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1
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Phan P, Hoang J, Kumar TKS. Overexpression and biophysical and functional characterization of a recombinant FGF21. BIOPHYSICAL REPORTS 2025; 5:100198. [PMID: 39884432 PMCID: PMC11869967 DOI: 10.1016/j.bpr.2025.100198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/17/2025] [Accepted: 01/24/2025] [Indexed: 02/01/2025]
Abstract
Fibroblast growth factor 21 (FGF21) is an endocrine FGF that plays a vital role in regulating essential metabolic pathways. FGF21 increases glucose uptake by cells, promotes fatty acid oxidation, reduces blood glucose levels, and alleviates metabolic diseases. However, detailed studies on its stability and biophysical characteristics have not been reported. Herein, we present the overexpression, biophysical characterization, and metabolic activity of a soluble recombinant FGF21 (rFGF21). The far-UV circular dichroism spectra of rFGF21 show a negative trough at 215 nm, indicating that the protein's backbone predominantly adopts a β sheet conformation. rFGF21 shows intrinsic tyrosine fluorescence at 305 nm. Thermal denaturation using differential scanning calorimetry reveals that rFGF21 is relatively thermally unstable, with a melting temperature of 46.8°C (±0.1°C). The urea-induced unfolding of rFGF21 is rapid, with a chemical transition midpoint of 0.4 M. rFGF21 is readily cleaved by trypsin in limited trypsin digestion assays. Isothermal titration calorimetry experiments show that rFGF21 does not bind to heparin. Interestingly, rFGF21 demonstrates proliferative activity in NIH/3T3 fibroblasts and enhances mitochondrial oxidative phosphorylation and fatty acid oxidation in 3T3-L1 adipocytes. These findings provide a crucial framework for the engineering of novel structure-based variants of FGF21 with improved stability and biological activity to treat metabolic disorders.
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Affiliation(s)
- Phuc Phan
- Department of Chemistry and Biochemistry, Fulbright College of Art and Sciences, University of Arkansas, Fayetteville, Arkansas
| | - Jason Hoang
- Department of Chemistry and Biochemistry, Fulbright College of Art and Sciences, University of Arkansas, Fayetteville, Arkansas
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2
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Chen G, Chen L, Li X, Mohammadi M. FGF-based drug discovery: advances and challenges. Nat Rev Drug Discov 2025:10.1038/s41573-024-01125-w. [PMID: 39875570 DOI: 10.1038/s41573-024-01125-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/2024] [Indexed: 01/30/2025]
Abstract
The fibroblast growth factor (FGF) family comprises 15 paracrine-acting and 3 endocrine-acting polypeptides, which govern a multitude of processes in human development, metabolism and tissue homeostasis. Therapeutic endocrine FGFs have recently advanced in clinical trials, with FGF19 and FGF21-based therapies on the cusp of approval for the treatment of primary sclerosing cholangitis and metabolic syndrome-associated steatohepatitis, respectively. By contrast, while paracrine FGFs were once thought to be promising drug candidates for wound healing, burns, tissue repair and ischaemic ailments based on their potent mitogenic and angiogenic properties, repeated failures in clinical trials have led to the widespread perception that the development of paracrine FGF-based drugs is not feasible. However, the observation that paracrine FGFs can exert FGF hormone-like metabolic activities has restored interest in these FGFs. The recent structural elucidation of the FGF cell surface signalling machinery and the formulation of a new threshold model for FGF signalling specificity have paved the way for therapeutically harnessing paracrine FGFs for the treatment of a range of metabolic diseases.
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Affiliation(s)
- Gaozhi Chen
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lingfeng Chen
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Xiaokun Li
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Moosa Mohammadi
- Institute of Cell Growth Factor, Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health, Wenzhou, Zhejiang, China.
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3
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Guo Y, Bao Y, Chen Z, Rao Z, Luo Y, Ye S, Liu S. Novel FGF21 analogues through structure-based optimization for therapeutic development. Acta Biochim Biophys Sin (Shanghai) 2024. [PMID: 39719877 DOI: 10.3724/abbs.2024227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2024] Open
Abstract
Fibroblast growth factor 21 (FGF21) plays a pivotal role in regulating metabolic processes and energy homeostasis, making it a promising therapeutic avenue for various obesity-related conditions. However, its therapeutic efficacy faces challenges due to its suboptimal pharmacokinetics and bioactivity. To overcome these limitations, we adapt a strategy in which key amino acid residues responsible for enhanced activity are pinpointed through sequence alignment and comparative analysis to develop long-acting FGF21 analogs. The mutant FGF21 analogs are fused with the Fc fragment. Here, we report the design, identification, and characterization of two distinct Fc-fused FGF21 analogs, Fc-FGF21(P119R) and Fc-FGF21(H125R), with significantly augmented potency. These findings hold promise for clinical applications, offering potential interventions for obesity-related metabolic disorders.
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Affiliation(s)
- Yiqing Guo
- Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, Tianjin 300072, China
| | - Yuxuan Bao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Zhichao Chen
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Zhiheng Rao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Yongde Luo
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Sheng Ye
- Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, Tianjin 300072, China
| | - Si Liu
- Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, Tianjin 300072, China
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4
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Boisclair YR, Giesy SL. Endocrine adaptations to demanding physiological states in ruminants. J Dairy Sci 2024:S0022-0302(24)01377-8. [PMID: 39647618 DOI: 10.3168/jds.2024-25799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 11/11/2024] [Indexed: 12/10/2024]
Abstract
Highly productive ruminants rely on hormonally driven adaptations to prioritize the use of limiting nutrients during the demanding phases of the pregnancy-lactation cycle. Glucose, the predominant oxidative fuel of fetal life and the absolute precursor of mammary lactose synthesis, illustrates the need and benefit of such adaptations. Endocrine mechanisms such as insulin resistance and/or hypoinsulinemia favor the diversion of maternal glucose to the placenta or mammary gland where uptake is independent of insulin. Research in dairy cows in the 1980s and 1990s identified growth hormone as a peripherally acting signal opposing the effects of insulin. The following decades have seen the discovery of a new generation of signals secreted almost exclusively by adipose tissue, skeletal muscle or liver, dynamically regulated by metabolic challenges, and engaged in cross-organ communication. The understanding of these signals in the coordination of metabolism in ruminants has been limited by the availability of assays to measure their circulating concentrations and materials to perform functional studies. Nevertheless, emerging data point to their importance during demanding physiological states in ruminants, including early lactation in dairy cows and late pregnancy in sheep. Examples include modulation of insulin action by liver-derived fibroblast growth factor 21 (FGF21) and regulation of energy allocation among tissues by the action of the adipose-derived hormone leptin via its ability to control the hypothalamic-pituitary-thyroid axis. Recent studies investigating the regulation and action of FGF21 and leptin in dairy cows and sheep will be used to illustrate the potential of recently discovered signals to coordinate metabolism during physiologically demanding states such as early lactation.
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Affiliation(s)
- Y R Boisclair
- Department of Animal Science, Cornell University, Ithaca, New York 14853.
| | - S L Giesy
- Department of Animal Science, Cornell University, Ithaca, New York 14853
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5
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Zhang QY, Liu HX. Insights into the role of FGF21 in coronary heart disease. Int J Biol Macromol 2024; 282:136911. [PMID: 39476920 DOI: 10.1016/j.ijbiomac.2024.136911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 10/22/2024] [Accepted: 10/23/2024] [Indexed: 11/11/2024]
Abstract
Coronary heart disease (CHD) remains a leading cause of global mortality, with an alarming increase in its incidence among the younger population in recent years. This has amplified the need for early diagnostic markers and advances in therapeutic strategies to improve patient outcomes. Fibroblast growth factor 21 (FGF21), an endocrine hormone crucial for the regulation of metabolic homeostasis, has garnered significant attention over the past decade, owing to its role in cardiovascular health. FGF21 exerts cardioprotective effects through various mechanisms, including regulation of myocardial energy metabolism, prevention of cardiac cell death, suppression of inflammation, and reduction of oxidative stress in the heart. Given these properties, FGF21 shows considerable promise as a pharmacological agent for the management of CHD. Moreover, it has emerged as a promising biomarker for the diagnosis and prognostic assessment of CHD. This review aims to clarify the molecular mechanisms underlying the favorable effects of FGF21 on CHD and its related risk factors, thereby providing valuable insights for future research on the role of FGF21 in CHD management.
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Affiliation(s)
- Qin-Yao Zhang
- Health Sciences Institute, China Medical University, Shenyang, China; Institute of Life Sciences, China Medical University, Shenyang, China; Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, China; Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hui-Xin Liu
- Health Sciences Institute, China Medical University, Shenyang, China; Institute of Life Sciences, China Medical University, Shenyang, China; Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, China.
