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Novel obesity therapeutic

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https://www.readbyqxmd.com/read/28220393/common-and-distinct-regulation-of-human-and-mouse-brown-and-beige-adipose-tissues-a-promising-therapeutic-target-for-obesity
#1
REVIEW
Xuejiao Liu, Christopher Cervantes, Feng Liu
Obesity, which underlies various metabolic and cardiovascular diseases, is a growing public health challenge for which established therapies are inadequate. Given the current obesity epidemic, there is a pressing need for more novel therapeutic strategies that will help adult individuals to manage their weight. One promising therapeutic intervention for reducing obesity is to enhance energy expenditure. Investigations into human brown fat and the recently discovered beige/brite fat have galvanized intense research efforts during the past decade because of their pivotal roles in energy dissipation...
February 20, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28195199/pemafibrate-a-novel-selective-peroxisome-proliferator-activated-receptor-alpha-modulator-improves-the-pathogenesis-in-a-rodent-model-of-nonalcoholic-steatohepatitis
#2
Yasushi Honda, Takaomi Kessoku, Yuji Ogawa, Wataru Tomeno, Kento Imajo, Koji Fujita, Masato Yoneda, Toshiaki Takizawa, Satoru Saito, Yoji Nagashima, Atsushi Nakajima
The efficacy of peroxisome proliferator-activated receptor α-agonists (e.g., fibrates) against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) in humans is not known. Pemafibrate is a novel selective peroxisome proliferator-activated receptor α modulator that can maximize the beneficial effects and minimize the adverse effects of fibrates used currently. In a phase-2 study, pemafibrate was shown to improve liver dysfunction in patients with dyslipidaemia. In the present study, we first investigated the effect of pemafibrate on rodent models of NASH...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28186980/diet-induced-obesity-links-to-er-positive-breast-cancer-progression-via-lpa-pkd-1-cd36-signaling-mediated-microvascular-remodeling
#3
Liuyi Dong, Ye Yuan, Cynthia Opansky, Yiliang Chen, Irene Aguilera-Barrantes, Shiyong Wu, Rong Yuan, Qi Cao, Yee Chung Cheng, Daisy Sahoo, Roy L Silverstein, Bin Ren
Obesity increases cancer risk including breast cancer (BC). However, the direct regulatory mechanisms by which obesity promotes BC progression remain largely unknown. We show that lysophosphatidic acid/protein kinase D1 (LPA/PKD-1)-CD36 signaling is a bona fide breast cancer promoter via stimulating microvascular remodeling in chronic diet-induced obesity (DIO). We observed that the growth of an estrogen receptor (ER) positive breast cancer was markedly increased when compared to the lean control, and specifically accompanied by increased microvascular remodeling in a syngeneic BC model in female DIO mice...
February 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28186649/bone-morphogenetic-protein-7-bmp-7-augments-insulin-sensitivity-in-mice-with-type-ii-diabetes-mellitus-by-potentiating-pi3k-akt-pathway
#4
Tandrika Chattopadhyay, Rajiv Ranjan Singh, Sarika Gupta, Avadhesha Surolia
A direct link between development of insulin resistance and the presence of chronic inflammation, in case of obesity exists, with cytokines playing an important role in glucose metabolism. Members of TGF-β superfamily, including bone morphogenetic proteins (BMPs), have been shown to be involved in islet morphogenesis, establishment of β-cell mass and adipose cell fate determination. Here, we demonstrate a novel and direct role of BMP-4 and -7 in the regulation of glucose homeostasis and insulin resistance...
February 10, 2017: BioFactors
https://www.readbyqxmd.com/read/28183360/fat-mass-and-fat-distribution-are-associated-with-low-back-pain-intensity-and-disability-results-from-a-cohort-study
#5
Sultana Monira Hussain, Donna M Urquhart, Yuanyuan Wang, Jonathan E Shaw, Dianna J Magliano, Anita E Wluka, Flavia M Cicuttini
BACKGROUND: Determining the association between body composition and low back pain (LBP) will improve our understanding of the mechanisms by which obesity affects LBP, and inform novel approaches to managing LBP. The aim of this study was to examine the relationship between body composition and LBP intensity and disability. METHODS: A total of 5058 participants (44% men) of the Australian Diabetes, Obesity and Lifestyle Study were assessed for LBP intensity and disability using the Chronic Pain Grade Questionnaire (2013-2014)...
