D-Mannitol Induces a Brown Fat-like Phenotype via a β3-Adrenergic Receptor-Dependent Mechanism

The presence of brown adipocytes within white adipose tissue is associated with phenotypes that exhibit improved metabolism and proper body weight maintenance. Therefore, a variety of dietary agents that facilitate the browning of white adipocytes have been investigated. In this study, we screened a natural product library comprising 133 compounds with the potential to promote the browning of white adipocytes, and found that D-mannitol induces the browning of 3T3-L1 adipocytes by enhancing the expression of brown fat-specific genes and proteins, and upregulating lipid metabolism markers. D-mannitol also increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase 1 (ACC), suggesting a possible role in lipolysis and fat oxidation. Moreover, an increase in the expression of genes associated with D-mannitol-induced browning was strongly correlated with the activation of the β3-adrenergic receptor as well as AMPK, protein kinase A (PKA), and PPARγ coactivator 1α (PGC1α). D-mannitol effectively reduced the body weight of mice fed a high-fat diet, and increased the expression of β1-oxidation and energy expenditure markers, such as Cidea, carnitine palmityl transferase 1 (CPT1), uncoupling protein 1 (UCP1), PGC1α, and acyl-coenzyme A oxidase (ACOX1) in the inguinal white adipose tissue. Our findings suggest that D-mannitol plays a dual regulatory role by inducing the generation of a brown fat-like phenotype and enhancing lipid metabolism. These results indicate that D-mannitol can function as an anti-obesity supplement.

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Proses Pencokelatan Jaringan Adiposa

Indonesian Journal of Health Science ◽

10.54957/ijhs.v1i2.104 ◽

2021 ◽

Vol 1 (2) ◽

pp. 42-46

Author(s):

Afifa Radhina

Keyword(s):

Adipose Tissue ◽

Energy Consumption ◽

White Adipose Tissue ◽

Uncoupling Protein ◽

The Body ◽

Brown Fat ◽

Uncoupling Protein 1 ◽

Brown Adipocytes ◽

Major Health Problem ◽

White Fat

Obesity is a common, serious, and detrimental condition. In 2014, more than 1.9 billion adults were overweight. Obesity is associated with many diseases and the increase in obesity has become a major health problem. Obesity is caused by an imbalance between energy intake and energy consumption. Adipose tissue is an endocrine organ that secretes many hormones and cytokines that can affect metabolism. There are two types of adipose tissue in the body with different functions, namely white adipose tissue and brown adipose tissue. White fat has a major function in storing energy and is increased in obesity, while brown fat produces heat (thermogenesis) and then increases energy consumption. Therefore, brown fat and the induction of brown fat-like properties in white fat, have been considered as targets in the fight against obesity. The complex process of cell differentiation leading to the appearance of active brown adipocytes has been identified. There are classic brown adipocytes and cream adipocytes. Beige adipocytes are brown adipocytes that appear on precursor cells of white adipose tissue due to stimuli. Brown adipocytes are equipped with mitochondria containing uncoupling protein 1 (UCP1), which, when activated, controls ATP synthesis and stimulates respiratory chain activity. The browning process of adipose tissue is controlled by factors such as exercise. Obesitas merupakan keadaan yang umum, serius, dan merugikan. Tahun 2014, lebih dari 1,9 milyar orang dewasa mengalami kelebihan berat badan. Obesitas berasosiasi dengan banyak penyakit dan peningkatan obesitas telah menjadi masalah kesehatan utama. Obesitas disebabkan oleh ketidakseimbangan antara energi yang masuk dan konsumsi energi. Jaringan adiposa dalam tubuh ada dua tipe yang fungsinya berbeda, yakni jaringan adiposa putih dan jaringan adiposa cokelat. Lemak putih berfungsi utama dalam menyimpan energi dan meningkat pada obesitas, sedangkan lemak cokelat menghasilkan panas (termogenesis) dan kemudian meningkatkan konsumsi energi. Oleh karena itu, lemak cokelat dan induksi sifat seperti lemak cokelat pada lemak putih, telah dipertimbangkan sebagai target dalam melawan obesitas. Tujuan penelitian ini adalah untuk mengetahui proses pencoklatan jaringan adiposa putih. Metode penelitian yang digunakan adalah metode penelusuran ilmiah. Hasil penelitian diperoleh bahwa adiposit krem merupakan adiposit cokelat yang muncul pada sel prekursor dari jaringan adiposa putih karena adanya stimuli. Adiposit krem sama seperti adiposit cokelat dilengkapi dengan mitokondria yang mengandung uncoupling protein 1 (UCP1), yang ketika teraktivasi akan mengendalikan sintesis ATP dan menstimulasi aktivitas rantai respirasi. Beberapa regulator seperti PPAR γ, PGC-1α, dan PRDM16 muncul sebagai pelaku utama dalam proses diferensiasi adiposit krem.

