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Ismael González-García, Johan Fernø, Carlos Diéguez, Rubén Nogueiras, Miguel López
Hypothalamic lipid metabolism plays a major role in the physiological regulation of energy balance. Modulation of several enzymatic activities that control lipid biosynthesis, such as fatty acid synthase (FAS) and AMP-activated protein kinase (AMPK), impacts both feeding and energy expenditure. However, lipids can also cause pathological alterations in the hypothalamus. Lipotoxicity is promoted by excess lipids in tissues non suitable for their storage. A large amount of evidence has demonstrated that lipotoxicity is a pathophysiological mechanism leading to metabolic diseases, such as insulin resistance, cardiomyopathy, atherosclerosis and steatohepatitis...
October 11, 2016: Neuroendocrinology
Lingman Ma, Lifen Qian, Qidi Ying, Yan Zhang, Changlin Zhou, Guanzhong Wu
Here, we investigated whether I4, which was initially developed as a hypoglycemic agent, possesses anti-atherosclerotic activity and attempted to elucidate the probable mechanism of action underlying this activity. ApoE(-/-) mice were fed a Western diet and simultaneously administered I4, glimepiride, or pioglitazone once daily for 12 weeks, and the atherosclerotic vascular lesions, lipid content, and expression levels of LOX-1, ICAM-1, VCAM-1 and Bax/Bcl-2 in mouse aortas were assessed. RAW264.7 macrophage-derived foam cells were obtained via ox-LDL stimulation to investigate the lipid-lowering, anti-atherosclerotic inflammation and anti-apoptotic effect of I4...
October 7, 2016: Molecular and Cellular Endocrinology
Agnieszka Mikłosz, Bartłomiej Łukaszuk, Małgorzata Żendzian-Piotrowska, Justyna Brańska-Januszewska, Halina Ostrowska, Adrian Chabowski
The Akt substrate of 160 kDa (AS160) is a key regulator of GLUT4 translocation from intracellular depots to the plasma membrane in myocytes. Likely, AS160 also controls LCFAs transport, which requires relocation of fatty acid transporters. The aim of the present study was to determine the impact of AS160 knockdown on lipid milieu in L6 myotubes incubated with palmitate (PA). Therefore, we compared two different settings, namely: 1) AS160 knockdown prior to palmitate incubation (pre-PA-silencing, AS160(-) /PA); 2) palmitate incubation with subsequent AS160 knockdown (post-PA-silencing, PA/AS160(-) )...
October 7, 2016: Journal of Cellular Physiology
Alexander Kalinkovich, Gregory Livshits
Sarcopenia, an age-associated decline in skeletal muscle mass coupled with functional deterioration, may be exacerbated by obesity leading to higher disability, frailty, morbidity and mortality rates. In the combination of sarcopenia and obesity, the state called sarcopenic obesity (SOB), some key age- and obesity-mediated factors and pathways may aggravate sarcopenia. This review will analyze the mechanisms underlying the pathogenesis of SOB. In obese adipose tissue (AT), adipocytes undergo hypertrophy, hyperplasia and activation resulted in accumulation of pro-inflammatory macrophages and other immune cells as well as dysregulated production of various adipokines that together with senescent cells and the immune cell-released cytokines and chemokines create a local pro-inflammatory status...
October 1, 2016: Ageing Research Reviews
Xin Yang, Zhipeng Xu, Chunlan Zhang, Zixin Cai, Jingjing Zhang
Metformin, a biguanide derivate, is known as the first-line antidiabetic agent for type 2 diabetes mellitus (T2DM) treatment. It reduces insulin resistance and decreases blood glucose concentration by inhibiting gluconeogenesis and suppressing hepatic glucose production with improved peripheral tissue insulin sensitivity. As an insulin sensitizer, metformin takes pleiotropic actions and exerts protective effects on multiple organs mainly in insulin-targeted tissues such as liver, muscle, and adipose tissues...
October 1, 2016: Biochimica et Biophysica Acta
Christian Klingler, Xinjie Zhao, Till Adhikary, Jia Li, Guowang Xu, Hans-Ulrich Häring, Erwin Schleicher, Rainer Lehmann, Cora Weigert
Metabolomics studies of human plasma demonstrate a correlation of lower plasma lysophosphatidylcholines (LPC) concentrations with insulin resistance, obesity, and inflammation. This relationship is not unraveled on a molecular level. Here we investigated the effects of the abundant LPC(16:0) and LPC(18:1) on human skeletal muscle cells differentiated to myotubes. Transcriptome analysis of human myotubes treated with 10μM LPC for 24h revealed enrichment of up-regulated peroxisome proliferator-activated receptor (PPAR) target transcripts, including ANGPTL4, PDK4, PLIN2, and CPT1A...
September 30, 2016: Biochimica et Biophysica Acta
Ove Andersen
HIV-associated lipodystrophy syndrome frequently presents as a relative lack of peripheral adipose tissue storage combined with an increase in visceral fat, associated with insulin resistance and dyslipidaemia. This thesis discusses explanations for the links between abnormalities in glucose metabolism, the steroid synthesis pathway, the growth hormone-insulin growth factor-1 axis, and chronic changes in adipose tissue distribution. Specifically, the mechanisms by which low-grade inflammation may affect the normal stimulatory effect of insulin on glucose and fat storage are reviewed...