February 10, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28181539/dissecting-the-brown-adipogenic-regulatory-network-using-integrative-genomics
#6
Rachana N Pradhan, Johannes J Bues, Vincent Gardeux, Petra C Schwalie, Daniel Alpern, Wanze Chen, Julie Russeil, Sunil K Raghav, Bart Deplancke
Brown adipocytes regulate energy expenditure via mitochondrial uncoupling, which makes them attractive therapeutic targets to tackle obesity. However, the regulatory mechanisms underlying brown adipogenesis are still poorly understood. To address this, we profiled the transcriptome and chromatin state during mouse brown fat cell differentiation, revealing extensive gene expression changes and chromatin remodeling, especially during the first day post-differentiation. To identify putatively causal regulators, we performed transcription factor binding site overrepresentation analyses in active chromatin regions and prioritized factors based on their expression correlation with the bona-fide brown adipogenic marker Ucp1 across multiple mouse and human datasets...
February 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28177124/acute-exercise-elicits-differential-expression-of-insulin-resistance-genes-in-the-skeletal-muscle-of-patients-with-polycystic-ovary-syndrome
#7
Wagner Silva Dantas, Igor Hisashi Murai, Luiz Augusto Perandini, Hatylas Azevedo, Carlos Alberto Moreira-Filho, Niels Olsen Saraiva Camara, Hamilton Roschel, Bruno Gualano
OBJECTIVE: This study aimed to explore the role of acute exercise on skeletal muscle gene expression related to insulin resistance in patients with polycystic ovary syndrome (PCOS) and controls. METHODS: Four obese women with PCOS and 4 body controls subjects (CTRL) participated in this study. After an overnight fast, the subjects underwent a single 40-minute bout of aerobic exercise. Muscle samples were obtained from vastus lateralis at baseline and 60 minutes after exercise...
February 8, 2017: Clinical Endocrinology
https://www.readbyqxmd.com/read/28169840/bile-acid-disease-the-emerging-epidemic
#8
Ibironke Oduyebo, Michael Camilleri
PURPOSE OF REVIEW: Our objective was to review advances in bile acids in health and disease published in the last 2 years. Bile acid diarrhea (BAD) is recognized as a common cause of chronic diarrhea, and its recognition has been facilitated by development of new screening tests. RECENT FINDINGS: Primary BAD can account for 30% of cases of chronic diarrhea. The mechanisms leading to BAD include inadequate feedback regulation by fibroblast growth factor 19 (FGF-19) from ileal enterocytes, abnormalities in synthesis or degradation of proteins involved in FGF-19 regulation in hepatocytes and variations as a function of the bile acid receptor, TGR5 (GPBAR1)...
February 6, 2017: Current Opinion in Gastroenterology
https://www.readbyqxmd.com/read/28165842/stagnation-of-autophagy-a-novel-mechanism-of-renal-lipotoxicity
#9
Yoshitsugu Takabatake, Takeshi Yamamoto, Yoshitaka Isaka
Excessive fat intake can lead to cellular injury and inflammation (termed lipotoxicity), but studies on lipid metabolism in the kidney have been scarce. We recently identified a novel mechanism of lipotoxicity in the kidney proximal tubules especially focusing on the effect of lipid overload on lysosomal function and autophagic activity. Lipid overload basically stimulates macroautophagy/autophagy for renovation of the plasma and organelle membranes, which plays an essential role in maintaining the integrity of proximal tubules...
February 6, 2017: Autophagy
https://www.readbyqxmd.com/read/28165482/pharmacological-inhibition-of-c-jun-n-terminal-kinase-reduces-food-intake-and-sensitizes-leptin-s-anorectic-signaling-actions
#10
Su Gao, Shannon Howard, Philip V LoGrasso
The role for c-Jun N-terminal Kinase (JNK) in the control of feeding and energy balance is not well understood. Here, by use of novel and highly selective JNK inhibitors, we investigated the actions of JNK in the control of feeding and body weight homeostasis. In lean mice, intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration of SR-3306, a brain-penetrant and selective pan-JNK (JNK1/2/3) inhibitor, reduced food intake and body weight. Moreover, i.p. and i.c.v. administrations of SR11935, a brain-penetrant and JNK2/3 isoform-selective inhibitor, exerted similar anorectic effects as SR3306, which suggests JNK2 or JNK3 mediates aspect of the anorectic effect by pan-JNK inhibition...
February 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28145500/muscle-specific-overexpression-of-adipor1-or-adipor2-gives-rise-to-common-and-discrete-local-effects-whilst-adipor2-promotes-additional-systemic-effects
#11
Sahar Keshvari, Darren C Henstridge, Choaping Ng, Mark A Febbraio, Jonathan P Whitehead
Hypoadiponectinemia and adiponectin resistance are implicated in the aetiology of obesity-related cardiometabolic disorders, hence represent a potential therapeutic axis. Here we characterised the effects of in vivo electrotransfer-mediated overexpression of the adiponectin receptors, AdipoR1 or AdipoR2, into tibialis anterior muscle (TAM) of lean or obese mice. In lean mice, TAM-specific overexpression of AdipoR1 ((TAM)R1) or AdipoR2 ((TAM)R2) increased phosphorylation of AMPK, AKT and ERK and expression of the insulin responsive glucose transporter glut4...
