Mulberry leaf activates brown adipose tissue and induces browning of inguinal white adipose tissue in type 2 diabetic rats through regulating AMPK signaling pathway

2021 ◽  
pp. 1-31
Author(s):  
Long Cheng ◽  
Jingkang Wang ◽  
Yongcheng An ◽  
Hongyu Dai ◽  
Yuhui Duan ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
White Adipose Tissue ◽  
Biological Activities ◽  
Fasting Blood Glucose ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mulberry Leaf ◽  
Brown Adipose

Abstract The current epidemic of type 2 diabetes mellitus (T2DM) significantly affects human health worldwide. Activation of brown adipocytes and browning of white adipocytes are considered as a promising molecular target for T2DM treatment. Mulberry leaf, a traditional Chinese medicine, has been demonstrated to have multi-biological activities, including anti-diabetic and anti-inflammatory effects. Our experiment results showed that mulberry leaf significantly alleviated the disorder of glucose and lipid metabolism in T2DM rats including reducing body weight (BW) gain, Lee’s index, food intake, inguinal white adipose tissue (IWAT) accumulation, blood lipid fasting insulin level and fasting blood glucose level, increasing the ratios of brown adipose tissue (BAT) mass to BW, and improving insulin sensitivity and liver function. In addition, mulberry leaf induced browning of IWAT by enhancing the expressions of brown-mark genes as well as beige-specific genes, including uncoupling protein-1 (UCP1), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), peroxisome proliferator-activated receptor alpha (PPARα), PRD1-BF-1-RIZ1 homologous domain containing protein 16 (PRDM16), cell death inducing DFFA like effector A (Cidea), CD137 and transmembrane protein 26 (TMEM26). Mulberry leaf also activated BAT by increasing the expressions of brown-mark genes including UCP1, PGC-1α, PPARα, PRDM16 and Cidea. Moreover, mulberry leaf enhanced the expression of nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM) genes that are responsible for mitochondrial biogenesis in IWAT and BAT. Importantly, mulberry leaf also increased the expression of UCP1 and carnitine palmitoyl transferase 1 (CPT1) protein in both IWAT and BAT via a mechanism involving Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and PGC-1α pathway. In conclusion, our findings identify the role of mulberry leaf in inducing adipose browning, indicating that mulberry leaf may be used as a candidate browning agent for the treatment of T2DM.

scholarly journals Remodeling of White Adipose Tissue after Retinoic Acid Administration in Mice

Endocrinology ◽  
2006 ◽  
Vol 147 (11) ◽  
pp. 5325-5332 ◽  
Author(s):  
Josep Mercader ◽  
Joan Ribot ◽  
Incoronata Murano ◽  
Francisco Felipe ◽  
Saverio Cinti ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Retinoic Acid ◽  
Brown Adipose Tissue ◽  
White Adipose Tissue ◽  
Peroxisome Proliferator ◽  
Atra Treatment ◽  
Peroxisome Proliferator Activated Receptor ◽  
Brown Adipose

A reduced brown adipose phenotype in white adipose tissue (WAT) may contribute to obesity and type 2 diabetes in humans. Retinoic acid, the carboxylic form of vitamin A, triggers in rodents a reduction of body weight and adiposity and an increased expression of uncoupling proteins in brown adipose tissue and skeletal muscle. In this study, we investigated possible remodeling effects of all-trans retinoic acid (ATRA) in WAT depots. Changes in the expression of genes related to thermogenesis and fatty acid oxidation and levels of phosphorylated retinoblastoma protein were analyzed in WAT depots of adult NMRI male mice acutely injected with ATRA or vehicle, together with biometric and blood parameters. Body fat loss after ATRA treatment was unaccompanied by any increase in circulating nonesterified fatty acids or ketone bodies and accompanied by increased rectal temperature. The treatment triggered an up-regulation of the mRNA levels of uncoupling proteins 1 and 2, peroxisome proliferator-activated receptor γ coactivator-1α, peroxisome proliferator-activated receptor α, muscle- and liver-type carnitine palmitoyltransferase 1, and subunit II of cytochrome oxidase in different WAT depots. Levels of phosphorylated retinoblastoma protein in WAT depots were increased after ATRA treatment. Adipocyte size was reduced, and the number of multilocular adipocytes was increased in inguinal WAT of ATRA-treated mice. The results indicate that ATRA favors the acquisition of brown adipose tissue-like properties in WAT. Understanding the mechanisms and effectors involved in the remodeling of WAT can contribute to new avenues of prevention and treatment of obesity and type 2 diabetes.