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6
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de La Bourdonnaye G, Ghazalova T, Fojtik P, Kutalkova K, Bednar D, Damborsky J, Rotrekl V, Stepankova V, Chaloupkova R. Computer-aided engineering of stabilized fibroblast growth factor 21. Comput Struct Biotechnol J 2024; 23:942-951. [PMID: 38379823 PMCID: PMC10877085 DOI: 10.1016/j.csbj.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 02/03/2024] [Accepted: 02/03/2024] [Indexed: 02/22/2024] Open
Abstract
FGF21 is an endocrine signaling protein belonging to the family of fibroblast growth factors (FGFs). It has emerged as a molecule of interest for treating various metabolic diseases due to its role in regulating glucogenesis and ketogenesis in the liver. However, FGF21 is prone to heat, proteolytic, and acid-mediated degradation, and its low molecular weight makes it susceptible to kidney clearance, significantly reducing its therapeutic potential. Protein engineering studies addressing these challenges have generally shown that increasing the thermostability of FGF21 led to improved pharmacokinetics. Here, we describe the computer-aided design and experimental characterization of FGF21 variants with enhanced melting temperature up to 15 °C, uncompromised efficacy at activation of MAPK/ERK signaling in Hep G2 cell culture, and ability to stimulate proliferation of Hep G2 and NIH 3T3 fibroblasts cells comparable with FGF21-WT. We propose that stabilizing the FGF21 molecule by rational design should be combined with other reported stabilization strategies to maximize the pharmaceutical potential of FGF21.
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Affiliation(s)
- Gabin de La Bourdonnaye
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
- Enantis Ltd., Biotechnology Incubator INBIT, Brno, Czech Republic
| | - Tereza Ghazalova
- Enantis Ltd., Biotechnology Incubator INBIT, Brno, Czech Republic
| | - Petr Fojtik
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | | | - David Bednar
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
- Loschmidt Laboratories, Centre for Toxic Compounds in the Environment RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | - Jiri Damborsky
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
- Loschmidt Laboratories, Centre for Toxic Compounds in the Environment RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | - Vladimir Rotrekl
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | | | - Radka Chaloupkova
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
- Enantis Ltd., Biotechnology Incubator INBIT, Brno, Czech Republic
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7
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Brinker EJ, Hardcastle MR, Dittmer KE, Graff EC. Endocrine fibroblast growth factors in domestic animals. Domest Anim Endocrinol 2024; 89:106872. [PMID: 39059301 DOI: 10.1016/j.domaniend.2024.106872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 06/28/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024]
Abstract
Fibroblast growth factors (FGFs) are a group of structurally homologous yet functionally pleiotropic proteins. Canonical and intracellular FGFs have primarily autocrine or paracrine effects. However, the FGF19 subfamily, composed of FGF15/19, FGF21, and FGF23, act as endocrine hormones that regulate bile acid, metabolic, and phosphorus homeostasis, respectively. Current research in human and rodent models demonstrates the potential of these endocrine FGFs to target various diseases, including disorders of inherited hypophosphatemia, chronic liver disease, obesity, and insulin resistance. Many diseases targeted for therapeutic use in humans have pathophysiological overlaps in domestic animals. Despite the potential clinical and economic impact, little is known about endocrine FGFs and their signaling pathways in major domestic animal species compared with humans and laboratory animals. This review aims to describe the physiology of these endocrine FGFs, discuss their current therapeutic use, and summarize the contemporary literature regarding endocrine FGFs in domestic animals, focusing on potential future directions.
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Affiliation(s)
- Emily J Brinker
- Department of Pathobiology, College of Veterinary Medicine, 166 Greene Hall, Auburn University, AL, USA 36849; Department of Comparative Pathobiology, Cummings School of Veterinary Medicine at Tufts University, 200 Westboro Road, North Grafton, MA, USA 01536
| | - Michael R Hardcastle
- IDEXX Laboratories Pty. Ltd., 20A Maui Street, Pukete, Hamilton 3200, New Zealand
| | - Keren E Dittmer
- School of Veterinary Sciences, Massey University, Private Bag 11-222, Palmerston North 4442, New Zealand
| | - Emily C Graff
- Department of Pathobiology, College of Veterinary Medicine, 166 Greene Hall, Auburn University, AL, USA 36849; Scott-Ritchey Research Center, College of Veterinary Medicine, Dr. Auburn University, 1265 HC Morgan, AL, USA 36849.
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8
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Huang P, Zhu Y, Qin J. Research advances in understanding crosstalk between organs and pancreatic β-cell dysfunction. Diabetes Obes Metab 2024; 26:4147-4164. [PMID: 39044309 DOI: 10.1111/dom.15787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/25/2024]
Abstract
Obesity has increased dramatically worldwide. Being overweight or obese can lead to various conditions, including dyslipidaemia, hypertension, glucose intolerance and metabolic syndrome (MetS), which may further lead to type 2 diabetes mellitus (T2DM). Previous studies have identified a link between β-cell dysfunction and the severity of MetS, with multiple organs and tissues affected. Identifying the associations between pancreatic β-cell dysfunction and organs is critical. Research has focused on the interaction between the liver, gut and pancreatic β-cells. However, the mechanisms and related core targets are still not perfectly elucidated. The aims of this review were to summarize the mechanisms of β-cell dysfunction and to explore the potential pathogenic pathways and targets that connect the liver, gut, adipose tissue, muscle, and brain to pancreatic β-cell dysfunction.
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Affiliation(s)
- Peng Huang
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Yunling Zhu
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Jian Qin
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
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9
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Trusz GJ. Fibroblast growth factor 21. Differentiation 2024; 139:100793. [PMID: 38991938 DOI: 10.1016/j.diff.2024.100793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 06/23/2024] [Accepted: 06/28/2024] [Indexed: 07/13/2024]
Abstract
Fibroblast growth factor 21 (FGF21) belongs to the FGF19 subfamily and acts systemically, playing a key role in inter-organ crosstalk. Ranging from metabolism, reproduction, and immunity, FGF21 is a pleiotropic hormone which contributes to various physiological processes. Although most of its production across species stems from hepatic tissues, expression of FGF21 in mice has also been identified in adipose tissue, thymus, heart, pancreas, and skeletal muscle. Elevated FGF21 levels are affiliated with various diseases and conditions, such as obesity, type 2 diabetes, preeclampsia, as well as cancer. Murine knockout models are viable and show modest weight gain, while overexpression and gain-of-function models display resistance to weight gain, altered bone volume, and enhanced immunity. In addition, FGF21-based therapies are at the forefront of biopharmaceutical strategies aimed at treating metabolic dysfunction-associated steatotic liver disease.
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Affiliation(s)
- Guillaume J Trusz
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
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10
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Harrison SA, Rolph T, Knott M, Dubourg J. FGF21 agonists: An emerging therapeutic for metabolic dysfunction-associated steatohepatitis and beyond. J Hepatol 2024; 81:562-576. [PMID: 38710230 DOI: 10.1016/j.jhep.2024.04.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 03/26/2024] [Accepted: 04/29/2024] [Indexed: 05/08/2024]
Abstract
The worldwide epidemics of obesity, hypertriglyceridemia, dyslipidaemia, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) represent a major economic burden on healthcare systems. Patients with at-risk MASH, defined as MASH with moderate or significant fibrosis, are at higher risk of comorbidity/mortality, with a significant risk of cardiovascular diseases and/or major adverse liver outcomes. Despite a high unmet medical need, there is only one drug approved for MASH. Several drug candidates have reached the phase III development stage and could lead to several potential conditional drug approvals in the coming years. Within the armamentarium of future treatment options, FGF21 analogues hold an interesting position thanks to their pleiotropic effects in addition to their significant effect on both MASH resolution and fibrosis improvement. In this review, we summarise preclinical and clinical data from FGF21 analogues for MASH and explore additional potential therapeutic indications.
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Affiliation(s)
- Stephen A Harrison
- Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU UK; Pinnacle Clinical Research, San Antonio, Texas, USA
| | - Tim Rolph
- Akero Therapeutics, South San Francisco, California, USA
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11
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Jacobsen JM, Petersen N, Torz L, Gerstenberg MK, Pedersen K, Østergaard S, Wulff BS, Andersen B, Raun K, Christoffersen BØ, John LM, Reitman ML, Kuhre RE. Housing mice near vs. below thermoneutrality affects drug-induced weight loss but does not improve prediction of efficacy in humans. Cell Rep 2024; 43:114501. [PMID: 39067024 PMCID: PMC11380917 DOI: 10.1016/j.celrep.2024.114501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 04/29/2024] [Accepted: 06/27/2024] [Indexed: 07/30/2024] Open
Abstract
Evaluation of weight loss drugs is usually performed in diet-induced obese mice housed at ∼22°C. This is a cold stress that increases energy expenditure by ∼35% compared to thermoneutrality (∼30°C), which may overestimate drug-induced weight loss. We investigated five anti-obesity mechanisms that have been in clinical development, comparing weight loss in mice housed at 22°C vs. 30°C. Glucagon-like peptide-1 (GLP-1), human fibroblast growth factor 21 (hFGF21), and melanocortin-4 receptor (MC4R) agonist induced similar weight losses. Peptide YY elicited greater vehicle-subtracted weight loss at 30°C (7.2% vs. 1.4%), whereas growth differentiation factor 15 (GDF15) was more effective at 22°C (13% vs. 6%). Independent of ambient temperature, GLP-1 and hFGF21 prevented the reduction in metabolic rate caused by weight loss. There was no simple rule for a better prediction of human drug efficacy based on ambient temperature, but since humans live at thermoneutrality, drug testing using mice should include experiments near thermoneutrality.
