비만에서 adipose tissue 호르몬에 의한 metabolic signaling

장영훈 한국생명과학회 2023 생명과학회지 Vol.33 No.3

Healthy adipose tissue is critical for preventing obesity by maintaining metabolic homeostasis. Adipose tissue plays an important role in energy homeostasis through glucose and lipid metabolism. Depending on nutritional status, adipose tissue expands to store lipids or can be consumed by lipolysis. The role of adipose tissue as an endocrine organ is emerging, and many studies have reported that there are various adipose tissue hormones that communicate with other organs and tissues through metabolic signaling. For example, leptin, a representative peptide hormone secreted from adipose tissues (adipokine), circulates and targets the central nervous system of the brain for appetite regression. Furthermore, adipocytes secrete inflammatory cytokines to target immune cells in adipose tissues. Not surprisingly, adipocytes can secrete fatty acid-derived hormones (lipokine) that bind to their specific receptors for paracrine and endocrine action. To understand organ crosstalk by adipose tissue hormones, specific metabolic signaling in adipocytes and other communicating cells should be defined. The dysfunction of metabolic signaling in adipocytes occurs in unhealthy adipose tissue in overweight and obese conditions. Therapy targeting novel adipose metabolic signaling could potentially lead to the development of an effective anti-obesity drug. This review summarizes the latest updates on adipose tissue hormone and metabolic signaling in terms of obesity and metabolic diseases.

Regulation of Osteoblast Metabolism by Wnt Signaling

Megan C. Moorer,Ryan C. Riddle 대한내분비학회 2018 Endocrinology and metabolism Vol.33 No.3

Wnt/β-catenin signaling plays a critical role in the achievement of peak bone mass, affecting the commitment of mesenchymal progenitorsto the osteoblast lineage and the anabolic capacity of osteoblasts depositing bone matrix. Recent studies suggest that thisevolutionarily-conserved, developmental pathway exerts its anabolic effects in part by coordinating osteoblast activity with intermediarymetabolism. These findings are compatible with the cloning of the gene encoding the low-density lipoprotein related receptor-5(LRP5) Wnt co-receptor from a diabetes-susceptibility locus and the now well-established linkage between Wnt signaling and metabolism. In this article, we provide an overview of the role of Wnt signaling in whole-body metabolism and review the literature regardingthe impact of Wnt signaling on the osteoblast’s utilization of three different energy sources: fatty acids, glucose, and glutamine. Special attention is devoted to the net effect of nutrient utilization and the mode of regulation by Wnt signaling. Mechanisticstudies indicate that the utilization of each substrate is governed by a unique mechanism of control with β-catenin-dependent signalingregulating fatty acid β-oxidation, while glucose and glutamine utilization are β-catenin-independent and downstream of mammaliantarget of rapamycin complex 2 (mTORC2) and mammalian target of rapamycin complex 1 (mTORC1) activation, respectively. The emergence of these data has provided a new context for the mechanisms by which Wnt signaling influences bone development.

Primary Cilia as a Signaling Platform for Control of Energy Metabolism

송도경,최종한,김민선 대한당뇨병학회 2018 Diabetes and Metabolism Journal Vol.42 No.2

Obesity has become a common healthcare problem worldwide. Cilia are tiny hair-like organelles on the cell surface that are generated and anchored by the basal body. Non-motile primary cilia have been considered to be evolutionary rudiments until a few decades, but they are now considered as important signaling organelles because many receptors, channels, and signaling molecules are highly expressed in primary cilia. A potential role of primary cilia in metabolic regulation and body weight maintenance has been suspected based on rare genetic disorders termed as ciliopathy, such as Bardet-Biedl syndrome and Alström syndrome, which manifest as obesity. Recent studies have demonstrated involvement of cilia-related cellular signaling pathways in transducing metabolic information in hypothalamic neurons and in determining cellular fate during adipose tissue development. In this review, we summarize the current knowledge about cilia and cilia-associated signaling pathways in the regulation of body metabolism.

