Theobromine enhances the conversion of white adipocytes into beige adipocytes in a PPARγ activation-dependent manner

Browning of white adipose tissue has been proven to be a potential target to fight against obesity and its metabolic commodities, making the exploration of molecules involved in browning process important. Among those browning agents reported recently, FGF21 play as a quite promising candidate for treating obesity for its obvious enhancement of thermogenic capacity in adipocyte and significant improvement of metabolic disorders in both mice and human. However, whether other members of fibroblast growth factor (FGF) family play roles in adipose thermogenesis and obese development is still an open question. Here, we examined the mRNA expression of all FGF family members in three adipose tissues of male C57BL/6 mice and found that FGF9 is highly expressed in adipose tissue and decreased under cold stress. Furthermore, FGF9 treatment inhibited thermogenic genes in the process of beige adipocytes differentiation from stromal vascular fraction (SVF) in a dose-dependent manner. Similar results were obtained with FGF9 overexpression. Consistently, knockdown of FGF9 in SVF cells by using lentiviral shRNA increased thermogenic genes in differentiated beige adipocytes. RNA sequencing analysis revealed a significant increment of hypoxia-inducible factor (HIF) pathway in the early stage of beige adipocytes differentiation under FGF9 treatment, which was validated by real-time PCR. FGF9 expression was increased in subcutaneous WAT of obese human and mice. This study shows that adipose-derived FGF9 play as an inhibitory role in the browning of white adipocytes. Activation of hypoxia signaling at early stage of adipose browning process may contribute to this anti-thermogenic effect of FGF9.

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Enhancement of the Antiobesity and Antioxidant Effect of Purple Sweet Potato Extracts and Enhancement of the Effects by Fermentation

Antioxidants ◽

10.3390/antiox10060888 ◽

2021 ◽

Vol 10 (6) ◽

pp. 888

Author(s):

Seul Gi Lee ◽

Jongbeom Chae ◽

Dong Se Kim ◽

Jung-Bok Lee ◽

Gi-Seok Kwon ◽

...

Keyword(s):

Sweet Potato ◽

Ipomoea Batatas ◽

Radical Scavenging ◽

The Body ◽

Brown Adipocyte ◽

Obese Mice ◽

Adipose Tissues ◽

White Adipocytes ◽

Beige Adipocytes ◽

Purple Sweet Potato

The browning of white adipocytes, which transforms energy-storing white adipocytes to heat-producing beige adipocytes, is considered a strategy against metabolic diseases. Several dietary compounds, such as anthocyanins, flavonoids, and phenolic acids, induce a brown adipocyte-like phenotype in white adipocytes. In this study, we demonstrated that purple sweet potato (Ipomoea batatas) extract (PSP) exhibited potent radical scavenging activity. In addition, PSP was found to contain large amounts of phenolic, flavonoid, and anthocyanin compounds; the amount of these compounds was affected by fermentation. Functionally, PSP-induced adipose browning in high-fat-diet (HFD)-induced obese mice. The administration of PSP significantly suppressed the body weight gain and abnormal expansion of white adipose tissues in the obese mice. The expression of adipose browning-related genes was higher in the inguinal white adipose tissues from the PSP-treated mice than those in the HFD-fed mice. Moreover, PSP-treated 3T3-L1 adipocytes formed multilocular lipid droplets, similar to those formed in the 3T3-L1 adipocytes treated with a browning induction cocktail. The PSP-treated cells had an increased expression level of mitochondria and lipolysis-related genes. The browning effects of PSP were enhanced by fermentation with Lactobacillus. This study, to our knowledge, is the first to identify a new mechanism to increase the antiobesity effects of PSP by inducing adipocyte browning of adipocytes.