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Affiliation(s)
- Julie M Jacobsen
- Obesity and Liver Pharmacology, Integrated Physiology Research, Novo Nordisk A/S, Bagsværd, Denmark
| | - Natalia Petersen
- Liver and Gut Biology, Obesity & NASH, Global Drug Discovery, Novo Nordisk A/S, Bagsværd, Denmark
| | - Lola Torz
- Liver and Gut Biology, Obesity & NASH, Global Drug Discovery, Novo Nordisk A/S, Bagsværd, Denmark
| | | | - Kent Pedersen
- Obesity and Liver Pharmacology, Integrated Physiology Research, Novo Nordisk A/S, Bagsværd, Denmark
| | - Søren Østergaard
- Obesity and Liver Pharmacology, Integrated Physiology Research, Novo Nordisk A/S, Bagsværd, Denmark
| | - Birgitte S Wulff
- Obesity and Liver Pharmacology, Integrated Physiology Research, Novo Nordisk A/S, Bagsværd, Denmark
| | - Birgitte Andersen
- Diabetes, Obesity and NASH, Global Drug Discovery, Novo Nordisk A/S, Bagsværd, Denmark
| | - Kirsten Raun
- Lead Portfolio Projects, Research and Early Development, Novo Nordisk A/S, Bagsværd, Denmark
| | | | - Linu M John
- Obesity and Liver Pharmacology, Integrated Physiology Research, Novo Nordisk A/S, Bagsværd, Denmark
| | - Marc L Reitman
- Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA
| | - Rune E Kuhre
- Obesity and Liver Pharmacology, Integrated Physiology Research, Novo Nordisk A/S, Bagsværd, Denmark; Department of Biomedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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12
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Phan P, Ternier G, Edirisinghe O, Kumar TKS. Exploring endocrine FGFs - structures, functions and biomedical applications. INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND MOLECULAR BIOLOGY 2024; 15:68-99. [PMID: 39309613 PMCID: PMC11411148 DOI: 10.62347/palk2137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 07/17/2024] [Indexed: 09/25/2024]
Abstract
The family of fibroblast growth factors (FGFs) consists of 22 members with diverse biological functions in cells, from cellular development to metabolism. The family can be further categorized into three subgroups based on their three modes of action. FGF19, FGF21, and FGF23 are endocrine FGFs that act in a hormone-like/endocrine manner to regulate various metabolic activities. However, all three members of the endocrine family require both FGF receptors (FGFRs) and klotho co-receptors to elicit their functions. α-klotho and β-klotho act as scaffolds to bring endocrine FGFs closer to their receptors (FGFRs) to form active complexes. Numerous novel studies about metabolic FGFs' structures, mechanisms, and physiological insights have been published to further understand the complex molecular interactions and physiological activities of endocrine FGFs. Herein, we aim to review the structures, physiological functions, binding mechanisms to cognate receptors, and novel biomedical applications of endocrine FGFs in recent years.
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Affiliation(s)
- Phuc Phan
- Department of Chemistry and Biochemistry, Fulbright College of Art and Sciences, University of ArkansasFayetteville, AR 72701, USA
| | - Gaёtane Ternier
- Department of Chemistry and Biochemistry, Fulbright College of Art and Sciences, University of ArkansasFayetteville, AR 72701, USA
| | - Oshadi Edirisinghe
- Cell and Molecular Biology Program, University of ArkansasFayetteville, AR 72701, USA
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13
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Sass-Ørum K, Tagmose TM, Olsen J, Sjölander A, Wahlund PO, Han D, Vegge A, Reedtz-Runge S, Wang Z, Gao X, Wieczorek B, Lamberth K, Lykkegaard K, Nielsen PK, Thøgersen H, Yu M, Wang J, Drustrup J, Zhang X, Garibay P, Hansen K, Hansen AMK, Andersen B. Development of Zalfermin, a Long-Acting Proteolytically Stabilized FGF21 Analog. J Med Chem 2024; 67:11769-11788. [PMID: 39013015 DOI: 10.1021/acs.jmedchem.4c00391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2024]
Abstract
Here, we describe the development of the FGF21 analog zalfermin (NNC0194-0499, 15), intended for once-weekly sc dosing. Protein engineering was needed to address inherent druggability issues of the natural FGF21 hormone. Thus, deamidation of Asp121 was solved by mutation to glutamine, and oxidation of Met168 was solved by mutation to leucine. N-terminal region degradation by dipeptidyl peptidase IV was prevented by alanine residue elongation. To prevent inactivating metabolism by fibroblast activation protein and carboxypeptidase-like activity in the C-terminal region, and to achieve t1/2 extension (53 h in cynomolgus monkeys), we introduced a C18 fatty diacid at the penultimate position 180. The fatty diacid binds albumin in a reversible manner, such that the free fraction of zalfermin potently activates the FGF-receptor complex and retains receptor selectivity compared with FGF21, providing strong efficacy on body weight loss in diet-induced obese mice. Zalfermin is currently being clinically evaluated for the treatment of metabolic dysfunction-associated steatohepatitis.
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Affiliation(s)
- Kristian Sass-Ørum
- Novo Nordisk A/S, Global Research Technologies, DK-2760 Maaloev, Denmark
| | | | - Jørgen Olsen
- Novo Nordisk A/S, Global Research Technologies, DK-2760 Maaloev, Denmark
| | - Annika Sjölander
- Novo Nordisk A/S, Global Research Technologies, DK-2760 Maaloev, Denmark
| | - Per-Olof Wahlund
- Novo Nordisk A/S, Global Research Technologies, DK-2760 Maaloev, Denmark
| | - Dan Han
- Novo Nordisk A/S, Novo Nordisk Research Center China, Beijing 102206, China
| | - Andreas Vegge
- Novo Nordisk A/S, Global Drug Discovery, DK-2760 Maaloev, Denmark
| | | | - Zhe Wang
- Novo Nordisk A/S, Novo Nordisk Research Center China, Beijing 102206, China
| | - Xiang Gao
- Novo Nordisk A/S, Novo Nordisk Research Center China, Beijing 102206, China
| | - Birgit Wieczorek
- Novo Nordisk A/S, Global Research Technologies, DK-2760 Maaloev, Denmark
| | - Kasper Lamberth
- Novo Nordisk A/S, Global Drug Discovery, DK-2760 Maaloev, Denmark
| | | | | | - Henning Thøgersen
- Novo Nordisk A/S, Global Research Technologies, DK-2760 Maaloev, Denmark
| | - Mingrui Yu
- Novo Nordisk A/S, Novo Nordisk Research Center China, Beijing 102206, China
| | - Jianhua Wang
- Novo Nordisk A/S, Novo Nordisk Research Center China, Beijing 102206, China
| | - Jørn Drustrup
- Novo Nordisk A/S, Global Research Technologies, DK-2760 Maaloev, Denmark
| | - Xujia Zhang
- Novo Nordisk A/S, Novo Nordisk Research Center China, Beijing 102206, China
| | - Patrick Garibay
- Novo Nordisk A/S, Global Research Technologies, DK-2760 Maaloev, Denmark
| | - Kristian Hansen
- Novo Nordisk A/S, Global Drug Discovery, DK-2760 Maaloev, Denmark
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14
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Chui ZSW, Shen Q, Xu A. Current status and future perspectives of FGF21 analogues in clinical trials. Trends Endocrinol Metab 2024; 35:371-384. [PMID: 38423900 DOI: 10.1016/j.tem.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 01/31/2024] [Accepted: 02/01/2024] [Indexed: 03/02/2024]
Abstract
Recent advances in fibroblast growth factor 21 (FGF21) biology and pharmacology have led to the development of several long-acting FGF21 analogues and antibody-based mimetics now in various phases of clinical trials for the treatment of obesity-related metabolic comorbidities. The efficacy of these FGF21 analogues/mimetics on glycaemic control and weight loss is rather mild and inconsistent; nevertheless, several promising therapeutic benefits have been reproducibly observed in most clinical studies, including amelioration of dyslipidaemia (particularly hypertriglyceridaemia) and hepatic steatosis, reduction of biomarkers of liver fibrosis and injury, and resolution of metabolic dysfunction-associated steatohepatitis (MASH). Evidence is emerging that combination therapy with FGF21 analogues and other hormones (such as glucagon-like peptide 1; GLP-1) can synergise their pharmacological benefits, thus maximising the therapeutic efficacy for obesity and its comorbidities.