Ginsenoside F2 enhances glucose metabolism by modulating insulin signal transduction in human hepatocarcinoma cells

Shengqiang Han,Long You,Yeye Hu,Shuai Wei,Tingwu Liu,Jae Youl Cho,Weicheng Hu The Korean Society of Ginseng 2023 Journal of Ginseng Research Vol.47 No.3

Background: Ginsenoside F2 (GF2), a minor component of Panax ginseng, has been reported to possess a wide variety of pharmacological activities. However, its effects on glucose metabolism have not yet been reported. Here, we investigated the underlying signaling pathways involved in its effects on hepatic glucose. Methods: HepG2 cells were used to establish insulin-resistant (IR) model and treated with GF2. Cell viability and glucose uptake-related genes were also examined by real-time PCR and immunoblots. Results: Cell viability assays showed that GF2 up to 50 μM did not affect normal and IR-HepG2 cell viability. GF2 reduced oxidative stress by inhibiting phosphorylation of the mitogen-activated protein kinases (MAPK) signaling components such as c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK1/2), and p38 MAPK, and reducing the nuclear translocation of NF-κB. Furthermore, GF2 activated PI3K/AKT signaling, upregulated the levels of glucose transporter 2 (GLUT-2) and GLUT-4 in IR-HepG2 cells, and promoted glucose absorption. At the same time, GF2 reduced phosphoenolpyruvate carboxykinase and glucose-6-phosphatase expression as well as inhibiting gluconeogenesis. Conclusion: Overall, GF2 improved glucose metabolism disorders by reducing cellular oxidative stress in IR-HepG2 cells via MAPK signaling, participating in the PI3K/AKT/GSK-3β signaling pathway, promoting glycogen synthesis, and inhibiting gluconeogenesis.

트레드밀 운동이 ICV-STZ 처치 흰쥐의 뇌 인슐린 신호전달, 포도당 대사 및 Tau 단백질 과인산화에 미치는 영향

강은범 ( Eun Bum Kang ),김창환 ( Chang Hwan Kim ),조준용 ( Joon Yong Cho ) 한국운동생리학회(구 한국운동과학회) 2014 운동과학 Vol.23 No.2