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Reduction of dietary obesity in aP2-Ucp transgenic mice: physiology and adipose tissue distribution

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.270.5.e768 ◽

1996 ◽

Vol 270 (5) ◽

pp. E768-E775 ◽

Cited By ~ 19

Author(s):

J. Kopecky ◽

Z. Hodny ◽

M. Rossmeisl ◽

I. Syrovy ◽

L. P. Kozak

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Transgenic Mice ◽

Body Weight Gain ◽

Uncoupling Protein ◽

Gene Promoter ◽

Lipid Binding ◽

Brown Fat ◽

Mitochondrial Uncoupling ◽

Dietary Obesity

We seek to determine whether increased energy dissipation in adipose tissue can prevent obesity. Transgenic mice with C57BL6/J background and the adipocyte lipid-binding protein (aP2) gene promoter directing expression of the mitochondrial uncoupling protein (UCP) gene in white and brown fat were used. Physiologically, UCP is essential for nonshivering thermogenesis in brown fat. Mice were assigned to a chow or a high-fat (HF) diet at 3 mo of age. Over the next 25 wk, gains of body weight were similar in corresponding subgroups (n = 6-8) of female and male mice: 4-5 g in chow nontransgenic and transgenic, 20 g in HF nontransgenic, and 9-11 g in HF transgenic mice. The lower body weight gain in the HF transgenic vs. nontransgenic mice corresponded to a twofold lower feed efficiency. Gonadal fat was enlarged, but subcutaneous white fat was decreased in the transgenic vs. nontransgenic mice in both dietary conditions. The results suggest that UCP synthesized from the aP2 gene promoter is capable of reducing dietary obesity.

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Anti-Obesity Effects of Collagen Peptide Derived from Skate (Raja kenojei) Skin Through Regulation of Lipid Metabolism

Marine Drugs ◽

10.3390/md16090306 ◽

2018 ◽

Vol 16 (9) ◽

pp. 306 ◽

Cited By ~ 14

Author(s):

Minji Woo ◽

Yeong Song ◽

Keon-Hee Kang ◽

Jeong Noh

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Fatty Acid ◽

Lipid Metabolism ◽

Protein Expression ◽

The Body ◽

Chow Diet ◽

Dependent Manner ◽

Hepatic Lipid ◽

Collagen Peptide

This study investigated the anti-obesity effects of collagen peptide derived from skate skin on lipid metabolism in high-fat diet (HFD)-fed mice. All C57BL6/J male mice were fed a HFD with 60% kcal fat except for mice in the normal group which were fed a chow diet. The collagen-fed groups received collagen peptide (1050 Da) orally (100, 200, or 300 mg/kg body weight per day) by gavage, whereas the normal and control groups were given water (n = 9 per group). The body weight gain and visceral adipose tissue weight were lower in the collagen-fed groups than in the control group (p < 0.05). Plasma and hepatic lipid levels were significantly reduced by downregulating the hepatic protein expression levels for fatty acid synthesis (sterol regulatory element binding protein-1 (SREBP-1), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC)) and cholesterol synthesis (SREBP-2 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)) and upregulating those for β-oxidation (peroxisome proliferator-activated receptor alpha (PPAR-α) and carnitine palmitoyltransferase 1 (CPT1)) and synthesis of bile acid (cytochrome P450 family 7 subfamily A member 1 (CYP7A1)) (p < 0.05). In the collagen-fed groups, the hepatic protein expression level of phosphorylated 5′ adenosine monophosphate-activated protein kinase (p-AMPK) and plasma adiponectin levels were higher, and the leptin level was lower (p < 0.05). Histological analysis revealed that collagen treatment suppressed hepatic lipid accumulation and reduced the lipid droplet size in the adipose tissue. These effects were increased in a dose-dependent manner. The findings indicated that skate collagen peptide has anti-obesity effects through suppression of fat accumulation and regulation of lipid metabolism.

