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https://www.readbyqxmd.com/read/29031905/fibroblast-growth-factor-21-decreases-after-liver-fat-reduction-via-growth-hormone-augmentation
#1
Laurie R Braun, Meghan N Feldpausch, Natalia Czerwonka, Martin Torriani, Steven K Grinspoon, Takara L Stanley
OBJECTIVE: Fibroblast growth factor 21 (FGF21) ameliorates steatohepatitis but is increased in humans with fatty liver, potentially due to compensatory mechanisms and/or FGF21 resistance. Further, animal models suggest that GH increases serum FGF21. Tesamorelin, a growth hormone releasing hormone agonist, reduces liver fat in HIV-infected individuals. The objectives of this study were to investigate changes in FGF21 during tesamorelin treatment, to elucide the interplay between FGF21, GH augmentation, and liver fat reduction in humans...
October 7, 2017: Growth Hormone & IGF Research
https://www.readbyqxmd.com/read/29029979/immunoaffinity-capture-coupled-with-capillary-electrophoresis-mass-spectrometry-to-study-protein-therapeutic-stability-in-vivo
#2
Mei Han, Josh T Pearson, Yunan Wang, Dwight Winters, Marcus Soto, Dan A Rock, Brooke M Rock
Protein engineering is at an all-time high in biopharmaceutics. As a result, absorption, distribution, metabolism and excretion (ADME) of proteins has become more important to understand in the context of engineering strategies to optimize therapeutic properties of potential lead constructs. Immunoaffinity capture coupled with a newly developed capillary electrophoresis - mass spectrometry (CE-MS) system was used to characterize intact protein mass analysis of a wildtype Fc-FGF21 construct and a sequence re-engineered Fc-FGF21 construct from an in vivo study...
October 10, 2017: Analytical Biochemistry
https://www.readbyqxmd.com/read/29020627/a-specific-chrebp-and-ppar%C3%AE-cross-talk-is-required-for-the-glucose-mediated-fgf21-response
#3
Alison Iroz, Alexandra Montagner, Fadila Benhamed, Françoise Levavasseur, Arnaud Polizzi, Elodie Anthony, Marion Régnier, Edwin Fouché, Céline Lukowicz, Michèle Cauzac, Emilie Tournier, Marcio Do-Cruzeiro, Martine Daujat-Chavanieu, Sabine Gerbal-Chalouin, Véronique Fauveau, Solenne Marmier, Anne-Françoise Burnol, Sandra Guilmeau, Yannick Lippi, Jean Girard, Walter Wahli, Renaud Dentin, Hervé Guillou, Catherine Postic
While the physiological benefits of the fibroblast growth factor 21 (FGF21) hepatokine are documented in response to fasting, little information is available on Fgf21 regulation in a glucose-overload context. We report that peroxisome-proliferator-activated receptor α (PPARα), a nuclear receptor of the fasting response, is required with the carbohydrate-sensitive transcription factor carbohydrate-responsive element-binding protein (ChREBP) to balance FGF21 glucose response. Microarray analysis indicated that only a few hepatic genes respond to fasting and glucose similarly to Fgf21...
October 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28990606/a-combined-docosahexaenoic-acid-thyroid-hormone-protocol-upregulates-rat-liver-%C3%AE-klotho-expression-and-downstream-components-of-fgf21-signaling-as-a-potential-novel-approach-to-metabolic-stress-conditions
#4
R Vargas, B Riquelme, J Fernández, L A Videla
Liver preconditioning by a docosahexaenoic acid (DHA) and triiodothyronine (T3) combined protocol underlies peroxisome-proliferator activated receptor α (PPARα)-fibroblast growth factor 21 (FGF21) upregulation, the study of the regulatory mechanisms involved being the aim of this work. Combined DHA (daily doses of 300 mg kg(-1) for 3 days)-T3 (0.05 mg kg(-1) at the fourth day) administration elicited higher levels of liver DHA and serum T3, with enhanced hepatic nuclear/cytosolic PPARα ratios, upregulation of FGF21 and β-Klotho expression, and a small reduction in that of FGF receptor 1 (FGFR1), compared with the respective controls...