본 연구의 목적은 intracerebroventricular(ICV)에 streptozotocin(STZ) 처치로 유도된 알츠하이머 치매 흰쥐를 대상으로 6주간의 트레드밀 운동이 brain insulin signaling, 포도당 대사 및 Tau 단백질 과인산화에 미치는 영향을 규명하는 것이다. 알츠하이머 질환 동물 모델을 만들기 위해 20주령의 Sprague-Dawley 흰쥐의 양쪽 대뇌 뇌실에 STZ(1.5mg/kg)를 주입하였다. 이들 실험동물은 ICV-Sham(n=6), ICV-STZ CON(n=6), ICV-STZ TE(n=6)로 구분하였다. 트레드밀 운동은 하루에 30분, 주5일, 6주간 실시하였다. 트레드밀 운동 실시 전과 후에 수중미로검사(Water Maze Test)를 실시하였다. ICV-STZ CON 그룹은 ICV-Sham 그룹에 비해 탈출시간과 탈출거리가 유의하게 증가된 것으로 나타났다. 하지만 6주간 트레드밀 운동을 실시한 ICV-STZ TE 집단은 ICV-STZ CON 그룹에 비해 탈출시간과 탈출거리가 유의하게 감소된 것으로 나타났다. ICV-STZ CON 그룹의 대뇌 해마에서 Tau 단백질의 과인산화가 증가하고 brain insulin signaling의 활성이 감소된 것으로 나타났다. 하지만 트레드밀 운동을 실시한 ICV-STZ TE 집단에서 Tau 단백질의 과인산화가 ICV-STZ CON 그룹에 비해 감소된 것으로 나타났으며 brain insulin signaling 관련 단백질(IR, PI3K, AKT)의 활성은 증가된 것으로 나타났다. 또한 Tau 단백질의 주요 kinase인 GSK3β의 인산화는 증가하여 활성이 감소됨을 확인할 수 있었다. 뇌 포도당 수송체인 GLUT1과 GLUT3은 해마에서 모두 발현이 감소되었지만 트레드밀 운동을 통해 포도당 이용효율이 높아진 것으로 나타났다. 이상의 결과를 종합하면 트레드밀 운동을 통해 neurofibrillary tangle의 구성요소인 Tau 단백질의 과인산화가 억제되었으며 인지능력이 개선되는 효과를 가져왔다. 즉 신체활동과 같은 유산소 운동은 알츠하이머 질환의 예방과 치료에 효과적인 대안으로 적용될 수 있음을 의미한다. The purpose of this study was to explore the effect of 6-week treadmill exercise on brain insulin signaling, glucose metabolism and hyperphosphorylation of Tau protein in Alzheimer dementia rats induced by intracerebroventricular (ICV) treatment of streptozotocin (STZ). To produce Alzheimer animal model, STZ (1.5 mg/kg) was injected in both cerebral ventricles of 20-week Sprague-Dawley rats, which were classified into ICV-Sham, ICV-STZ CON and ICV-STZ TE (treadmill exercise). Treadmill exercises were conducted for 3 0 minutes a d ay, 5 days a w eek and for the duration of 6 weeks. Water maze tests were performed before and after the treadmill exercises. Time and distance of escape significantly increased in ICV-STZ CON group compared with those in ICV-Sham group. Nevertheless, time and distance of escape significantly decreased in ICV-STZ TE group with 6-week treadmill exercise compared with those in ICV-STZ CON group. The treatment of ICV-STZ increased hyper phosphorylation of Tau protein and decreased the activity of brain insulin signaling in cerebral hippocampus of rats. Yet, hyperphosphorylation of Tau protein decreased more in I CV-STZ TE group, for which treadmill exercise were administered, than in I CV-STZ C ON group while the activity of proteins related to brain insulin signaling (IR, PI3K, AKT) increased. In addition, phosphorylation of GSK3, a major kinase of Tau protein, increased which resulted in the decrease of activity. Although both GLUT1 and GLUT3, glucose transporters in brain, decreased expression in hippocampus, treadmill exercise increased utilization efficiency of glucose in the brain. Treadmill exercise suppressed hyperphosphorylation of Tau protein, a component of neurofibrillary tangle, and resulted in the enhancement of perceptive ability. In conclusion, aerobic exercise can be administered as an effective alternative in the prevention and treatment of Alzheimer`s disease.

Fucosylated Chondroitin Sulfate From Sea Cucumber Improves Glucose Metabolism and Activates Insulin Signaling in the Liver of Insulin-Resistant Mice

Shiwei Hu,Ying-Ying Tian,Yao-Guang Chang,Zhao-Jie Li,Chang-Hu Xue,Yu-Ming Wang 한국식품영양과학회 2014 Journal of medicinal food Vol.17 No.7