October 2016: Danish Medical Journal
Seiya Arita, Yuta Kinoshita, Kaori Ushida, Atsushi Enomoto, Kyoko Inagaki-Ohara
Obesity increases the risk for gastric cancers. However, the occurrence and mechanisms of precancerous atrophic gastritis induced by high-fat diet (HFD) remain unclear. Here, we show that HFD-associated lipotoxicity induces precancerous lesions that are accompanied by the disruption of organelle homeostasis, tissue integrity, and deregulated expression of stemness genes in the gastric epithelium mediated by leptin receptor (ObR) signaling. Following HFD feeding, ectopic fat accumulated and expression of LAMP2A in lysosome and COX IV in mitochondria increased in the gastric mucosa...
September 28, 2016: Archives of Biochemistry and Biophysics
Qihai Xie, Tong Wei, Chenglin Huang, Penghao Liu, Mengwei Sun, Weili Shen, Pingjin Gao
NLRP3 is involved in obesity-induced cardiac remodeling and dysfunction. In this study, we evaluated whether the cardiac protective effects of nebivolol relied on attenuating NLRP3 activation in a juvenile-adolescent animal model of diet-induced obesity. Weaning male Sprague-Dawley rats were fed with either a standard chow diet (ND) or a high-fat diet (HFD) for 8 weeks. The obese rats were subsequently subdivided into three groups: 1) HFD control group; 2) HFD with low-dose nebivolol (5 mg/kg/d); 3) HFD with high-dose nebivolol (10 mg/kg/d)...
September 30, 2016: Scientific Reports
Andrzej Smereczyński, Katarzyna Kołaczyk
So far, a fatty pancreas has been related to obesity and the ageing processes in the body. The current list of pathogenetic factors of the condition is clearly extended with genetically conditioned diseases (cystic fibrosis, Shwachman-Diamond syndrome and Johanson-Blizzard syndrome), pancreatitis, especially hereditary and obstructive, metabolic and hormonal disorders (hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hypercortisolemia), alcohol overuse, taking some medicines (especially adrenal cortex hormones), disease of the liver and visceral adiposis...
September 2016: Journal of Ultrasonography
Qin He, Dan Mei, Sha Sha, Shanshan Fan, Lin Wang, Ming Dong
Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem and is considered as a hepatic manifestation of metabolic syndrome. Increasing evidence demonstrates that berberine (BBR), a natural plant alkaloid, is beneficial for obesity-associated NAFLD. However, the mechanisms about how BBR improves hepatic steatosis remain uncertain. Recently, some reports revealed that enhance autophagy could decrease hepatic lipid accumulation. In this study, we first established a high-fed diet (HFD) mice model and oleate-palmitate-induced lipotoxicity hepatocytes to explore the association between BBR, autophagy, and hepatic steatosis...
September 22, 2016: Journal of Molecular Endocrinology
Andrea Lim, Jin Zhou, Rohit A Sinha, Brijesh K Singh, Sujoy Ghosh, Kiat-Hon Lim, Pierce Kah-Hoe Chow, Esther C Y Woon, Paul M Yen
Non-alcoholic steatohepatitis (NASH) is one of the most common causes of liver failure worldwide. It is characterized by excess fat accumulation, inflammation, and increased lipotoxicity in hepatocytes. Currently, there are limited treatment options for NASH due to lack of understanding of its molecular etiology. In the present study, we demonstrate that the expression of fat mass and obesity associated gene (FTO) is significantly increased in the livers of NASH patients and in a rodent model of NASH. Furthermore, using human hepatic cells, we show that genetic silencing of FTO protects against palmitate-induced oxidative stress, mitochondrial dysfunction, ER stress, and apoptosis in vitro...
October 21, 2016: Biochemical and Biophysical Research Communications
Angélica Ruiz-Ramírez, Ocarol López-Acosta, Miguel Angel Barrios-Maya, Mohammed El-Hafidi
Metabolic diseases such as obesity, metabolic syndrome, and type II diabetes are often characterized by increased reactive oxygen species (ROS) generation in mitochondrial respiratory complexes, associated with fat accumulation in cardiomyocytes, skeletal muscle, and hepatocytes. Several rodents studies showed that lipid accumulation in cardiac myocytes produces lipotoxicity that causes apoptosis and leads to heart failure, a dynamic pathological process. Meanwhile, several tissues including cardiac tissue develop an adaptive mechanism against oxidative stress and lipotoxicity by overexpressing uncoupling proteins (UCPs), specific mitochondrial membrane proteins...
2016: Oxidative Medicine and Cellular Longevity
Yan Yang, Jiangong Ren, Yuzhen Tong, Xuejian Hu, Qingguo Lv, Nanwei Tong
Lipoapoptosis plays an important role in the pathogenesis of type 2 diabetes. Peroxisome proliferator-activated receptor delta (PPARdelta), a vital regulator of glucose and lipid metabolism, may reduce fatty acid-induced pancreatic β cell lipotoxicity in diabetes. However, the detailed molecular mechanisms underlying this process are not fully understood. In this study, we investigated the effect of activation of PPARdelta on palmitate-induced β cell apoptosis, and we explored the potential mechanism of the antiapoptotic effect...