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Iodothyronine 5′-deiodinase activity as an early event of prenatal brown-fat differentiation in bovine development

Biochemical Journal ◽

10.1042/bj2590555 ◽

1989 ◽

Vol 259 (2) ◽

pp. 555-559 ◽

Cited By ~ 25

Author(s):

M Giralt ◽

L Casteilla ◽

O Viñas ◽

T Mampel ◽

R Iglesias ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Uncoupling Protein ◽

Brown Fat ◽

Early Event ◽

Type I ◽

Fetal Life ◽

Reverse T3 ◽

Deiodinase Activity ◽

Brown Adipose

Iodothyronine 5'-deiodinase activity appears to be a type I enzyme in bovine brown adipose tissue, on the basis of its high Km for 3,3',5'-tri-iodothyronine (‘reverse T3’) (in the micromolar range) and sensitivity to propylthiouracil inhibition. This enzyme activity is already detectable in perirenal adipose tissue of bovine fetuses in the second month of gestation, reaches peak values around the seventh month of fetal life, declines before birth, becomes lower after parturition and finally undetectable in the adult cow. Iodothyronine 5'-deiodinase activity is present in the pericardic, peritoneal and intermuscular adipose depots of the neonatal calf, but it is always undetectable in the subcutaneous adipose tissue. It is concluded that iodothyronine 5'-deiodinase is a specific feature of brown fat in the bovine species that is not shared by white adipose tissue. white adipose tissue. Peak values of 5'-deiodinating activity appear as an early event in the prenatal differentiation programme of bovine brown-fat cells as they occur when uncoupling-protein-gene expression first starts.

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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.

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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.

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Deciphering White Adipose Tissue Heterogeneity

Biology ◽

10.3390/biology8020023 ◽

2019 ◽

Vol 8 (2) ◽

pp. 23 ◽

Cited By ~ 19

Author(s):

Quyen Luong ◽

Jun Huang ◽

Kevin Y. Lee

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Lineage Tracing ◽

The Body ◽

Functional Heterogeneity ◽

Tissue Heterogeneity ◽

Adipose Tissue Depots ◽

White Adipocytes ◽

Increased Risk ◽

Beige Adipocytes

Adipose tissue not only stores energy, but also controls metabolism through secretion of hormones, cytokines, proteins, and microRNAs that affect the function of cells and tissues throughout the body. Adipose tissue is organized into discrete depots throughout the body, and these depots are differentially associated with insulin resistance and increased risk of metabolic disease. In addition to energy-dissipating brown and beige adipocytes, recent lineage tracing studies have demonstrated that individual adipose depots are composed of white adipocytes that are derived from distinct precursor populations, giving rise to distinct subpopulations of energy-storing white adipocytes. In this review, we discuss this developmental and functional heterogeneity of white adipocytes both between and within adipose depots. In particular, we will highlight findings from our recent manuscript in which we find and characterize three major subtypes of white adipocytes. We will discuss these data relating to the differences between subcutaneous and visceral white adipose tissue and in relationship to previous work deciphering adipocyte heterogeneity within adipose tissue depots. Finally, we will discuss the possible implications of adipocyte heterogeneity may have for the understanding of lipodystrophies.