This study investigated the effects of fucosylated chondroitin sulfate (CHS) isolated from sea cucumber on glucose metabolism and insulin signaling in the liver of insulin-resistant C57BL/6 mice fed a high-fat, high-sucrose diet (HFSD). Male C57BL/6J mice were randomly assigned into six groups: control; HFSD; 1mg RSG/kg$body weight (RSG); 80 mg CHS/kg$body weight (CHS); 20 mg CHS + 1mg RSG/kg$body weight (20 CHS + RSG); and 80 mg CHS + 1mg RSG/kg$body weight (80 CHS + RSG). Blood glucose, insulin parameters, glucose metabolism-related enzymes activities and insulin-signaling transducers in the liver were analyzed at 19 weeks. Results showed that CHS significantly decreased body weight gain, adipose tissue weight, and fasting blood glucose and serum insulin levels in insulin-resistant mice. Rosiglitazone (RSG) is an effective thiazolidinedione hypoglycemic agent, and CHS synergistically enhanced the effect of RSG. CHS feeding normalized the activities of hexokinase, pyruvate kinase, glycogen phosphorylase, glucose-6-phosphatase, and increased glycogen reserves in the liver. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis showed that CHS promoted the mRNA expression of insulin receptors (IR), insulin receptor substrate 2 (IRS-2), phosphatidylinositol 3 kinase (PI3K), protein kinase B (PKB), and glycogen synthase (GS) in the liver of insulin resistant mice, and inhibited glycogen synthase kinase-3 (GSK-3b) mRNA expression. The results suggested that CHS treatment improved glucose metabolism by modulating metabolic enzymes and promoting the PI3K/PKB/GSK-3b signaling pathway mediated by insulin at the transcriptional level. These results provided strong justification for the development of CHS as a functional food.

Ishophloroglucin A, derived from Ishige okamurae, regulates high-fat-dietinduced fat accumulation via the leptin signaling pathway, associated with peripheral metabolism

Nalae Kang,Seyeon Oh,Hyun-Soo Kim,Hyosang Ahn,Junwon Choi,Soo-Jin Heo,Kyunghee Byun,You-Jin Jeon 제주대학교 해양과학연구소 2020 해양과환경연구소 연구논문집 Vol.44 No.-

Leptin, a well-known appetite hormone, plays a role in fat metabolism in peripheral tissues including the adipose, liver, and muscle tissues. In this study, we investigated the antiobesity and fat accumulation regulatory effects of Ishophloroglucin A, derived from the brown seaweed Ishige okamurae, which acts via the leptin signaling pathway in the peripheral tissues of a high-fat-diet-induced obese mouse model. Obesity in C57BL/6J mice was induced by feeding them with a high-fat diet for 10 weeks and Ishophloroglucin A (2.5 mg/kg) was orally treated for the last 4 weeks. Body weights were monitored once per week during the experimental period. After the experiment, several serum biochemical parameters were measured using commercial kits and the white adipose, liver, and muscle tissues were observed using immunohistochemistry methods. Ishophloroglucin A significantly reduced glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and leptin level, which increase as a result of high-fat diet. Also, Ishophloroglucin A clearly activated the leptin signaling pathway in all examined peripheral tissues, reduced the adipose tissue size, and alleviated steatosis in the liver and muscle tissues. These results implied that Ishophloroglucin A treatment for 4 weeks positively induced molecular mechanisms and histologic changes related with leptin signaling. These findings suggested that constant Ishophloroglucin A treatment clearly regulates obesity and peripheral fat accumulation via the leptin signaling pathway in high-fat-diet-induced obese mice.

Calcium phosphate-bearing matrices induce osteogenic differentiation of stem cells through adenosine signaling

Shih, Yu-Ru V.,Hwang, YongSung,Phadke, Ameya,Kang, Heemin,Hwang, Nathaniel S.,Caro, Eduardo J.,Nguyen, Steven,Siu, Michael,Theodorakis, Emmanuel A.,Gianneschi, Nathan C.,Vecchio, Kenneth S.,Chien, Shu National Academy of Sciences 2014 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.111 No.3