September 8, 2016: Lipids
Alexandra M Hetherington, Cynthia G Sawyez, Emma Zilberman, Alexandra M Stoianov, Debra L Robson, Nica M Borradaile
BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) progression to fibrosis, cirrhosis and hepatocellular carcinoma, alters the cellular composition of this organ. During late-stage NAFLD, fibrotic and possibly cancerous cells can proliferate and, like normal hepatocytes, are exposed to high concentrations of fatty acids from both surrounding tissue and circulating lipid sources. We hypothesized that primary human activated hepatic stellate cells and epithelial hepatoma (HepG2) cells respond differently to lipotoxic conditions, and investigated the mechanisms involved...
2016: Cellular Physiology and Biochemistry
Alexandra M Hetherington, Cynthia G Sawyez, Brian G Sutherland, Debra L Robson, Rigya Arya, Karen Kelly, René L Jacobs, Nica M Borradaile
Eukaryotic elongation factor EEF1A1 is induced by oxidative and ER stress, and contributes to subsequent cell death in many cell types, including hepatocytes. We recently showed that blocking the protein synthesis activity of EEF1A1 with the peptide inhibitor, didemnin B, decreases saturated fatty acid overload-induced cell death in HepG2 cells. In light of this and other recent work suggesting that limiting protein synthesis may be beneficial in treating ER stress-related disease, we hypothesized that acute intervention with didemnin B would decrease hepatic ER stress and lipotoxicity in obese mice with nonalcoholic fatty liver disease (NAFLD)...
September 2016: Physiological Reports
Hua Qin, Yan Zhang, Ru Wang, Xiaoyan Du, Liping Li, Haiwei Du
Puerarin, a type of isoflavone, was shown to have multiple protective effects on myocardial injury. The objective of this study was to investigate the role of puerarin in the progression of lipotoxic cardiomyopathy. Primary cardiomyocytes were isolated from FATP1 transgenic (Tg) mice with lipotoxic cardiomyopathy, and various concentrations of puerarin were used to incubate with the cardiomyocytes. Our results showed low dose puerarin (≤ 20 μM) treatment increased the cell viability and decreased the accumulation of free fatty acid (FFA)...
September 6, 2016: Journal of Cardiovascular Pharmacology
Akiko Suzuki, Keisuke Kakisaka, Yuji Suzuki, Ting Wang, Yasuhiro Takikawa
AIM: To clarify the relationship between autophagy and lipotoxicity-induced apoptosis, which is termed "lipoapoptosis," in non-alcoholic steatohepatitis. METHODS: Male C57BL/6J mice were fed a high-fat diet (HFD) for 12 wk, after which the liver histology and expression of proteins such as p62 or LC3 were evaluated. Alpha mouse liver 12 (AML12) cells treated with palmitate (PA) were used as an in vitro model. RESULTS: LC3-II, p62, and Run domain Beclin-1 interacting and cysteine-rich containing (Rubicon) proteins increased in both the HFD mice and in AML12 cells in response to PA treatment...
July 28, 2016: World Journal of Gastroenterology: WJG
Xiwen Xiong, Xupeng Sun, Qingzhi Wang, Xinlai Qian, Yang Zhang, Xiaoyan Pan, Xiaocheng Charlie Dong
Chronic exposure of pancreatic β-cells to abnormally elevated levels of free fatty acids can lead to β-cell dysfunction and even apoptosis, contributing to type 2 diabetes pathogenesis. In pancreatic β-cells, SIRT6 has been shown to regulate insulin secretion in response to glucose stimulation. However, what roles SIRT6 play in β-cells in response to lipotoxicity remain poorly understood. Our data indicated that SIRT6 protein and mRNA levels were reduced in islets from diabetic and aged mice. High concentrations of palmitate also led to a decrease in SIRT6 expression in MIN6 β-cells and resulted in cell dysfunction and apoptosis...
September 6, 2016: Journal of Endocrinology
Daniel A Cunha, Monia Cito, Per-Ola Carlsson, Jean-Marie Vanderwinden, Jeffery D Molkentin, Marco Bugliani, Piero Marchetti, Décio L Eizirik, Miriam Cnop
The failure of β-cells has a central role in the pathogenesis of type 2 diabetes, and the identification of novel approaches to improve functional β-cell mass is essential to prevent/revert the disease. Here we show a critical novel role for thrombospondin 1 (THBS1) in β-cell survival during lipotoxic stress in rat, mouse and human models. THBS1 acts from within the endoplasmic reticulum to activate PERK and NRF2 and induce a protective antioxidant defense response against palmitate. Prolonged palmitate exposure causes THBS1 degradation, oxidative stress, activation of JNK and upregulation of PUMA, culminating in β-cell death...
September 2, 2016: Cell Death and Differentiation
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