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Unripe Rubus coreanus Miquel Extract Containing Ellagic Acid Promotes Lipolysis and Thermogenesis In Vitro and In Vivo

Molecules ◽

10.3390/molecules25245954 ◽

2020 ◽

Vol 25 (24) ◽

pp. 5954

Author(s):

Kyeong Jo Kim ◽

Eui-Seon Jeong ◽

Ki Hoon Lee ◽

Ju-Ryun Na ◽

Soyi Park ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Ellagic Acid ◽

Uncoupling Protein ◽

Hormone Sensitive Lipase ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Rubus Coreanus ◽

Associated Proteins

Previously, we demonstrated that a 5% ethanol extract of unripe Rubus coreanus (5-uRCK) and ellagic acid has hypocholesterolemic and antiobesity activity, at least partially mediated by the downregulation of adipogenic and lipogenic gene expression in high-fat diet (HFD)-fed animals. The present study investigated the thermogenic and lipolytic antiobesity effects of 5-uRCK and ellagic acid in HFD-induced obese C57BL/6 mice and explored its mechanism of action. Mice fed an HFD received 5-uRCK or ellagic acid as a post-treatment or pretreatment. Both post-treated and pretreated mice showed significant reductions in body weight and adipose tissue mass compared to the HFD-fed mice. The protein levels of lipolysis-associated proteins, such as adipose triglyceride lipase (ATGL), phosphorylated hormone-sensitive lipase (p-HSL), and perilipin1 (PLIN1), were significantly increased in both the 5-uRCK- and ellagic acid-treated mouse epididymal white adipose tissue (eWAT). Additionally, thermogenesis-associated proteins, such as peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyl transferase-1 (CPT1), uncoupling protein 1 (UCP1), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), in inguinal white adipose tissue (ingWAT) were clearly increased in both the 5-uRCK- and ellagic acid-treated mice compared to HFD-fed mice. These results suggest that 5-uRCK and ellagic acid are effective for suppressing body weight gain and enhancing the lipid profile.

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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.

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Regulation of the level of uncoupling protein in brown adipose tissue by insulin

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1990.258.2.r418 ◽

1990 ◽

Vol 258 (2) ◽

pp. R418-R424 ◽

Cited By ~ 4

Author(s):

A. Geloen ◽

P. Trayhurn

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Protein Content ◽

White Adipose Tissue ◽

Oxidase Activity ◽

Uncoupling Protein ◽

Mitochondrial Protein ◽

Brown Adipose ◽

Epididymal White Adipose Tissue

The role of insulin in the regulation of the thermogenic activity and capacity (uncoupling protein content) of brown adipose tissue (BAT) has been investigated using mice made diabetic with streptozotocin and then subsequently infused with different doses of insulin. After 12 days of diabetes, the animals received either 0, 8, 16, or 32 units of insulin.kg body wt-1.day-1 delivered by osmotic minipumps implanted subcutaneously for 12 days. After 12 days of diabetes, body weight, interscapular BAT, and epididymal white adipose tissue weights were each reduced. In BAT, significant decreases (P less than 0.05) in the mitochondrial protein content (63%), cytochrome oxidase activity (79%), mitochondrial GDP binding (51%), and the specific mitochondrial concentration and total tissue content of uncoupling protein (71 and 89%, respectively) were obtained, indicating that the thermogenic activity and capacity of the tissue were reduced in diabetes. The infusion of insulin at a dose of 8 units.kg-1.day-1 normalized mitochondrial GDP binding and doubled the concentration of uncoupling protein. Body weight, epididymal white adipose tissue weight, and the mitochondrial protein content of BAT were restored with 16 units of insulin.kg-1.day-1. Higher doses of insulin did not further increase the specific mitochondrial concentration of uncoupling protein, but the mitochondrial content (and thereby the total uncoupling protein content) of BAT was increased and blood glucose normalized. There was a significant correlation between the dose of insulin replacement and several of the parameters measured in BAT: mitochondrial protein content (r = 0.68, P less than 0.001), cytochrome oxidase activity (r = 0.54, P less than 0.001), and total uncoupling protein content (r = 0.68, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

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