<P>Synthetic matrices emulating the physicochemical properties of tissue-specific ECMs are being developed at a rapid pace to regulate stem cell fate. Biomaterials containing calcium phosphate (CaP) moieties have been shown to support osteogenic differentiation of stem and progenitor cells and bone tissue formation. By using a mineralized synthetic matrix mimicking a CaP-rich bone microenvironment, we examine a molecular mechanism through which CaP minerals induce osteogenesis of human mesenchymal stem cells with an emphasis on phosphate metabolism. Our studies show that extracellular phosphate uptake through solute carrier family 20 (phosphate transporter), member 1 (SLC20a1) supports osteogenic differentiation of human mesenchymal stem cells via adenosine, an ATP metabolite, which acts as an autocrine/paracrine signaling molecule through A2b adenosine receptor. Perturbation of SLC20a1 abrogates osteogenic differentiation by decreasing intramitochondrial phosphate and ATP synthesis. Collectively, this study offers the demonstration of a previously unknown mechanism for the beneficial role of CaP biomaterials in bone repair and the role of phosphate ions in bone physiology and regeneration. These findings also begin to shed light on the role of ATP metabolism in bone homeostasis, which may be exploited to treat bone metabolic diseases.</P>

Involvement of S6K1 in mitochondria function and structure in HeLa cells

Park, J.,Tran, Q.,Mun, K.,Masuda, K.,Kwon, S.H.,Kim, S.H.,Kim, D.H.,Thomas, G.,Park, J. Pergamon Press ; Elsevier Science Ltd 2016 Cellular signalling Vol.28 No.12

The major biological function of mitochondria is to generate cellular energy through oxidative phosphorylation. Apart from cellular respiration, mitochondria also play a key role in signaling processes, including aging and cancer metabolism. It has been shown that S6K1-knockout mice are resistant to obesity due to enhanced beta-oxidation, with an increased number of large mitochondria. Therefore, in this report, the possible involvement of S6K1 in regulating mitochondria dynamics and function has been investigated in stable lenti-shS6K1-HeLa cells. Interestingly, S6K1-stably depleted HeLa cells showed phenotypical changes in mitochondria morphology. This observation was further confirmed by detailed image analysis of mitochondria shape. Corresponding molecular changes were also observed in these cells, such as the induction of mitochondrial fission proteins (Drp1 and Fis1). Oxygen consumption is elevated in S6K1-depeleted HeLa cells and FL5.12 cells. In addition, S6K1 depletion leads to enhancement of ATP production in cytoplasm and mitochondria. However, the relative ratio of mitochondrial ATP to cytoplasmic ATP is actually decreased in lenti-shS6K1-HeLa cells compared to control cells. Lastly, induction of mitophagy was found in lenti-shS6K1-HeLa cells with corresponding changes of mitochondria shape on electron microscope analysis. Taken together, our results indicate that S6K1 is involved in the regulation of mitochondria morphology and function in HeLa cells. This study will provide novel insights into S6K1 function in mitochondria-mediated cellular signaling.

Pu-Erh Tea Hot-Water Extract Activates Akt and Induces Insulin-Independent Glucose Transport in Rat Skeletal Muscle

Xiao Ma,Satoshi Tsuda,Xin Yang,Ning Gu,Hiroko Tanabe,Rieko Oshima,Tetsuya Matsushita,Tatsuro Egawa,Ai-Jun Dong,Bei-Wei Zhu,Tatsuya Hayashi 한국식품영양과학회 2013 Journal of medicinal food Vol.16 No.3

Skeletal muscle is a major organ that is important for whole-body glucose metabolism. We found that when isolated rat epitrochlearis muscle was incubated with a Pu-erh tea hot-water extract (PTE) for 30 min, the rate of 3-O-methyl-D-glucose (3MG) transport increased in the absence of insulin. This activation was associated with an increase in Ser473 phosphorylation of Akt, a signaling intermediary leading to insulin-dependent glucose transport, but not Tyr458 phosphorylation of phosphoinositide 3-kinase p85, an upstream molecule of Akt. PTE-stimulated 3MG transport was also not accompanied by Thr172 phosphorylation of the catalytic α-subunit of 5′-AMP-activated protein kinase (AMPK). Gallic acid, a water-soluble ingredient in Pu-erh tea, stimulated Akt phosphorylation, but not AMPK phosphorylation. These results suggest that Pu-erh tea potentially promotes skeletal muscle glucose transport at least in part by activating Akt.