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Affiliation(s)
- Zara Siu Wa Chui
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, SAR, China; Department of Medicine, The University of Hong Kong, Hong Kong, SAR, China; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, SAR, China
| | - Qing Shen
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, SAR, China; Department of Medicine, The University of Hong Kong, Hong Kong, SAR, China
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, SAR, China; Department of Medicine, The University of Hong Kong, Hong Kong, SAR, China; Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, SAR, China.
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15
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Dewal RS, Yang FT, Baer LA, Vidal P, Hernandez-Saavedra D, Seculov NP, Ghosh A, Noé F, Togliatti O, Hughes L, DeBari MK, West MD, Soroko R, Sternberg H, Malik NN, Puchulu-Campanella E, Wang H, Yan P, Wolfrum C, Abbott RD, Stanford KI. Transplantation of committed pre-adipocytes from brown adipose tissue improves whole-body glucose homeostasis. iScience 2024; 27:108927. [PMID: 38327776 PMCID: PMC10847743 DOI: 10.1016/j.isci.2024.108927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/15/2023] [Accepted: 01/12/2024] [Indexed: 02/09/2024] Open
Abstract
Obesity and its co-morbidities including type 2 diabetes are increasing at epidemic rates in the U.S. and worldwide. Brown adipose tissue (BAT) is a potential therapeutic to combat obesity and type 2 diabetes. Increasing BAT mass by transplantation improves metabolic health in rodents, but its clinical translation remains a challenge. Here, we investigated if transplantation of 2-4 million differentiated brown pre-adipocytes from mouse BAT stromal fraction (SVF) or human pluripotent stem cells (hPSCs) could improve metabolic health. Transplantation of differentiated brown pre-adipocytes, termed "committed pre-adipocytes" from BAT SVF from mice or derived from hPSCs improves glucose homeostasis and insulin sensitivity in recipient mice under conditions of diet-induced obesity, and this improvement is mediated through the collaborative actions of the liver transcriptome, tissue AKT signaling, and FGF21. These data demonstrate that transplantation of a small number of brown adipocytes has significant long-term translational and therapeutic potential to improve glucose metabolism.
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Affiliation(s)
- Revati S. Dewal
- Department of Physiology and Cell Biology, College of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Felix T. Yang
- Department of Physiology and Cell Biology, College of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
- Department of Surgery, College of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Lisa A. Baer
- Department of Physiology and Cell Biology, College of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
- Department of Surgery, College of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Pablo Vidal
- Department of Physiology and Cell Biology, College of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
- Department of Surgery, College of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Diego Hernandez-Saavedra
- Department of Physiology and Cell Biology, College of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Nickolai P. Seculov
- Department of Physiology and Cell Biology, College of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Adhideb Ghosh
- Laboratory of Translational Nutritional Biology, Institute of Food, Nutrition and Health, ETH Zurich, 8603 Schwerzenbach, Switzerland
| | - Falko Noé
- Laboratory of Translational Nutritional Biology, Institute of Food, Nutrition and Health, ETH Zurich, 8603 Schwerzenbach, Switzerland
| | - Olivia Togliatti
- Department of Physiology and Cell Biology, College of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Lexis Hughes
- Department of Physiology and Cell Biology, College of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Megan K. DeBari
- Department of Biomedical Engineering, College of Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
| | - Michael D. West
- AgeX Therapeutics, Inc., 1101 Marina Village Parkway, Suite 201, Alameda, CA 94501, USA
| | - Richard Soroko
- AgeX Therapeutics, Inc., 1101 Marina Village Parkway, Suite 201, Alameda, CA 94501, USA
| | - Hal Sternberg
- AgeX Therapeutics, Inc., 1101 Marina Village Parkway, Suite 201, Alameda, CA 94501, USA
| | - Nafees N. Malik
- AgeX Therapeutics, Inc., 1101 Marina Village Parkway, Suite 201, Alameda, CA 94501, USA
| | - Estella Puchulu-Campanella
- Genomics Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Huabao Wang
- Genomics Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Pearlly Yan
- Genomics Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Christian Wolfrum
- Laboratory of Translational Nutritional Biology, Institute of Food, Nutrition and Health, ETH Zurich, 8603 Schwerzenbach, Switzerland
| | - Rosalyn D. Abbott
- Department of Biomedical Engineering, College of Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
| | - Kristin I. Stanford
- Department of Physiology and Cell Biology, College of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
- Department of Surgery, College of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
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16
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Zangerolamo L, Carvalho M, Velloso LA, Barbosa HCL. Endocrine FGFs and their signaling in the brain: Relevance for energy homeostasis. Eur J Pharmacol 2024; 963:176248. [PMID: 38056616 DOI: 10.1016/j.ejphar.2023.176248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 11/10/2023] [Accepted: 11/30/2023] [Indexed: 12/08/2023]
Abstract
Since their discovery in 2000, there has been a continuous expansion of studies investigating the physiology, biochemistry, and pharmacology of endocrine fibroblast growth factors (FGFs). FGF19, FGF21, and FGF23 comprise a subfamily with attributes that distinguish them from typical FGFs, as they can act as hormones and are, therefore, referred to as endocrine FGFs. As they participate in a broad cross-organ endocrine signaling axis, endocrine FGFs are crucial lipidic, glycemic, and energetic metabolism regulators during energy availability fluctuations. They function as powerful metabolic signals in physiological responses induced by metabolic diseases, like type 2 diabetes and obesity. Pharmacologically, FGF19 and FGF21 cause body weight loss and ameliorate glucose homeostasis and energy expenditure in rodents and humans. In contrast, FGF23 expression in mice and humans has been linked with insulin resistance and obesity. Here, we discuss emerging concepts in endocrine FGF signaling in the brain and critically assess their putative role as therapeutic targets for treating metabolic disorders.
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Affiliation(s)
- Lucas Zangerolamo
- Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, Sao Paulo, Brazil
| | - Marina Carvalho
- Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, Sao Paulo, Brazil
| | - Licio A Velloso
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, Sao Paulo, Brazil
| | - Helena C L Barbosa
- Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, Sao Paulo, Brazil.
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17
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Phan P, Sonnaila S, Ternier G, Edirisinghe O, Okoto PS, Kumar TKS. Overexpression and Purification of Mitogenic and Metabolic Fibroblast Growth Factors. Methods Mol Biol 2024; 2762:151-181. [PMID: 38315365 PMCID: PMC11784987 DOI: 10.1007/978-1-0716-3666-4_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2024]
Abstract
Fibroblast growth factors (FGFs) are proteins with a vast array of biological activity, such as cell development and repair, glucose and bile acid metabolisms, and wound healing. Due to their critical and diverse physiological functions, FGFs are believed to possess potential as therapeutic agents for many diseases and conditions that warrant further investigations. Thus, a simple, cost-efficient method to purify these biologically active signaling proteins is desirable. Herein, we introduce such techniques to purify FGFs that possess either high heparin-binding affinity or low to no heparin-binding affinity. This method takes advantage of the high affinity toward heparin sulfate from paracrine FGF1 to isolate the targeted protein. It also accounts for FGF members that have low heparin affinity, such as the metabolic FGFs, by introducing poly-histidine tags in the recombinant protein in combination with the immobilized metal affinity chromatography. Subsequently, the purified FGF products are separated from the other small protein by high-speed centrifugation. Products are then subjected to other biophysical experiments like SDS-PAGE, mass spectrometry, circular dichroism, intrinsic fluorescence, isothermal titration calorimetry, differential scanning calorimetry, and biological cell activity assay to confirm that the target proteins are purified with intact native conformation and no significant change in the intrinsic characteristics and biological activities.