October 9, 2017: Food & Function
https://www.readbyqxmd.com/read/28988823/fgf19-fgf21-and-an-fgfr1-%C3%AE-klotho-activating-antibody-act-on-the-nervous-system-to-regulate-body-weight-and-glycemia
#5
Tian Lan, Donald A Morgan, Kamal Rahmouni, Junichiro Sonoda, Xiaorong Fu, Shawn C Burgess, William L Holland, Steven A Kliewer, David J Mangelsdorf
Despite the different physiologic functions of FGF19 and FGF21 as hormonal regulators of fed and fasted metabolism, their pharmacologic administration causes similar increases in energy expenditure, weight loss, and enhanced insulin sensitivity in obese animals. Here, in genetic loss-of-function studies of the shared co-receptor β-Klotho, we show that these pharmacologic effects are mediated through a common, tissue-specific pathway. Surprisingly, FGF19 and FGF21 actions in liver and adipose tissue are not required for their longer-term weight loss and glycemic effects...
October 5, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28985411/tethered-variable-cl-bispecific-igg-an-antibody-platform-for-rapid-bispecific-antibody-screening
#6
Hok Seon Kim, Diana Ronai Dunshee, Angie Yee, Raymond K Tong, Ingrid Kim, Farzam Farahi, Jo-Anne Hongo, James A Ernst, Junichiro Sonoda, Christoph Spiess
Bispecific antibodies offer a clinically validated platform for drug discovery. In generating functionally active bispecific antibodies, it is necessary to identify a unique parental antibody pair to merge into a single molecule. However, technologies that allow high-throughput production of bispecific immunoglobulin Gs (BsIgGs) for screening purposes are limited. Here, we describe a novel bispecific antibody format termed tethered-variable CLBsIgG (tcBsIgG) that allows robust production of intact BsIgG in a single cell line, concurrently ensuring cognate light chain pairing and preserving key antibody structural and functional properties...
July 7, 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/28982014/the-role-of-suppression-of-hepatic-scd1-expression-in-the-metabolic-effects-of-dietary-methionine-restriction
#7
Laura A Forney, Kirsten P Stone, Desiree Wanders, James M Ntambi, Thomas W Gettys
Dietary methionine restriction (MR) produces concurrent increases in energy intake and expenditure, but the proportionately larger increase in energy expenditure (EE) effectively limits weight gain and adipose tissue accretion over time. Increased hepatic FGF21 is essential to MR-dependent increases in EE, but it is unknown whether the downregulation of hepatic stearoyl-CoA desaturase-1 (SCD1) by MR could also be a contributing factor. Global deletion of SCD1 mimics cold exposure in mice housed at 23°C by compromising the insular properties of the skin...
October 5, 2017: Applied Physiology, Nutrition, and Metabolism, Physiologie Appliquée, Nutrition et Métabolisme
https://www.readbyqxmd.com/read/28980322/fibroblast-growth-factor-21-attenuates-calcification-of-vascular-smooth-muscle-cells-in%C3%A2-vitro
#8
Fangying Cao, Shaoping Wang, Xiangrong Cao, Xiaoxiao Liu, Kun Fu, Peng Hao, Jinghua Liu
OBJECTIVES: Vascular calcification is a dysfunction of the vasculature. Recent findings indicate that fibroblast growth factor21 (FGF21), a protector of the cardiovascular system, is related to the mineral deposition of bone and enhances the osteogenic activity of bone morphogenic protein (BMP)-2. In this study, we explored whether FGF21 suppresses vascular calcification. METHODS: A calcifying model was established by culturing primary rat vascular aortic smooth muscle cells (VSMCs) in a beta-glycerophosphate (BGP)-containing calcifying medium for 14 days...