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Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue

Nature Communications ◽

10.1038/s41467-021-22579-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Anastasia Georgiadi ◽

Valeria Lopez-Salazar ◽

Rabih El- Merahbi ◽

Rhoda Anane Karikari ◽

Xiaochuan Ma ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Dependent Manner ◽

Metabolic Dysfunction ◽

Functional Interaction ◽

White Adipocyte ◽

White Adipocytes ◽

Obesity And Diabetes ◽

Adhesion Gpcr ◽

Circulating Levels

AbstractThe proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes.

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Cissus Quadrangularis enhances UCP1 mRNA, indicative of white adipocyte browning and decreases central obesity in humans in a randomized trial

Scientific Reports ◽

10.1038/s41598-021-81606-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Saimai Chatree ◽

Chantacha Sitticharoon ◽

Pailin Maikaew ◽

Kitchaya Pongwattanapakin ◽

Issarawan Keadkraichaiwat ◽

...

Keyword(s):

Treated Group ◽

Dependent Manner ◽

Hip Circumference ◽

White Adipocyte ◽

Ppar Γ ◽

White Adipocytes ◽

Cissus Quadrangularis ◽

Baseline Values ◽

Dose Dependent ◽

Vehicle Treated Group

AbstractObesity is associated with the growth and expansion of adipocytes which could be decreased via several mechanisms. Cissus Quadrangularis (CQ) extract has been shown to reduce obesity in humans; however, its effect on human white adipocytes (hWA) has not been elucidated. This study aimed to investigate the effects of CQ on obesity, lipolysis, and browning of hWA. CQ treatment in obese humans significantly decreased waist circumference at week 4 and week 8 when compared with the baseline values (p < 0.05 all) and significantly decreased hip circumference at week 8 when compared with the baseline and week 4 values (p < 0.05 all). Serum leptin levels of the CQ-treated group were significantly higher at week 8 compared to baseline levels (p < 0.05). In hWA, glycerol release was reduced in the CQ-treated group when compared with the vehicle-treated group. In the browning experiment, pioglitazone, the PPAR-γ agonist, increased UCP1 mRNA when compared to vehicle (p < 0.01). Interestingly, 10, 100, and 1000 ng/ml CQ extract treatment on hWA significantly enhanced UCP1 expression in a dose-dependent manner when compared to pioglitazone treatment (p < 0.001 all). In conclusion, CQ decreased waist and hip circumferences in obese humans and enhanced UCP1 mRNA in hWA suggestive of its action via browning of hWA.

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Characteristics of Beige Adipocytes Induced from White Adipocytes by <i>Kikyo</i> Extract

Journal of Biomedical Science and Engineering ◽

10.4236/jbise.2016.97029 ◽

2016 ◽

Vol 09 (07) ◽

pp. 342-353 ◽

Cited By ~ 2

Author(s):

Naofumi Shiomi ◽

Marie Ito ◽

Keiko Watanabe

Keyword(s):

White Adipocytes ◽

Beige Adipocytes

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Betatrophin knockdown induces beiging and mitochondria biogenesis of white adipocytes

Journal of Endocrinology ◽

10.1530/joe-19-0447 ◽

2020 ◽

Vol 245 (1) ◽

pp. 93-100 ◽

Cited By ~ 1

Author(s):

Zhe-Zhen Liao ◽

Xiao-Yan Qi ◽

Ya-Di Wang ◽

Jiao-Yang Li ◽

Qian-Qian Gu ◽

...

Keyword(s):