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Affiliation(s)
- Phuc Phan
- Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR, USA
| | - Shivakumar Sonnaila
- Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR, USA
| | - Gaetane Ternier
- Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR, USA
| | - Oshadi Edirisinghe
- Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR, USA
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18
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Hirai T, Wang W, Murono N, Iwasa K, Inoue M. Potential role of Akt in the regulation of fibroblast growth factor 21 by berberine. J Nat Med 2024; 78:169-179. [PMID: 37951850 DOI: 10.1007/s11418-023-01755-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 10/16/2023] [Indexed: 11/14/2023]
Abstract
Fibroblast growth factor 21 (FGF21) is expressed in several organs, including the liver, adipose tissue, and cardiovascular system, and plays an important role in cross-talk with other organs by binding to specific FGF receptors and their co-receptors. FGF21 represents a potential target for the treatment of obesity, type 2 diabetes mellitus, and non-alcoholic steatohepatitis (NASH). The production of FGF21 in skeletal muscle was recently suggested to be beneficial for metabolic health through its autocrine and paracrine effects. However, the regulatory mechanisms of FGF21 in skeletal muscle remain unclear. In the present study, we showed that berberine regulated FGF21 production in C2C12 myotubes in a dose-dependent manner. We also examined the effects of A-674563, a selective Akt1 inhibitor, on the berberine-mediated regulation of FGF21 expression in C2C12 myotubes. Berberine significantly increased the secretion of FGF21 in C2C12 myotubes, while A-674563 attenuated this effect. Moreover, a pre-treatment with A-674563 effectively suppressed berberine-induced increases in Bmal1 expression in C2C12 myotubes, indicating that the up-regulation of Bmal1 after the berberine treatment was dependent on Akt1. Additionally, berberine-induced increases in FGF21 secretion were significantly attenuated in C2C12 cells transfected with Bmal1 siRNA, indicating the contribution of the core clock transcription factor BMAL1 to Akt-regulated FGF21 in response to berberine. Collectively, these results indicate that berberine regulates the expression of FGF21 through the Akt1 pathway in C2C12 myotubes. Moreover, the core clock gene Bmal1 may participate in the control of the myokine FGF21. Berberine stimulated Akt1-dependent FGF21 expression in C2C12 myotubes. The up-regulation of FGF21 through the modulation of PI3K/AKT1/BMAL1 in response to berberine may be involved in the regulation of cellular function (such as Glut1 expression) by acting in an autocrine and/or paracrine manner in skeletal muscle.
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Affiliation(s)
- Takao Hirai
- Laboratory of Medicinal Resources, School of Pharmacy, Aichi Gakuin University, Nagoya, 464-8650, Japan.
- Laboratory of Biochemical Pharmacology, Department of Health and Medical Sciences, Ishikawa Prefectural Nursing University, 1-1 Gakuendai, Kahoku, Ishikawa, 929-1210, Japan.
| | - Wei Wang
- Laboratory of Medicinal Resources, School of Pharmacy, Aichi Gakuin University, Nagoya, 464-8650, Japan
| | - Naoko Murono
- Community Health Nursing, Ishikawa Prefectural Nursing University, Kahoku, Ishikawa, 929-1210, Japan
| | - Kazuo Iwasa
- Department of Health and Medical Sciences, Ishikawa Prefectural Nursing University, Kahoku, Ishikawa, 929-1210, Japan
| | - Makoto Inoue
- Laboratory of Medicinal Resources, School of Pharmacy, Aichi Gakuin University, Nagoya, 464-8650, Japan
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19
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Wasilewska M, Dąbkowska M, Pomorska A, Batys P, Kowalski B, Michna A, Adamczyk Z. Mechanisms of Fibroblast Growth Factor 21 Adsorption on Macroion Layers: Molecular Dynamics Modeling and Kinetic Measurements. Biomolecules 2023; 13:1709. [PMID: 38136581 PMCID: PMC10741725 DOI: 10.3390/biom13121709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/20/2023] [Accepted: 11/21/2023] [Indexed: 12/24/2023] Open
Abstract
Molecular dynamic modeling and various experimental techniques, including multi-angle dynamic light scattering (MADLS), streaming potential, optical waveguide light spectroscopy (OWLS), quartz crystal microbalance with dissipation (QCM), and atomic force microscopy (AFM), were applied to determine the basic physicochemical parameters of fibroblast growth factor 21 in electrolyte solutions. The protein size and shape, cross-section area, dependence of the nominal charge on pH, and isoelectric point of 5.3 were acquired. These data enabled the interpretation of the adsorption kinetics of FGF 21 on bare and macrocation-covered silica investigated by OWLS and QCM. It was confirmed that the protein molecules irreversibly adsorbed on the latter substrate, forming layers with controlled coverage up to 0.8 mg m-2, while their adsorption on bare silica was much smaller. The viability of two cell lines, CHO-K1 and L-929, on both bare and macrocation/FGF 21-covered substrates was also determined. It is postulated that the acquired results can serve as useful reference systems for designing complexes that can extend the half-life of FGF 21 in its active state.
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Affiliation(s)
- Monika Wasilewska
- Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Niezapominajek 8, 30-239 Krakow, Poland; (M.W.); (A.P.); (P.B.)
| | - Maria Dąbkowska
- Independent Laboratory of Pharmacokinetic and Clinical Pharmacy, Pomeranian Medical University, Rybacka 1, 70-204 Szczecin, Poland; (M.D.); (B.K.)
| | - Agata Pomorska
- Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Niezapominajek 8, 30-239 Krakow, Poland; (M.W.); (A.P.); (P.B.)
| | - Piotr Batys
- Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Niezapominajek 8, 30-239 Krakow, Poland; (M.W.); (A.P.); (P.B.)
| | - Bogusław Kowalski
- Independent Laboratory of Pharmacokinetic and Clinical Pharmacy, Pomeranian Medical University, Rybacka 1, 70-204 Szczecin, Poland; (M.D.); (B.K.)
| | - Aneta Michna
- Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Niezapominajek 8, 30-239 Krakow, Poland; (M.W.); (A.P.); (P.B.)
| | - Zbigniew Adamczyk
- Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Niezapominajek 8, 30-239 Krakow, Poland; (M.W.); (A.P.); (P.B.)
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20
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Carbonetti MP, Almeida-Oliveira F, Majerowicz D. Use of FGF21 analogs for the treatment of metabolic disorders: a systematic review and meta-analysis. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2023; 68:e220493. [PMID: 37948566 PMCID: PMC10916804 DOI: 10.20945/2359-4292-2022-0493] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 04/23/2023] [Indexed: 11/12/2023]
Abstract
FGF21 is a hormone produced primarily by the liver with several metabolic functions, such as induction of heat production, control of glucose homeostasis, and regulation of blood lipid levels. Due to these actions, several laboratories have developed FGF21 analogs to treat patients with metabolic disorders such as obesity and diabetes. Here, we performed a systematic review and meta-analysis of randomized controlled trials that used FGF21 analogs and analyzed metabolic outcomes. Our search yielded 236 articles, and we included eight randomized clinical trials in the meta-analysis. The use of FGF21 analogs exhibited no effect on fasting blood glucose, glycated hemoglobin, HOMA index, blood free fatty acids or systolic blood pressure. However, the treatment significantly reduced fasting insulinemia, body weight and total cholesterolemia. None of the included studies were at high risk of bias. The quality of the evidence ranged from moderate to very low, especially due to imprecision and indirection issues. These results indicate that FGF21 analogs can potentially treat metabolic syndrome. However, more clinical trials are needed to increase the quality of evidence and confirm the effects seen thus far.
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Affiliation(s)
- Maria Paula Carbonetti
- Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
| | - Fernanda Almeida-Oliveira
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
| | - David Majerowicz
- Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
- Programa de Pós-graduação em Biociências, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brasil,
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21
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Wong C, Dash A, Fredrickson J, Lewin-Koh N, Chen S, Yoshida K, Liu Y, Gutierrez J, Kunder R. Fibroblast growth factor receptor 1/Klothoβ agonist BFKB8488A improves lipids and liver health markers in patients with diabetes or NAFLD: A phase 1b randomized trial. Hepatology 2023; 78:847-862. [PMID: 35993161 DOI: 10.1002/hep.32742] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 08/11/2022] [Accepted: 08/12/2022] [Indexed: 12/08/2022]
Abstract
BACKGROUND AND AIMS BFKB8488A is a bispecific antibody targeting fibroblast growth factor receptor 1c and Klothoβ. This phase 1b study assessed safety, tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics of BFKB8488A in patients with type 2 diabetes mellitus (T2DM) or NAFLD. APPROACH AND RESULTS Patients were randomized to receive multiple doses of BFKB8488A at various dose levels and dosing intervals (weekly, every 2 weeks, or every 4 weeks) or placebo for 12 weeks. The primary outcome was the safety of BFKB8488A. Overall, 153 patients (T2DM: 91; NAFLD: 62) were enrolled and received at least one dose of treatment. Of these, 102 patients (62.7%) reported at least one adverse event (BFKB8488A: 83 [68.6%]; placebo: 19 [59.4%]). BFKB8488A exhibited nonlinear pharmacokinetics, with greater than dose-proportional increases in exposure. The treatment-emergent antidrug antibody incidence was 22.7%. Overall, trends in exposure-dependent increases in high-density lipoprotein (HDL) and decreases in triglyceride levels were observed. Decreases in alanine aminotransferase and aspartate aminotransferase were 0.7% and 9.2% for medium exposure and 7.3% and 11.2% for high-exposure tertiles, compared with increases of 7.5% and 17% in the placebo group, respectively, at Day 85. In patients with NAFLD, the mean decrease from baseline liver fat was 13.0%, 34.5%, and 49.0% in the low-, medium-, and high-exposure tertiles, respectively, compared with 0.1% with placebo at Day 85. CONCLUSIONS BFKB8488A was adequately tolerated in patients with T2DM or NAFLD, leading to triglyceride reduction, HDL improvements, and trends in improvement in markers of liver health for both populations and marked liver fat reduction in patients with NAFLD. ( ClinicalTrials.gov : NCT03060538).
