autophagic cell death through interference with Beclin 1 and the mTOR signaling pathways. We evaluated connections between SIRT1 activity and induction of autophagy in murine (m) and human (h) embryonic stem cells (ESCs) upon ROS challenge. Exogenous H2 O2 (1mM) induced apoptosis and autophagy in wild-type (WT) and Sirt1-/- mESCs. High concentrations of H2 O2 (1mM) induced more apoptosis in Sirt1-/-, than in WT mESCs. However, addition of 3-Methyladenine (3-MA), a widely used autophagy inhibitor, in combination with H2 O2 induced more cell death in WT than in Sirt1-/- mESCs. Decreased induction of autophagy in Sirt1-/- mESCs was demonstrated by decreased conversion of LC3-I to LC3-II, lowered expression of Beclin-1, decreased LC3 punctae and LysoTracker staining. H2 O2 induced autophagy with loss of mitochondrial membrane potential and disruption of mitochondrial dynamics in Sirt1-/- mESCs. Increased phosphorylation of P70/85-S6 kinase and ribosomal S6 was noted in Sirt1-/- mESCs, suggesting that SIRT1 regulates the mTOR pathway. Consistent with effects in mESCs, inhibition of SIRT1 using Lentivirus-mediated SIRT1 shRNA in hESCs demonstrated that knock-down of SIRT1 decreased H2 O2 -induced autophagy. This suggests a role for SIRT1 in regulating autophagy and mitochondria function in ESCs upon oxidative stress, effects mediated at least in part by the class III PI3K/Beclin 1 and mTOR pathways. Stem Cells 2014.
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Brown and beige fat: Development, function and therapeutic potential
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Adipose tissue, best known for its role in fat storage, can also suppress weight gain and metabolic disease through the action of specialized, heat-producing adipocytes. Brown adipocytes are located in dedicated depots and express constitutively high levels of thermogenic genes, whereas inducible 'brown-like' adipocytes, also known as beige cells, develop in white fat in response to various activators. The activities of brown and beige fat cells reduce metabolic disease, including obesity, in mice and correlate with leanness in humans. Many genes and pathways that regulate brown and beige adipocyte biology have now been identified, providing a variety of promising therapeutic targets for metabolic disease.
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PPAR?? signaling and metabolism: The good, the bad and the future
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Thiazolidinediones (TZDs) are potent insulin sensitizers that act through the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) and are highly effective oral medications for type 2 diabetes. However, their unique benefits are shadowed by the risk for fluid retention, weight gain, bone loss and congestive heart failure. This raises the question as to whether it is possible to build a safer generation of PPARγ-specific drugs that evoke fewer side effects while preserving insulin-sensitizing potential. Recent studies that have supported the continuing physiologic and therapeutic relevance of the PPARγ pathway also provide opportunities to develop newer classes of molecules that reduce or eliminate adverse effects. This review highlights key advances in understanding PPARγ signaling in energy homeostasis and metabolic disease and also provides new explanations for adverse events linked to TZD-based therapy.
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A novel JNK2/SREBP-1c pathway involved in insulin-induced fatty acid synthesis in human adipocytes
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  • Mar 2013
Insulin plays important roles in apoptosis and lipid droplet (LD) formation, and it is one of the determinants involved in increasing fat mass. However, the mechanisms underlying insulin-induced enlargement of fat mass remain unclear. Our previous study suggested that insulin-induced increases in LD are related to JNK2-mediated upregulation of CIDEC in human adipocytes. However, other genes involved in insulin/JNK2-induced LD formation are unknown. Here, we explored insulin/JNK2-regulated genes to clarify the mechanism of enlargement of LD. Microarray analysis revealed that an insulin/JNK2 pathway mostly regulates expression of genes involved in lipid metabolism, including sterol regulatory element binding protein (SREBP)-1, a key transcription factor of lipogenesis. The JNK inhibitor SP600125 blocked insulin-induced upregulation of SREBP-1c expression. Small interfering RNA-mediated depletion of JNK2 suppressed insulin-induced nuclear accumulation of the active form of SREBP-1 protein and upregulation of SREBP-1c. Furthermore, depletion of JNK2 attenuated insulin-induced upregulation of SREBP-1c target lipogenic enzymes, leading to reduced de novo fatty acid synthesis. In addition, JNK2 coimmunoprecipitated with SREBP-1, reinforcing the correlation between JNK2 and SREBP-1. These results suggest that SREBP-1c is a novel insulin/JNK2-regulated gene and that the JNK2/SREBP-1c pathway mediates insulin-induced fatty acid synthesis, which may lead to enlargement of LD in human adipocytes.