Signaling Pathway ◽

Ampk Signaling ◽

White Adipocytes ◽

Beige Adipocytes ◽

Beige Fat ◽

Mitochondria Biogenesis ◽

Paracrine Actions ◽

White Fat

Remodeling of energy-storing white fat into energy-consuming beige fat has led to a promising new approach to alleviate adiposity. Several studies have shown adipokines can induce white adipose tissue (WAT) beiging through autocrine or paracrine actions. Betatrophin, a novel adipokine, has been linked to energy expenditure and lipolysis but not clearly clarified. Here, we using high-fat diet-induced obesity to determine how betatrophin modulate beiging and adiposity. We found that betatrophin-knockdown mice displayed less white fat mass and decreased plasma TG and NEFA levels. Consistently, inhibition of betatrophin leads to the phenotype change of adipocytes characterized by increased mitochondria contents, beige adipocytes and mitochondria biogenesis-specific markers both in vivo and in vitro. Of note, blocking AMP-activated protein kinase (AMPK) signaling pathway is able to abolish enhanced beige-like characteristics in betatrophin-knockdown adipocytes. Collectively, downregulation of betatrophin induces beiging in white adipocytes through activation of AMPK signaling pathway. These processes suggest betatrophin as a latent therapeutic target for obesity.

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Lsd1 prevents age-programed loss of beige adipocytes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1702641114 ◽

2017 ◽

Vol 114 (20) ◽

pp. 5265-5270 ◽

Cited By ~ 16

Author(s):

Delphine Duteil ◽

Milica Tosic ◽

Dominica Willmann ◽

Anastasia Georgiadi ◽

Toufike Kanouni ◽

...

Keyword(s):

Adipose Tissue ◽

Peroxisome Proliferator ◽

Fat Cell ◽

White Adipocyte ◽

White Adipocytes ◽

Age Related ◽

Beige Adipocytes ◽

Beige Fat ◽

And Function

Aging is accompanied by major changes in adipose tissue distribution and function. In particular, with time, thermogenic-competent beige adipocytes progressively gain a white adipocyte morphology. However, the mechanisms controlling the age-related transition of beige adipocytes to white adipocytes remain unclear. Lysine-specific demethylase 1 (Lsd1) is an epigenetic eraser enzyme positively regulating differentiation and function of adipocytes. Here we show that Lsd1 levels decrease in aging inguinal white adipose tissue concomitantly with beige fat cell decline. Accordingly, adipocyte-specific increase of Lsd1 expression is sufficient to rescue the age-related transition of beige adipocytes to white adipocytes in vivo, whereas loss of Lsd1 precipitates it. Lsd1 maintains beige adipocytes by controlling the expression of peroxisome proliferator-activated receptor α (Ppara), and treatment with a Ppara agonist is sufficient to rescue the loss of beige adipocytes caused by Lsd1 ablation. In summary, our data provide insights into the mechanism controlling the age-related beige-to-white adipocyte transition and identify Lsd1 as a regulator of beige fat cell maintenance.

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Anti-Adipogenic Effects of Delphinidin-3-O-β-Glucoside in 3T3-L1 Preadipocytes and Primary White Adipocytes

Molecules ◽

10.3390/molecules24101848 ◽

2019 ◽

Vol 24 (10) ◽

pp. 1848 ◽

Cited By ~ 10

Author(s):

Miey Park ◽

Anshul Sharma ◽

Hae-Jeung Lee

Keyword(s):

Fatty Acid Synthase ◽

Regulatory Element ◽

Adenosine Monophosphate ◽

Immunoblot Analysis ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

White Adipocytes ◽

Health Promoting ◽

Treatment Of Obesity

Delphinidin-3-O-β-glucoside (D3G) is a health-promoting anthocyanin whose anti-obesity activity has not yet been thoroughly investigated. We examined the effects of D3G on adipogenesis and lipogenesis in 3T3-L1 adipocytes and primary white adipocytes using real-time RT-PCR and immunoblot analysis. D3G significantly inhibited the accumulation of lipids in a dose-dependent manner without displaying cytotoxicity. In the 3T3-L1 adipocytes, D3G downregulated the expression of key adipogenic and lipogenic markers, which are known as peroxisome proliferator-activated receptor gamma (PPARγ), sterol regulatory element-binding transcription factor 1 (SREBP1), CCAAT/enhancer-binding protein alpha (C/EBPα), and fatty acid synthase (FAS). Moreover, the relative protein expression of silent mating type information regulation 2 homolog 1 (SIRT1) and carnitine palmitoyltransferase-1 (CPT-1) were increased, alongside reduced lipid levels and the presence of several small lipid droplets. Furthermore, D3G increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), which suggests that D3G may play a role in AMPK and ACC activation in adipocytes. Our data indicate that D3G attenuates adipogenesis and promotes lipid metabolism by activating AMPK-mediated signaling, and, hence, could have a therapeutic role in the management and treatment of obesity.