October 4, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28970566/selective-homogeneous-assay-for-circulating-endopeptidase-fibroblast-activation-protein-fap
#9
Travis W Bainbridge, Diana Ronai Dunshee, Noelyn M Kljavin, Nicholas J Skelton, Junichiro Sonoda, James A Ernst
Fibroblast Activation Protein (FAP) is a membrane-bound serine protease whose expression is often elevated in activated fibroblasts associated with tissue remodeling in various common diseases such as cancer, arthritis and fibrosis. Like the closely related dipeptidyl peptidase DPPIV, the extracellular domain of FAP can be released into circulation as a functional enzyme, and limited studies suggest that the circulating level of FAP correlates with the degree of tissue fibrosis. Here we describe a novel homogeneous fluorescence intensity assay for circulating FAP activity based on a recently identified natural substrate, FGF21...
October 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28949374/fibroblast-growth-factor-21-protects-rat-cardiomyocytes-from-endoplasmic-reticulum-stress-by-promoting-the-fibroblast-growth-factor-receptor-1-extracellular-signal%C3%A2-regulated-kinase-1-2-signaling-pathway
#10
Pingping Liang, Lin Zhong, Lei Gong, Jiahui Wang, Yujie Zhu, Weifeng Liu, Jun Yang
Fibroblast growth factor 21 (FGF21), as an endocrine factor, is secreted into circulation by injured cardiomyocytes. Endoplasmic reticulum (ER) stress-induced apoptosis has been proposed as an important pathophysiological mechanism for cardiomyocyte injury. However, whether the enhanced expression of FGF21 in cardiomyocytes is linked to ER stress, and the effect and underlying mechanism of FGF21 on ER stress-induced cardiomyocyte apoptosis remain unclear. In the present study, it was demonstrated that mild ER stress resulted in upregulated expression levels of FGF21 and its main receptors, as a response to cell compensation, at the induction of ≤5 µM tunicamycin (TM)...
September 19, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28948603/process-development-of-a-fgf21-protein-antibody-conjugate
#11
Anouk Dirksen, Keith A Davis, Joe T Collins, Keshab Bhattacharya, Jari I Finneman, Erin L Pepin, Jeffrey S Ryczek, Paul W Brown, William B Wellborn, Ratish Mangalathillam, Brad P Evans, Mark J Pozzo, Rory F Finn
A scalable, viable process was developed for the Fibroblast Growth Factor 21 (FGF21) protein-antibody conjugate, CVX-343, an extended half-life therapeutic for the treatment of metabolic disease. CVX-343 utilizes the CovX antibody scaffold technology platform that was specifically developed for peptide and protein half-life extension. CVX-343 is representative of a growing number of complex novel peptide- and protein-based bioconjugate molecules currently being explored as therapeutic candidates. The complexity of these bioconjugates, assembled using well-established chemistries, can lead to very difficult production schemes requiring multiple starting materials and a combination of diverse technologies...
September 26, 2017: Biopolymers
https://www.readbyqxmd.com/read/28938478/roux-en-y-gastric-bypass-surgery-has-unique-effects-on-postprandial-fgf21-but-not-fgf19-secretion
#12
Lydia-Ann L S Harris, Gordon I Smith, Bettina Mittendorfer, J Christopher Eagon, Adewole L Okunade, Bruce W Patterson, Samuel Klein
Context: Fibroblast growth factors (FGF) 19 and FGF21 are secreted by the intestine and liver in response to macronutrient intake. Intestinal resection and reconstruction via bariatric surgery may alter their regulation. Objective: We tested the hypothesis that weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery, but not matched weight loss induced by laparoscopic adjustable gastric banding (LAGB), increases postprandial plasma FGF19 and FGF21 concentrations...