scholarly journals Comprehensive Messenger Ribonucleic Acid Profiling Reveals That Peroxisome Proliferator-Activated Receptor γ Activation Has Coordinate Effects on Gene Expression in Multiple Insulin-Sensitive Tissues

Endocrinology ◽  
2001 ◽  
Vol 142 (3) ◽  
pp. 1269-1277 ◽  
Author(s):  
James M. Way ◽  
W. Wallace Harrington ◽  
Kathleen K. Brown ◽  
William K. Gottschalk ◽  
Scott S. Sundseth ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Brown Adipose Tissue ◽  
White Adipose Tissue ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Expression Of Genes ◽  
Brown Adipose ◽  
Pparγ Agonists

Abstract Peroxisome proliferator-activated receptor γ (PPARγ) agonists, including the glitazone class of drugs, are insulin sensitizers that reduce glucose and lipid levels in patients with type 2 diabetes mellitus. To more fully understand the molecular mechanisms underlying their therapeutic actions, we have characterized the effects of the potent, tyrosine-based PPARγ ligand GW1929 on serum glucose and lipid parameters and gene expression in Zucker diabetic fatty rats. In time-course studies, GW1929 treatment decreased circulating FFA levels before reducing glucose and triglyceride levels. We used a comprehensive and unbiased messenger RNA profiling technique to identify genes regulated either directly or indirectly by PPARγ in epididymal white adipose tissue, interscapular brown adipose tissue, liver, and soleus skeletal muscle. PPARγ activation stimulated the expression of a large number of genes involved in lipogenesis and fatty acid metabolism in both white adipose tissue and brown adipose tissue. In muscle, PPARγ agonist treatment decreased the expression of pyruvate dehydrogenase kinase 4, which represses oxidative glucose metabolism, and also decreased the expression of genes involved in fatty acid transport and oxidation. These changes suggest a molecular basis for PPARγ-mediated increases in glucose utilization in muscle. In liver, PPARγ activation coordinately decreased the expression of genes involved in gluconeogenesis. We conclude from these studies that the antidiabetic actions of PPARγ agonists are probably the consequence of 1) their effects on FFA levels, and 2), their coordinate effects on gene expression in multiple insulin-sensitive tissues.

scholarly journals Current Progress in Adipose Tissue Biology: Implications in Obesity and Its Comorbidities

2020 ◽  
Vol 12 (2) ◽  
pp. 85-101
Author(s):  
Anna Meiliana ◽  
Nurrani Mustika Dewi ◽  
Andi Wijaya
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Uncoupling Protein ◽  
Common Factor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Brown Adipose ◽  
Key Factor ◽  
Beige Fat

BACKGROUND: Obesity has been decades become a highly interest study, accompanied by the realization that adipose tissue (AT) plays a major role in the regulation of metabolic function.CONTENT: In past few years, adipocytes classification, development, and differentiation has been significant changes. The white adipose tissue (WAT) can transform to a phenotype like brown adipose (BAT) type and function. Exercise and cold induction were the most common factor for fat browning; however batokines such as fibroblast growth factor (FGF)-21, interleukin (IL)-6, Slit homolog 2 protein (SLIT2)-C, and Meteorin-like protein (METRNL) perform a beneficial browning action by increasing peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α protein levels, a key factor to stimulate mitochondrial biogenesis and uncoupling Protein 1 (UCP1) transcription, thus change the WAT phenotype into beige.SUMMARY: AT recently known as a complex organ, not only bearing a storage function but as well as the master regulator of energy balance and nutritional homeostasis; brown and beige fat express constitutively high levels of thermogenic genes and raise our expectation on new strategies for fighting obesity and metabolic disorders.KEYWORDS: obesity, white adipose tissue, brown adipose tissue, beige adipose tissue, inflammation, IR, metabolic disease