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Scd1 controls de novo beige fat biogenesis through succinate-dependent regulation of mitochondrial complex II

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1914553117 ◽

2020 ◽

Vol 117 (5) ◽

pp. 2462-2472 ◽

Cited By ~ 6

Author(s):

Keli Liu ◽

Liangyu Lin ◽

Qing Li ◽

Yueqing Xue ◽

Fanjun Zheng ◽

...

Keyword(s):

Cell Fate ◽

Metabolic Diseases ◽

De Novo ◽

Great Promise ◽

Mitochondrial Complex ◽

Differentiation Potential ◽

Complex Ii ◽

White Adipocytes ◽

Beige Adipocytes ◽

Adipocyte Progenitors

Preadipocytes can give rise to either white adipocytes or beige adipocytes. Owing to their distinct abilities in nutrient storage and energy expenditure, strategies that specifically promote “beiging” of adipocytes hold great promise for counterbalancing obesity and metabolic diseases. Yet, factors dictating the differentiation fate of adipocyte progenitors remain to be elucidated. We found that stearoyl-coenzyme A desaturase 1 (Scd1)-deficient mice, which resist metabolic stress, possess augmentation in beige adipocytes under basal conditions. Deletion of Scd1 in mature adipocytes expressing Fabp4 or Ucp1 did not affect thermogenesis in mice. Rather, Scd1 deficiency shifted the differentiation fate of preadipocytes from white adipogenesis to beige adipogenesis. Such effects are dependent on succinate accumulation in adipocyte progenitors, which fuels mitochondrial complex II activity. Suppression of mitochondrial complex II by Atpenin A5 or oxaloacetic acid reverted the differentiation potential of Scd1-deficient preadipocytes to white adipocytes. Furthermore, supplementation of succinate was found to increase beige adipocyte differentiation both in vitro and in vivo. Our data reveal an unappreciated role of Scd1 in determining the cell fate of adipocyte progenitors through succinate-dependent regulation of mitochondrial complex II.

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Mitochondria in White, Brown, and Beige Adipocytes

Stem Cells International ◽

10.1155/2016/6067349 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 71

Author(s):

Miroslava Cedikova ◽

Michaela Kripnerová ◽

Jana Dvorakova ◽

Pavel Pitule ◽

Martina Grundmanova ◽

...

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Energy Metabolism ◽

Oxygen Radicals ◽

Adipocyte Differentiation ◽

Nonshivering Thermogenesis ◽

Adipose Tissues ◽

White Adipocytes ◽

Beige Adipocytes ◽

Colour Appearance

Mitochondria play a key role in energy metabolism in many tissues, including cardiac and skeletal muscle, brain, liver, and adipose tissue. Three types of adipose depots can be identified in mammals, commonly classified according to their colour appearance: the white (WAT), the brown (BAT), and the beige/brite/brown-like (bAT) adipose tissues. WAT is mainly involved in the storage and mobilization of energy and BAT is predominantly responsible for nonshivering thermogenesis. Recent data suggest that adipocyte mitochondria might play an important role in the development of obesity through defects in mitochondrial lipogenesis and lipolysis, regulation of adipocyte differentiation, apoptosis, production of oxygen radicals, efficiency of oxidative phosphorylation, and regulation of conversion of white adipocytes into brown-like adipocytes. This review summarizes the main characteristics of each adipose tissue subtype and describes morphological and functional modifications focusing on mitochondria and their activity in healthy and unhealthy adipocytes.

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