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Affiliation(s)
- Chin Wong
- Genentech, Inc. , South San Francisco , California , USA
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22
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Aaldijk AS, Verzijl CRC, Jonker JW, Struik D. Biological and pharmacological functions of the FGF19- and FGF21-coreceptor beta klotho. Front Endocrinol (Lausanne) 2023; 14:1150222. [PMID: 37260446 PMCID: PMC10229096 DOI: 10.3389/fendo.2023.1150222] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 04/13/2023] [Indexed: 06/02/2023] Open
Abstract
Beta klotho (KLB) is a fundamental component in fibroblast growth factor receptor (FGFR) signaling as it serves as an obligatory coreceptor for the endocrine hormones fibroblast growth factor 19 (FGF19) and fibroblast growth factor 21 (FGF21). Through the development of FGF19- and FGF21 mimetics, KLB has emerged as a promising drug target for treating various metabolic diseases, such as type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease. While rodent studies have significantly increased our understanding of KLB function, current clinical trials that test the safety and efficacy of KLB-targeting drugs raise many new scientific questions about human KLB biology. Although most KLB-targeting drugs can modulate disease activity in humans, individual patient responses differ substantially. In addition, species-specific differences in KLB tissue distribution may explain why the glucose-lowering effects that were observed in preclinical studies are not fully replicated in clinical trials. Besides, the long-term efficacy of KLB-targeting drugs might be limited by various pathophysiological conditions known to reduce the expression of KLB. Moreover, FGF19/FGF21 administration in humans is also associated with gastrointestinal side effects, which are currently unexplained. A better understanding of human KLB biology could help to improve the efficacy and safety of existing or novel KLB/FGFR-targeting drugs. In this review, we provide a comprehensive overview of the current understanding of KLB biology, including genetic variants and their phenotypic associations, transcriptional regulation, protein structure, tissue distribution, subcellular localization, and function. In addition, we will highlight recent developments regarding the safety and efficacy of KLB-targeting drugs in clinical trials. These insights may direct the development and testing of existing and future KLB-targeting drugs.
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23
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Goutam RS, Kumar V, Lee U, Kim J. Exploring the Structural and Functional Diversity among FGF Signals: A Comparative Study of Human, Mouse, and Xenopus FGF Ligands in Embryonic Development and Cancer Pathogenesis. Int J Mol Sci 2023; 24:ijms24087556. [PMID: 37108717 PMCID: PMC10146080 DOI: 10.3390/ijms24087556] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/11/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Fibroblast growth factors (FGFs) encode a large family of growth factor proteins that activate several intracellular signaling pathways to control diverse physiological functions. The human genome encodes 22 FGFs that share a high sequence and structural homology with those of other vertebrates. FGFs orchestrate diverse biological functions by regulating cellular differentiation, proliferation, and migration. Dysregulated FGF signaling may contribute to several pathological conditions, including cancer. Notably, FGFs exhibit wide functional diversity among different vertebrates spatiotemporally. A comparative study of FGF receptor ligands and their diverse roles in vertebrates ranging from embryonic development to pathological conditions may expand our understanding of FGF. Moreover, targeting diverse FGF signals requires knowledge regarding their structural and functional heterogeneity among vertebrates. This study summarizes the current understanding of human FGF signals and correlates them with those in mouse and Xenopus models, thereby facilitating the identification of therapeutic targets for various human disorders.
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Affiliation(s)
- Ravi Shankar Goutam
- Department of Biochemistry, Institute of Cell Differentiation and Aging, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
| | - Vijay Kumar
- Department of Biochemistry, Institute of Cell Differentiation and Aging, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
- iPS Bio, Inc., 3F, 16 Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si 13522, Republic of Korea
| | - Unjoo Lee
- Department of Electrical Engineering, Hallym University, Chuncheon 24252, Republic of Korea
| | - Jaebong Kim
- Department of Biochemistry, Institute of Cell Differentiation and Aging, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
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24
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Chikamatsu M, Watanabe H, Shintani Y, Murata R, Miyahisa M, Nishinoiri A, Imafuku T, Takano M, Arimura N, Yamada K, Kamimura M, Mukai B, Satoh T, Maeda H, Maruyama T. Albumin-fused long-acting FGF21 analogue for the treatment of non-alcoholic fatty liver disease. J Control Release 2023; 355:42-53. [PMID: 36690035 DOI: 10.1016/j.jconrel.2023.01.039] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 01/03/2023] [Accepted: 01/14/2023] [Indexed: 01/25/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) currently affects about 25% of the world's population, and the numbers continue to rise as the number of obese patients increases. However, there are currently no approved treatments for NAFLD. This study reports on the evaluation of the therapeutic effect of a recombinant human serum albumin-fibroblast growth factor 21 analogue fusion protein (HSA-FGF21) on the pathology of NAFLD that was induced by using two high-fat diets (HFD), HFD-60 and STHD-01. The HFD-60-induced NAFLD model mice with obesity, insulin resistance, dyslipidemia and hepatic lipid accumulation were treated with HSA-FGF21 three times per week for 4 weeks starting at 12 weeks after the HFD-60 feeding. The administration of HSA-FGF21 suppressed the increased body weight, improved hyperglycemia, hyperinsulinemia, and showed a decreased accumulation of plasma lipid and hepatic lipid levels. The elevation of C16:0, C18:0 and C18:1 fatty acids in the liver that were observed in the HFD-60 group was recovered by the HSA-FGF21 administration. The increased expression levels of the hepatic fatty acid uptake receptor (CD36) and fatty acid synthase (SREBP-1c, FAS, SCD-1, Elovl6) were also suppressed. In adipose tissue, HSA-FGF21 caused an improved adipocyte hypertrophy, a decrease in the levels of inflammatory cytokines and induced the expression of adiponectin and thermogenic factors. The administration of HSA-FGF21 to the STHD-01-induced NAFLD model mice resulted in suppressed plasma ALT and AST levels, oxidative stress, inflammatory cell infiltration and fibrosis. Together, HSA-FGF21 has some potential for use as a therapeutic agent for the treatment of NAFLD.
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Affiliation(s)
- Mayuko Chikamatsu
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Hiroshi Watanabe
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
| | - Yuhi Shintani
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Ryota Murata
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Masako Miyahisa
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Ayano Nishinoiri
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Tadashi Imafuku
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Mei Takano
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Nanaka Arimura
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Kohichi Yamada
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Miya Kamimura
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Baki Mukai
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Takao Satoh
- Kumamoto Industrial Research Institute, Kumamoto, Japan
| | - Hitoshi Maeda
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Toru Maruyama
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
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Tian H, Zhang S, Liu Y, Wu Y, Zhang D. Fibroblast Growth Factors for Nonalcoholic Fatty Liver Disease: Opportunities and Challenges. Int J Mol Sci 2023; 24:ijms24054583. [PMID: 36902015 PMCID: PMC10003526 DOI: 10.3390/ijms24054583] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 02/24/2023] [Accepted: 02/24/2023] [Indexed: 03/02/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), a chronic condition associated with metabolic dysfunction and obesity, has reached epidemic proportions worldwide. Although early NAFLD can be treated with lifestyle changes, the treatment of advanced liver pathology, such as nonalcoholic steatohepatitis (NASH), remains a challenge. There are currently no FDA-approved drugs for NAFLD. Fibroblast growth factors (FGFs) play essential roles in lipid and carbohydrate metabolism and have recently emerged as promising therapeutic agents for metabolic diseases. Among them, endocrine members (FGF19 and FGF21) and classical members (FGF1 and FGF4) are key regulators of energy metabolism. FGF-based therapies have shown therapeutic benefits in patients with NAFLD, and substantial progress has recently been made in clinical trials. These FGF analogs are effective in alleviating steatosis, liver inflammation, and fibrosis. In this review, we describe the biology of four metabolism-related FGFs (FGF19, FGF21, FGF1, and FGF4) and their basic action mechanisms, and then summarize recent advances in the biopharmaceutical development of FGF-based therapies for patients with NAFLD.