scholarly journals INDUCTION OF BROWN ADIPOSE TISSUE: A REVIEW

2018 ◽  
Vol 11 (5) ◽  
pp. 472
Author(s):  
Ivo Romauld Sagayaraj ◽  
Akilashree S ◽  
Brindha Devi P
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Secreted Proteins ◽  
Peroxisome Proliferator ◽  
Basic Study ◽  
Peroxisome Proliferator Activated Receptor ◽  
Efficient Treatment ◽  
Major Health ◽  
Brown Adipose

Objective: Obesity is the major problem which may lead to many other health ailments such as atherosclerosis, stroke, and depression. Both the cause as well as the treatment lies in the adipose tissue. The two main adipocytes, white adipose tissue (WAT) and brown adipose tissue (BAT) are responsible for the accumulation of fat and transformation of fat into heat, respectively. This review discusses the induction of BAT and browning of WAT by different pathways and activators to decrease the rate of obesity. Methods: Understanding the regulators, activators and secreted proteins which induce browning of WAT to BAT, as the BAT engage in thermogenesis process and transform fat into heat rather than storing it (WAT). Some of the core regulators are peroxisome proliferator-activated receptor-γ, PRDM16, PGC-1α. Results: A basic study explained about the origin of BAT and its functions, the function of hormones in BAT growth and its regulations. These studies provided the platform to understand about the mechanism of regulators, activators and secreted proteins which help in treating obesity and its related disorders by inducing the amount of BAT. Conclusion: The major health ailments caused by obesity can be reduced by increasing the activity of BAT and transforming WAT into BAT. A challenging way to treat these ailments is by regulating the activators and hormones responsible for the induction of BAT, so it transforms the excess fat into heat and avoiding the accumulation of fat. By understanding the role of regulators in the adipose tissue can provide various methods to reduce the chance of obesity and enhance efficient treatment in both children and adults.

scholarly journals Characterization of the human, mouse and rat PGC1beta (peroxisome-proliferator-activated receptor-gamma co-activator 1beta) gene in vitro and in vivo

2003 ◽  
Vol 373 (1) ◽  
pp. 155-165 ◽  
Author(s):  
Aline MEIRHAEGHE ◽  
Vivion CROWLEY ◽  
Carol LENAGHAN ◽  
Christopher LELLIOTT ◽  
Kath GREEN ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Thyroid Hormone Receptor ◽  
Ectopic Expression ◽  
Cdna Libraries ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Brown Adipose

PGC1α is a co-activator involved in adaptive thermogenesis, fatty-acid oxidation and gluconeogenesis. We describe the identification of several isoforms of a new human PGC1α homologue, cloned independently and named PGC1β. The human PGC1β gene is localized to chromosome 5, has 13 exons and spans more than 78 kb. Two different 5′ and 3′ ends due to differential splicing were identified by rapid amplification of cDNA ends PCR and screening of human cDNA libraries. We show that PGC1β variants in humans, mice and rats are expressed predominantly in heart, brown adipose tissue, brain and skeletal muscle. PGC1β expression, unlike PGC1α, is not up-regulated in brown adipose tissue in response to cold or obesity. Fasting experiments showed that PGC1α, but not PGC1β, is induced in liver and this suggests that only PGC1α is involved in the hepatic gluconeogenesis. No changes in PGC1β gene expression were observed associated with exercise. Human PGC1β-1a and −2a isoforms localized to the cell nucleus and, specifically, the isoform PGC1β-1a co-activated peroxisome-proliferator-activated receptor-γ, -α and the thyroid hormone receptor β1. Finally, we show that ectopic expression PGC1β leads to increased mitochondrial number and basal oxygen consumption. These results suggest that PGC1β may play a role in constitutive adrenergic-independent mitochondrial biogenesis.