February 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28137218/metabolic-and-cardiovascular-actions-of-nesfatin-1-implications-in-health-and-disease
#12
Naresh Ramesh, Kavishankar Gawli, Venkatakiran Pasupulleti, Suraj Unniappan
BACKGROUND: Metabolic homeostasis is achieved by proper functioning of a complex endocrine milieu, comprising of signals arising from the brain and peripheral tissues. Our knowledge of the factors regulating such balance is rapidly evolving, as new signaling molecules are characterized. Of central interest is nesfatin-1, owing to its multifunctional tissue specific actions regulating food intake, body weight, blood glucose and cardiac functions. METHOD: This review discusses the tissue/system wide distribution and actions of nesfatin-1 in regulating metabolic and cardiovascular functions in healthy conditions and diseases...
January 30, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28135625/histone-demethylase-kdm3a-a-novel-regulator-of-vascular-smooth-muscle-cells-controls-vascular-neointimal-hyperplasia-in-diabetic-rats
#13
Jing Chen, Jing Zhang, Jian Yang, Lin Xu, Qi Hu, Changwu Xu, Shuo Yang, Hong Jiang
BACKGROUND AND AIMS: Deregulation of histone demethylase KDM3a, an important regulator for H3K9 methylation, is correlated with obesity and abnormal metabolism in rodent models. However, the function of KDM3a in vascular remodeling under diabetic condition is unknown. METHODS: Adenoviruses expressing KDM3a and lentiviruses expressing KDM3a-targeting siRNA were generated to study the role of KDM3a both in vivo and in vitro. The carotid artery balloon injury model was established in diabetic SD rats to evaluate the significance of KDM3a in vascular injury...
December 9, 2016: Atherosclerosis
https://www.readbyqxmd.com/read/28134508/synthetic-triterpenoid-inhibition-of-human-ghrelin-o-acyltransferase-the-involvement-of-a-functionally-required-cysteine-provides-mechanistic-insight-into-ghrelin-acylation
#14
Kayleigh R McGovern-Gooch, Nivedita S Mahajani, Ariana Garagozzo, Anthony J Schramm, Lauren G Hannah, Michelle A Sieburg, John D Chisholm, James L Hougland
The peptide hormone ghrelin plays a key role in regulating hunger and energy balance within the body. Ghrelin signaling presents a promising and unexploited target for development of small molecule therapeutics for treatment of obesity, diabetes, and other health conditions. Inhibition of ghrelin O-acyltransferase (GOAT), which catalyzes an essential octanoylation step in ghrelin maturation, offers a potential avenue for controlling ghrelin signaling. Through screening a small molecule library, we have identified a class of synthetic triterpenoids that efficiently inhibit ghrelin acylation by the human isoform of GOAT (hGOAT)...
February 21, 2017: Biochemistry
https://www.readbyqxmd.com/read/28133767/the-human-longevity-gene-homolog-indy-and-interleukin-6-interact-in-hepatic-lipid-metabolism
#15
Christian von Loeffelholz, Stefanie Lieske, Frank Neuschäfer-Rube, Diana M Willmes, Nathanael Raschzok, Igor M Sauer, Jörg König, Martin Fromm, Paul Horn, Antonis Chatzigeorgiou, Andrea Pathe-Neuschäfer-Rube, Jens Jordan, Andreas F H Pfeiffer, Geltrude Mingrone, Stefan R Bornstein, Peter Stroehle, Christoph Harms, F Thomas Wunderlich, Stephen L Helfand, Michel Bernier, Rafael de Cabo, Gerald I Shulman, Triantafyllos Chavakis, Gerhard P Püschel, Andreas L Birkenfeld
Reduced expression of the Indy ('I am Not Dead, Yet') gene in lower organisms promotes longevity in a manner akin to caloric restriction. Deletion of the mammalian homolog of Indy (mIndy, Slc13a5) encoding for a plasma membrane associated citrate transporter expressed highly in the liver, protects mice from high-fat diet and aging-induced obesity and hepatic fat accumulation through a mechanism resembling caloric restriction. We aimed to study a possible role of mIndy in human hepatic fat metabolism. In obese, insulin resistant patients with NAFLD, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis...