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Identification and Importance of Brown Adipose Tissue in Adult Humans
Article
  • Aug 2009
Although brown adipose tissue in infants and young children is important for regulation of energy expenditure, there has been considerable debate on whether brown adipose tissue normally exists in adult humans and has physiologic relevance in this population. In the last decade, radiologic studies in adults have identified areas of adipose tissue with high 18F-fluorodeoxyglucose (18F-FDG) uptake, putatively identified as brown fat. This radiologic study assessed the presence of physiologically significant brown adipose tissue among 1972 adult patients who had 3640 consecutive 18F-FDG positron-emission tomographic and computed tomographic whole-body scans between 2003 and 2006. Brown adipose tissue was defined as areas of tissue that were more than 4 mm in diameter, had the CT density of adipose tissue, and had maximal standardized uptake values of 18F-FDG of at least 2.0 gm per mL. A sample of 204 date-matched patients without brown adipose tissue served as the control group. Using these criteria, positron-emission tomographic and computed tomographic scans identified brown adipose tissue in 106 of the 1972 patients (5.4%). The most common location for substantial amounts of brown adipose tissue was the region extending from the anterior neck to supraclavicular region. Immunohistochemical staining for uncoupling protein 1 in this region confirmed the identity of immunopositive, multilocular adipocytes as brown adipose tissue. More brown adipose tissue was detected in women (7.5% [76/1013]) than in men (3.1% [30/959]); the female:male ratio was 2.4:1.0 (P 64) (P 64 years) (P for trend = 0.007). These findings show that functional brown adipose tissue is prevalent in adult humans, and significantly more frequently in women. The inverse correlation of body mass index with the amount of brown adipose tissue, especially in older patients, suggests to the investigators a possible role of brown adipose tissue in protecting against obesity.
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What We Talk About When We Talk About Fat
Article
  • Jan 2014
There has been an upsurge of interest in the adipocyte coincident with the onset of the obesity epidemic and the realization that adipose tissue plays a major role in the regulation of metabolic function. The past few years, in particular, have seen significant changes in the way that we classify adipocytes and how we view adipose development and differentiation. We have new perspective on the roles played by adipocytes in a variety of homeostatic processes and on the mechanisms used by adipocytes to communicate with other tissues. Finally, there has been significant progress in understanding how these relationships are altered during metabolic disease and how they might be manipulated to restore metabolic health.
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Adipose tissue browning and metabolic health
Article
Accumulation of excess white adipose tissue (WAT) has deleterious consequences for metabolic health. The activation of brown adipose tissue (BAT), the primary organ for heat production, confers beneficial effects on adiposity, insulin resistance and hyperlipidaemia, at least in mice. As the amount of metabolically active BAT seems to be particularly low in patients with obesity or diabetes mellitus who require immediate therapy, new avenues are needed to increase the capacity for adaptive thermogenesis. In this light, we review the findings that BAT in human adults might consist of not only classic brown adipocytes but also inducible brown adipocytes (also called beige, brown-in-white, or brite adipocytes), which are phenotypically distinct from both white and brown adipocytes. Stimulating the development of beige adipocytes in WAT (so called 'browning') might reduce adverse effects of WAT and could help to improve metabolic health. This article focuses on the development and regulatory control of beige adipocytes at the transcriptional and hormonal levels. Emerging insights into the metabolic role of beige adipocytes are also discussed, along with the developments that can be expected from these promising targets for therapy of metabolic disease in the future.
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