August 17, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28938440/sex-differences-in-the-hormonal-and-metabolic-response-to-dietary-protein-dilution
#13
Karlton R Larson, Kimberly A Russo, Yanbin Fang, Niloufar Mohajerani, Michael L Goodson, Karen K Ryan
Consumption of a low-protein, high-carbohydrate diet induces a striking increase in circulating fibroblast growth factor-21 (FGF21), which is associated with improved cardiometabolic health and increased longevity. Increased lifespan during this dietary protein "dilution" has been explained by resource-mediated trade-offs between reproduction and survival, such that fecundity is optimized at a greater relative intake of proteins/carbohydrates. The magnitude of this trade-off is thought to be sex-dependent. In this study, we tested the hypothesis that metabolic responses to dietary protein dilution are likewise dependent on sex...
October 1, 2017: Endocrinology
https://www.readbyqxmd.com/read/28938434/fgf21-is-an-insulin-dependent-postprandial-hormone-in-adult-humans
#14
Ricardo J Samms, Jo E Lewis, Luke Norton, Francis B Stephens, Christopher J Gaffney, Tony Butterfield, Dennis Smith, Christine Cheng, James W Perfield, Andrew C Adams, Francis J P Ebling, Kostas Tsintzas
Context: Fibroblast growth factor 21 (FGF21) secretion has been shown to respond directly to carbohydrate consumption, with glucose, fructose and sucrose all reported to increase plasma levels of FGF21 in rodents and humans. However, carbohydrate consumption also results in secretion of insulin. Objective: The aim of this study was to examine the combined and independent effects of hyperglycemia and hyperinsulinemia on total and bioactive FGF21 in the postprandial period in humans, and determine whether this effect is attenuated in conditions of altered insulin secretion and action...
August 4, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28938407/fibroblast-growth-factor-21-metabolic-role-in-mice-and-men
#15
Harald Staiger, Michaela Keuper, Lucia Berti, Martin Hrabe de Angelis, Hans-Ulrich Häring
Since its identification in 2000, the interest of scientists in the hepatokine fibroblast growth factor (FGF) 21 has tremendously grown, and still remains high, due to a wealth of very robust data documenting this factor's favorable effects on glucose and lipid metabolism in mice. For more than ten years now, intense in vivo and ex vivo experimentation addressed the physiological functions of FGF21 in humans as well as its pathophysiological role and pharmacological effects in human metabolic disease. This work produced a comprehensive collection of data revealing overlaps in FGF21 expression and function but also significant differences between mice and humans that have to be considered before translation from bench to bedside can be successful...
October 1, 2017: Endocrine Reviews
https://www.readbyqxmd.com/read/28920014/plasma-fibroblast-growth-factor-21-levels-in-patients-with-inborn-errors-of-metabolism
#16
Brian Kirmse, Juan Cabrerra-Luque, Omar Ayyub, Kristina Cusmano, Kimberly Chapman, Marshall Summar
Fibroblast growth factor-21 (FGF21) levels are elevated in patients with primary mitochondrial disorders but have not been studied in patients with inborn errors of metabolism (IEM) known to have secondary mitochondrial dysfunction. We measured plasma FGF21 by ELISA in patients with and without IEM. FGF21 levels were higher in patients with IEM compared to without IEM (370 pg/dL vs. 0-65 pg/dL). Further study of FGF21 as a biomarker in IEM is warranted.
December 2017: Molecular Genetics and Metabolism Reports
https://www.readbyqxmd.com/read/28898910/balanced-coagonist-of-glp-1-and-glucagon-receptors-corrects-dyslipidemia-by-improving-fgf21-sensitivity-in-hamster-model
#17
Vishal Patel, Amit Joharapurkar, Samadhan Kshirsagar, Hiren M Patel, Dheerendra Pandey, Dipam Patel, Brijesh Sutariya, Maulik Patel, Rajesh Bahekar, Mukul R Jain
Hyperlipidemia is often associated with obesity and diabetes, and can lead to serious complications like atherosclerosis and fatty liver disease. Coagonist of GLP-1 and glucagon receptors is a therapy under clinical investigation for treatment of obesity and diabetes. In this study, we have characterized the mechanism of hypolipidemic effect of a balanced coagonist using high cholesterol-fed hamsters. Tyloxapol-induced hypertriglyceridemia, lipolysis in adipose tissue, and bile homeostasis were assessed after repeated dose treatment of the coagonist of GLP-1 and glucagon receptors (Aib2 C24 chimera 2, SC)...