January 30, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28126203/skin-derived-tslp-systemically-expands-regulatory-t-cells
#16
Theresa M Leichner, Atsushi Satake, Victor Sanoe Harrison, Yukinori Tanaka, Angela S Archambault, Brian S Kim, Mark C Siracusa, Warren J Leonard, Ali Naji, Gregory F Wu, David Artis, Taku Kambayashi
Regulatory T cells (Tregs) are a subset of CD4(+) T cells with suppressive function and are critical for limiting inappropriate activation of T cells. Hence, the expansion of Tregs is an attractive strategy for the treatment of autoimmune diseases. Here, we demonstrate that the skin possesses the remarkable capacity to systemically expand Treg numbers by producing thymic stromal lymphopoietin (TSLP) in response to vitamin D receptor stimulation. An ∼2-fold increase in the proportion and absolute number of Tregs was observed in mice treated topically but not systemically with the Vitamin D3 analog MC903...
January 23, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28121618/leptin-and-adiponectin-pathophysiological-role-and-possible-therapeutic-target-of-inflammation-in-ischemic-stroke
#17
Jitender Gairolla, Rupinder Kler, Manish Modi, Dheeraj Khurana
Stroke is a multifactorial disease contributing to significant noncommunicable disease burden in developing countries. Risk of stroke is largely a consequence of morbidities of diabetes, obesity, hypertension, and heart diseases. Incidence of stroke is directly proportional to body mass index. Adipose tissue stores energy as well as acts as an active endocrine organ, which secretes numerous humoral factors. Adiponectin and leptin are the commonest adipocytokines and have been invariably linked to the development of coronary heart disease and may be involved in the underlying biological mechanism of stroke...
January 25, 2017: Reviews in the Neurosciences
https://www.readbyqxmd.com/read/28117025/recent-advances-in-development-of-gpr40-modulators-ffa1-ffar1-an-emerging-target-for-type-2-diabetes
#18
Nutan Sharma, Sunita Bhagat, Tejpal Singh Chundawat
GPR40, an orphan G-protein coupled receptor that is activated by medium and long-chain fatty acids and is highly expressed in pancreatic islets, adipose depots and the gastrointestinal tract are involved in energy source recognition, absorption, storage and/or metabolism. Since its deorphanization in 2003, G-protein-coupled receptor GPR40 have emerged as potential target for type II diabetes because they have been hypothesized to participate in the adverse effects of chronic fatty acid exposure on function of β-cell...
January 20, 2017: Mini Reviews in Medicinal Chemistry
https://www.readbyqxmd.com/read/28110193/effects-of-polyphenol-compounds-melanin-on-nafld-nash-prevention
#19
Natalia Belemets, Nazarii Kobyliak, Oleksandr Virchenko, Tetyana Falalyeyeva, Tsyryuk Olena, Petro Bodnar, Oleksiy Savchuk, Tetyana Galenova, Martin Caprnda, Luis Rodrigo, Lubomir Skladany, Delian Delev, Radka Opatrilova, Peter Kruzliak, Tetyana Beregova, Lyudmyla Ostapchenko
BACKGROUND: One of the pathogenic mechanisms of the progression non-alcoholic liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) is the accumulation of reactive oxygen species (ROS). So, antioxidant therapy is necessary for successful treatment of the liver injury. We have paid attention to melanin produced by yeast Nadsoniella nigra strain X-1 as novel antioxidant and anti-inflammatory agents with low toxicity. In current study we aimed to investigate the preventive effect of melanin on the monosodium glutamate (MSG) induced NAFLD model in rats...
January 19, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28105274/design-synthesis-and-evaluation-of-novel-and-selective-g-protein-coupled-receptor-120-gpr120-spirocyclic-agonists
#20
Jason M Cox, Hong D Chu, Mariappan V Chelliah, John S Debenham, Keith Eagen, Ping Lan, Matthew Lombardo, Clare London, Michael A Plotkin, Unmesh Shah, Zhongxiang Sun, Henry M Vaccaro, Srikanth Venkatraman, Takao Suzuki, Nengxue Wang, Eric R Ashley, Alejandro Crespo, Maria Madeira, Dennis H Leung, Candice Alleyne, Aimie M Ogawa, Sarah Souza, Brande Thomas-Fowlkes, Jerry Di Salvo, Adam Weinglass, Melissa Kirkland, Michele Pachanski, Mary Ann Powles, Effie Tozzo, Taro E Akiyama, Feroze Ujjainwalla, James R Tata, Christopher J Sinz
Type 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the identification of safe and effective insulin sensitizers, absent of weight gain, has been a long-standing goal of diabetes research. G-protein coupled receptor 120 (GPR120) has recently emerged as a potential therapeutic target for treating T2DM. Natural occurring, and more recently, synthetic agonists have been associated with insulin sensitizing, anti-inflammatory, and fat metabolism effects. Herein we describe the design, synthesis, and evaluation of a novel spirocyclic GPR120 agonist series, which culminated in the discovery of potent and selective agonist 14...
January 12, 2017: ACS Medicinal Chemistry Letters
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