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Affiliation(s)
- Haoyu Tian
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Shuairan Zhang
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Ying Liu
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Yifan Wu
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Dianbao Zhang
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
- Correspondence: or
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Brinker EJ, Towns TJ, Watanabe R, Ma X, Bashir A, Cole RC, Wang X, Graff EC. Direct activation of the fibroblast growth factor-21 pathway in overweight and obese cats. Front Vet Sci 2023; 10:1072680. [PMID: 36756310 PMCID: PMC9900002 DOI: 10.3389/fvets.2023.1072680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 01/03/2023] [Indexed: 01/24/2023] Open
Abstract
Introduction Feline obesity is common, afflicting ~25-40% of domestic cats. Obese cats are predisposed to many metabolic dyscrasias, such as insulin resistance, altered blood lipids, and feline hepatic lipidosis. Fibroblast Growth Factor-21 (FGF21) is an endocrine hormone that mediates the fat-liver axis, and in humans and animals, FGF21 can ameliorate insulin resistance, non-alcoholic fatty liver disease, and obesity. Activation of the FGF21 pathway may have therapeutic benefits for obese cats. Methods In this preliminary cross-sectional study, ad libitum fed, purpose-bred, male-neutered, 6-year-old, obese and overweight cats were administered either 10 mg/kg/day of an FGF21 mimetic (FGF21; n = 4) or saline (control; n = 3) for 14 days. Body weight, food, and water intake were quantified daily during and 2 weeks following treatment. Changes in metabolic and liver parameters, intrahepatic triglyceride content, liver elasticity, and gut microbiota were evaluated. Results Treatment with FGF21 resulted in significant weight loss (~5.93%) compared to control and a trend toward decreased intrahepatic triglyceride content. Cats treated with FGF21 had decreased serum alkaline phosphatase. No significant changes were noted in liver elasticity, serum, liver, or metabolic parameters, or gut microbiome composition. Discussion In obese and overweight cats, activation of the FGF21 pathway can safely induce weight loss with trends to improve liver lipid content. This exploratory study is the first to evaluate the FGF21 pathway in cats. Manipulation of the FGF21 pathway has promising potential as a therapeutic for feline obesity. Further studies are needed to see if FGF21-pathway manipulation can be therapeutic for feline hepatic lipidosis.
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Affiliation(s)
- Emily J. Brinker
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States,Scott Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States
| | - T. Jordan Towns
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States,Scott Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States
| | - Rie Watanabe
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States
| | - Xiaolei Ma
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States,School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Adil Bashir
- Department of Electrical and Computer Engineering, Samuel Ginn College of Engineering, Auburn University, Auburn, AL, United States
| | - Robert C. Cole
- Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL, United States
| | - Xu Wang
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States,Scott Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States,Center for Advanced Science, Innovation and Commerce, Alabama Agricultural Experiment Station, Auburn, AL, United States,HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States
| | - Emily C. Graff
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States,Scott Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States,*Correspondence: Emily C. Graff ✉
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Jin L, Yang R, Geng L, Xu A. Fibroblast Growth Factor-Based Pharmacotherapies for the Treatment of Obesity-Related Metabolic Complications. Annu Rev Pharmacol Toxicol 2023; 63:359-382. [PMID: 36100222 DOI: 10.1146/annurev-pharmtox-032322-093904] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The fibroblast growth factor (FGF) family, which comprises 22 structurally related proteins, plays diverse roles in cell proliferation, differentiation, development, and metabolism. Among them, two classical members (FGF1 and FGF4) and two endocrine members (FGF19 and FGF21) are important regulators of whole-body energy homeostasis, glucose/lipid metabolism, and insulin sensitivity. Preclinical studies have consistently demonstrated the therapeutic benefits of these FGFs for the treatment of obesity, diabetes, dyslipidemia, and nonalcoholic steatohepatitis (NASH). Several genetically engineered FGF19 and FGF21 analogs with improved pharmacodynamic and pharmacokinetic properties have been developed and progressed into various stages of clinical trials. These FGF analogs are effective in alleviating hepatic steatosis, steatohepatitis, and liver fibrosis in biopsy-confirmed NASH patients, whereas their antidiabetic and antiobesity effects are mildand vary greatly in different clinical trials. This review summarizes recent advances in biopharmaceutical development of FGF-based therapies against obesity-related metabolic complications, highlights major challenges in clinical implementation, and discusses possible strategies to overcome these hurdles.
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Affiliation(s)
- Leigang Jin
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Ranyao Yang
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Leiluo Geng
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Medicine, The University of Hong Kong, Hong Kong, China.,Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China;
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Heating-mediated purification of active FGF21 and structure-based design of its variant with enhanced potency. Sci Rep 2023; 13:1005. [PMID: 36653390 PMCID: PMC9849446 DOI: 10.1038/s41598-023-27717-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 01/06/2023] [Indexed: 01/20/2023] Open
Abstract
Fibroblast growth factor 21 (FGF21) has pharmaceutical potential against obesity-related metabolic disorders, including non-alcoholic fatty liver disease. Since thermal stability is a desirable factor for therapeutic proteins, we investigated the thermal behavior of human FGF21. FGF21 remained soluble after heating; thus, we examined its temperature-induced structural changes using circular dichroism (CD). FGF21 showed inter-convertible temperature-specific CD spectra. The CD spectrum at 100 °C returned to that at 20 °C when the heated FGF21 solution was cooled. Through loop swapping, the connecting loop between β10 and β12 in FGF21 was revealed to be associated with the unique thermal behavior of FGF21. According to surface plasmon resonance (SPR) experiments, in vitro cell-based assays, and model high-fat diet (HFD)-induced obesity studies, heated FGF21 maintained biological activities that were comparable to those of non-heated and commercial FGF21s. Based on sequence comparison and structural analysis, five point-mutations were introduced into FGF21. Compared with the wild type, the heated FGF21 variant displayed improved therapeutic potential in terms of body weight loss, the levels of hepatic triglycerides and lipids, and the degree of vacuolization of liver in HFD-fed mice.
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Corbee RJ, van Everdingen DL, Kooistra HS, Penning LC. Fibroblast growth factor-21 (FGF21) analogs as possible treatment options for diabetes mellitus in veterinary patients. Front Vet Sci 2023; 9:1086987. [PMID: 36699319 PMCID: PMC9868460 DOI: 10.3389/fvets.2022.1086987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 12/13/2022] [Indexed: 01/10/2023] Open
Abstract
Fibroblast growth factors (FGFs) are involved in numerous metabolic processes. The endocrine subfamily of FGFs, consisting of FGF19, FGF21, and FGF23, might have beneficial effects in the treatment of diabetes mellitus (DM) and/or obesity. The analog with the greatest potential, FGF21, lowers blood glucose levels, improves insulin sensitivity, and induces weight loss in several animal models. In this review we summarize recent (pre)clinical findings with FGF21 analogs in animal models and men. Furthermore, possible applications of FGF21 analogs for pets with DM will be discussed. As currently, information about the use of FGF21 analogs in pet animals is scarce.
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30
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Chen Z, Yang L, Liu Y, Huang P, Song H, Zheng P. The potential function and clinical application of FGF21 in metabolic diseases. Front Pharmacol 2022; 13:1089214. [PMID: 36618930 PMCID: PMC9810635 DOI: 10.3389/fphar.2022.1089214] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022] Open
Abstract
As an endocrine hormone, fibroblast growth factor 21 (FGF21) plays a crucial role in regulating lipid, glucose, and energy metabolism. Endogenous FGF21 is generated by multiple cell types but acts on restricted effector tissues, including the brain, adipose tissue, liver, heart, and skeletal muscle. Intervention with FGF21 in rodents or non-human primates has shown significant pharmacological effects on a range of metabolic dysfunctions, including weight loss and improvement of hyperglycemia, hyperlipidemia, insulin resistance, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). Due to the poor pharmacokinetic and biophysical characteristics of native FGF21, long-acting FGF21 analogs and FGF21 receptor agonists have been developed for the treatment of metabolic dysfunction. Clinical trials of several FGF21-based drugs have been performed and shown good safety, tolerance, and efficacy. Here we review the actions of FGF21 and summarize the associated clinical trials in obesity, type 2 diabetes mellitus (T2DM), and NAFLD, to help understand and promote the development of efficient treatment for metabolic diseases via targeting FGF21.
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Affiliation(s)
- Zhiwei Chen
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lili Yang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yang Liu
- Teaching Experiment Center, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ping Huang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Haiyan Song
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China,*Correspondence: Peiyong Zheng, ; Haiyan Song,
| | - Peiyong Zheng
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China,*Correspondence: Peiyong Zheng, ; Haiyan Song,
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Falamarzi K, Malekpour M, Tafti MF, Azarpira N, Behboodi M, Zarei M. The role of FGF21 and its analogs on liver associated diseases. Front Med (Lausanne) 2022; 9:967375. [PMID: 36457562 PMCID: PMC9705724 DOI: 10.3389/fmed.2022.967375] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 09/12/2022] [Indexed: 07/25/2023] Open
Abstract
Fibroblast growth factor 21 (FGF21), a member of fibroblast growth factor family, is a hormone-like growth factor that is synthesized mainly in the liver and adipose tissue. FGF21 regulates lipid and glucose metabolism and has substantial roles in decreasing lipogenesis and increasing hepatic insulin sensitivity which causing lipid profile improvement. FGF21 genetic variations also affect nutritional and addictive behaviors such as smoking and alcohol consumption and eating sweets. The role of FGF21 in metabolic associated diseases like diabetes mellitus had been confirmed previously. Recently, several studies have demonstrated a correlation between FGF21 and liver diseases. Non-alcoholic fatty liver disease (NAFLD) is the most prevalent type of chronic liver disease worldwide. NAFLD has a wide range from simple steatosis to steatohepatitis with or without fibrosis and cirrhosis. Elevated serum levels of FGF21 associated with NAFLD and its pathogenesis. Alcoholic fatty liver disease (AFLD), another condition that cause liver injury, significantly increased FGF21 levels as a protective factor; FGF21 can reverse the progression of AFLD and can be a potential therapeutic agent for it. Also, NAFLD and AFLD are the most important risk factors for hepatocellular carcinoma (HCC) which is the fourth deadliest cancer in the world. Several studies showed that lack of FGF21 induced oncogenic condition and worsened HCC. In this review article, we intend to discuss different aspects of FGF21 in NAFLD, AFLD and HCC; including the role of FGF21 in pathophysiology of these conditions, the effects of FGF21 mutations, the possible use of the FGF21 as a biomarker in different stages of these diseases, as well as the usage of FGF21 and its analog molecules in the treatment of these diseases.