scholarly journals Effect of nutmeg extract on the white adipose tissue (WAT) browning process of aging rats

2022 ◽  
pp. 1-7
Author(s):  
Yuni Susanti Pratiwi ◽  
Melisa Siannoto ◽  
Hanna Goenawan ◽  
Nova Sylviana ◽  
Vita Murniati Tarawan ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Standard Diet ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Interscapular Brown Adipose Tissue ◽  
Aging Rats ◽  
Pparγ Agonist ◽  
Brown Adipose

The white adipose tissue (WAT) browning process has become one of the promising methods for managing obesity. During this process, WAT is transformed into brown-like adipose tissue, which is also known as beige adipose tissue. The browning process can be activated by several inducers. One of the best candidates is peroxisome proliferator-activated receptor γ (PPARγ) agonist. Nutmeg (Myristica fragrans Houtt) is a natural PPARα/γ partial agonist that is known to contribute to the browning effect. This study aimed to explore the potential effect of nutmeg seed extract (NuSE) on body weight reduction and uncoupling protein (UCP)1, UCP2, UCP3, and peroxisome proliferator-activated receptor gamma coactivator-1 PGC-1α levels in aging rats. Eight male Wistar rats (80 weeks old) were divided into control and treatment groups. Both groups were fed a standard diet, and the treatment group was given 8.1 mg/kg body weight/day of NuSE via oral gavage for 12 weeks. After 12 weeks, the levels of UCP1, UCP2, UCP3, and PGC-1α from both inguinal WAT (iWAT) and interscapular brown adipose tissue (BAT) were examined. We observed that the administration of NuSE has no significant effect to the decreasement of rats body weights (p = 0.464), levels of UCP1 (p = 0.686), UCP2 (p = 0.360), UCP3 (p = 0.076), and PGC-1α (p = 0.200).

scholarly journals Acute hypoxia induces hypertriglyceridemia by decreasing plasma triglyceride clearance in mice

2012 ◽  
Vol 303 (3) ◽  
pp. E377-E388 ◽  
Author(s):  
Jonathan C. Jun ◽  
Mi-Kyung Shin ◽  
Qiaoling Yao ◽  
Shannon Bevans-Fonti ◽  
James Poole ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Brown Adipose Tissue ◽  
Acute Hypoxia ◽  
Plasma Catecholamines ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Brown Adipose ◽  
Obstructive Sleep ◽  
Adipose Tissue Lipoprotein Lipase

Obstructive sleep apnea (OSA) induces intermittent hypoxia (IH) during sleep and is associated with elevated triglycerides (TG). We previously demonstrated that mice exposed to chronic IH develop elevated TG. We now hypothesize that a single exposure to acute hypoxia also increases TG due to the stimulation of free fatty acid (FFA) mobilization from white adipose tissue (WAT), resulting in increased hepatic TG synthesis and secretion. Male C57BL6/J mice were exposed to FiO2 = 0.21, 0.17, 0.14, 0.10, or 0.07 for 6 h followed by assessment of plasma and liver TG, glucose, FFA, ketones, glycerol, and catecholamines. Hypoxia dose-dependently increased plasma TG, with levels peaking at FiO2 = 0.07. Hepatic TG levels also increased with hypoxia, peaking at FiO2 = 0.10. Plasma catecholamines also increased inversely with FiO2. Plasma ketones, glycerol, and FFA levels were more variable, with different degrees of hypoxia inducing WAT lipolysis and ketosis. FiO2 = 0.10 exposure stimulated WAT lipolysis but decreased the rate of hepatic TG secretion. This degree of hypoxia rapidly and reversibly delayed TG clearance while decreasing [3H]triolein-labeled Intralipid uptake in brown adipose tissue and WAT. Hypoxia decreased adipose tissue lipoprotein lipase (LPL) activity in brown adipose tissue and WAT. In addition, hypoxia decreased the transcription of LPL, peroxisome proliferator-activated receptor-γ, and fatty acid transporter CD36. We conclude that acute hypoxia increases plasma TG due to decreased tissue uptake, not increased hepatic TG secretion.

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