September 12, 2017: Drug Research
https://www.readbyqxmd.com/read/28895785/preclinical-pharmacokinetic-characterization-of-an-adipose-tissue-targeting-monoclonal-antibody-in-obese-and-non-obese-animals
#18
Sharmila Rajan, Danielle Mandikian, Amos Baruch, Thomas R Gelzleichter, Dale Stevens, Junichiro Sonoda, Kyra Cowan, C Andrew Boswell, Eric Stefanich
Target receptor levels can influence pharmacokinetics (PK) or pharmacodynamics (PD) of monoclonal antibodies (mAbs), and can affect drug development of this class of molecules. We generated an effector-less humanized bispecific antibody that selectively activates fibroblast growth factor receptor (FGFR)1 and βKlotho receptor, a FGF21 receptor complex highly expressed in both white and brown adipocytes. The molecule shows cross-species binding with comparable equilibrium binding affinity (Kd) for human, cynomolgus monkey, and mouse FGFR1/βKlotho...
September 12, 2017: MAbs
https://www.readbyqxmd.com/read/28895643/thyroid-hormone-induced-expression-of-the-hepatic-scaffold-proteins-sestrin2-%C3%AE-klotho-and-frs2%C3%AE-in-relation-to-fgf21-ampk-signaling
#19
Luis A Videla, Romina Vargas, Barbara Riquelme, Javier Fernández, Virginia Fernández
Thyroid hormone (3,3',5-triiodothyronine, T3) accelerates energy metabolism in the liver through mechanisms involving upregulation of AMP-activated protein kinase (AMPK). This study aims to assess the influence of T3 on the expression of the scaffold proteins β-Klotho, fibroblast growth factor receptor substrate 2α (FRS2α), and Sestrin2 in relation to FGF21-AMPK signaling. Male Sprague-Dawley rats were given 0.1 mg T3/kg or hormone vehicle (controls) and studies were done 24 h after treatment. These include measurements of the mRNA expression (qPCR) of hepatic β-Klotho, FGF21, FGF21 receptor-1 (FGFR1), extracellular-signal-regulated kinase 1/2 (ERK1/2), FRS2α, ribosomal S6 kinase-1 (RSK1), liver kinase B1 (LKB1), AMPK, and Sestrin2...
September 11, 2017: Experimental and Clinical Endocrinology & Diabetes
https://www.readbyqxmd.com/read/28889722/effects-of-central-fibroblast-growth-factor-21-fgf21-in-energy-balance
#20
L Recinella, S Leone, C Ferrante, A Chiavaroli, C Di Nisio, S Martinotti, M Vacca, L Brunetti, G Orlando
Fibroblast growth factor 21 (FGF21) is known as a major metabolic regulator of glucose and lipid homeostasis. Continuous intracerebroventricular (i.c.v.) administration of FGF21 was found to modulate feeding and energy expenditure in rats with diet-induced obesity, suggesting a central effect by the peptide. In this context, in the present work, we studied the effects of a single central FGF21 administration (0.5-5 µg) on feeding and energy expenditure by evaluating locomotor activity, interscapular brown adipose tissue (BAT) weight, gene expression of uncoupling protein-1 (UCP-1) in BAT and plasma norepinephrine (NE) levels in Sprague-Dawley fed rats...
September 11, 2017: Journal of Biological Regulators and Homeostatic Agents
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