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Affiliation(s)
- Kimia Falamarzi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahdi Malekpour
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mobin Fallah Tafti
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehrdad Behboodi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Zarei
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
- John B. Little Center for Radiation Sciences, Harvard T. H. Chan School of Public Health, Boston, MA, United States
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Hou HW, Bishop CA, Huckauf J, Broer I, Klaus S, Nausch H, Buyel JF. Seed- and leaf-based expression of FGF21-transferrin fusion proteins for oral delivery and treatment of non-alcoholic steatohepatitis. FRONTIERS IN PLANT SCIENCE 2022; 13:998596. [PMID: 36247628 PMCID: PMC9557105 DOI: 10.3389/fpls.2022.998596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 08/29/2022] [Indexed: 06/16/2023]
Abstract
Non-alcoholic steatohepatitis (NASH) is a global disease with no effective medication. The fibroblast growth factor 21 (FGF21) can reverse this liver dysfunction, but requires targeted delivery to the liver, which can be achieved via oral administration. Therefore, we fused FGF21 to transferrin (Tf) via a furin cleavage site (F), to promote uptake from the intestine into the portal vein, yielding FGF21-F-Tf, and established its production in both seeds and leaves of commercial Nicotiana tabacum cultivars, compared their expression profile and tested the bioavailability and bioactivity in feeding studies. Since biopharmaceuticals need to be produced in a contained environment, e.g., greenhouses in case of plants, the seed production was increased in this setting from 239 to 380 g m-2 a-1 seed mass with costs of 1.64 € g-1 by side branch induction, whereas leaves yielded 8,193 g m-2 a-1 leave mass at 0.19 € g-1. FGF21-F-Tf expression in transgenic seeds and leaves yielded 6.7 and 5.6 mg kg-1 intact fusion protein, but also 4.5 and 2.3 mg kg-1 additional Tf degradation products. Removing the furin site and introducing the liver-targeting peptide PLUS doubled accumulation of intact FGF21-transferrin fusion protein when transiently expressed in Nicotiana benthamiana from 0.8 to 1.6 mg kg-1, whereas truncation of transferrin (nTf338) and reversing the order of FGF21 and nTf338 increased the accumulation to 2.1 mg kg-1 and decreased the degradation products to 7% for nTf338-FGF21-PLUS. Application of partially purified nTf338-FGF21-PLUS to FGF21-/- mice by oral gavage proved its transfer from the intestine into the blood circulation and acutely affected hepatic mRNA expression. Hence, the medication of NASH via oral delivery of nTf338-FGF21-PLUS containing plants seems possible.
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Affiliation(s)
- Hsuan-Wu Hou
- Department Bioprocess Engineering, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany
- Chair for Agrobiotechnology, University of Rostock, Rostock, Germany
| | - Christopher A. Bishop
- Department of Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
- Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - Jana Huckauf
- Chair for Agrobiotechnology, University of Rostock, Rostock, Germany
| | - Inge Broer
- Chair for Agrobiotechnology, University of Rostock, Rostock, Germany
| | - Susanne Klaus
- Department of Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
- Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - Henrik Nausch
- Department Bioprocess Engineering, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany
| | - Johannes F. Buyel
- Department Bioprocess Engineering, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany
- Institute of Molecular Biotechnology, RWTH Aachen University, Aachen, Germany
- Department of Biotechnology (DBT), Institute of Bioprocess Science and Engineering (IBSE), University of Natural Resources and Life Sciences (BOKU), Vienna, Austria
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Liu Y, Chen Q, Li Y, Bi L, He Z, Shao C, Jin L, Peng R, Zhang X. Advances in FGFs for diabetes care applications. Life Sci 2022; 310:121015. [PMID: 36179818 DOI: 10.1016/j.lfs.2022.121015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 09/24/2022] [Accepted: 09/26/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Diabetes mellitus (DM) is an endocrine and metabolic disease caused by a variety of pathogenic factors, including genetic factors, environmental factors and behavior. In recent decades, the number of cases and the prevalence of diabetes have steadily increased, and it has become one of the most threatening diseases to human health in the world. Currently, insulin is the most effective and direct way to control hyperglycemia for diabetes treatment at a low cost. However, hypoglycemia is often a common complication of insulin treatment. Moreover, with the extension of treatment time, insulin resistance, considered the typical adverse symptom, can appear. Therefore, it is urgent to develop new targets and more effective and safer drugs for diabetes treatment to avoid adverse reactions and the insulin tolerance of traditional hypoglycemic drugs. SCOPE OF REVIEW In recent years, it has been found that some fibroblast growth factors (FGFs), including FGF1, FGF19 and FGF21, can safely and effectively reduce hyperglycemia and have the potential to be developed as new drugs for the treatment of diabetes. FGF23 is also closely related to diabetes and its complications, which provides a new approach for regulating blood glucose and solving the problem of insulin tolerance. MAJOR CONCLUSIONS This article reviews the research progress on the physiology and pharmacology of fibroblast growth factor in the treatment of diabetes. We focus on the application of FGFs in diabetes care and prevention.
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Affiliation(s)
- Yinai Liu
- Institute of Life Sciences & Biomedicine Collaborative Innovation Center of Zhejiang Province, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China
| | - Qianqian Chen
- Institute of Life Sciences & Biomedicine Collaborative Innovation Center of Zhejiang Province, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China
| | - Yaoqi Li
- Institute of Life Sciences & Biomedicine Collaborative Innovation Center of Zhejiang Province, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China
| | - Liuliu Bi
- Institute of Life Sciences & Biomedicine Collaborative Innovation Center of Zhejiang Province, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China
| | - Zhiying He
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
| | - Chuxiao Shao
- Department of Hepatopancreatobiliary Surgery, Lishui Central Hospital, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Hospital of Zhejiang University, Lishui 323000, China
| | - Libo Jin
- Institute of Life Sciences & Biomedicine Collaborative Innovation Center of Zhejiang Province, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China.
| | - Renyi Peng
- Institute of Life Sciences & Biomedicine Collaborative Innovation Center of Zhejiang Province, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China.
| | - Xingxing Zhang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China.
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She QY, Li LJ, Liu MH, Tan RY, Zhong YW, Bao JF, Xie JD. Bibliometric analysis of fibroblast growth factor 21 research over the period 2000 to 2021. Front Pharmacol 2022; 13:1011008. [PMID: 36238554 PMCID: PMC9551462 DOI: 10.3389/fphar.2022.1011008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/06/2022] [Indexed: 01/10/2023] Open
Abstract
Background: Fibroblast growth factor 21 (FGF-21) is an evolutionarily conserved protein that plays multiple roles in metabolic regulation. Over the past two decades, numerous studies have deepened our understanding of its various functions and its pharmacological value. Nevertheless, most clinical trials have not achieved the desired results, which raises issues regarding its clinical value. In this bibliometric analysis, we evaluated the state of FGF-21 research over the last 20 years and identified important topics, achievements, and potential future directions. Methods: Publications related to FGF-21 were collected from the Web of Science Core Collection-Science Citation Index Expanded. HistCite, VOSviewer, and CiteSpace were used for bibliometric analysis and visualization, including the analysis of annual publications, leading countries, active institutions and authors, core journals, co-cited references, and keywords. Results: Altogether, 2,490 publications related to FGF-21 were obtained. A total of 12,872 authors from 2,628 institutions in 77 countries or regions reported studies on FGF-21. The United States of America was the most influential country in FGF-21 research. Alexei Kharitonenkov, Steven A. Kliewer, and David J. Mangelsdorf were the most influential scholars, and endocrinology journals had a core status in the field. The physiological roles, clinical translation, and FGF-21-based drug development were the main topics of research, and future studies may concentrate on the central effects of FGF-21, FGF-21-based drug development, and the effects of FGF-21 on non-metabolic diseases. Conclusion: The peripheral metabolic effects of FGF-21, FGF-21-based drug development, and translational research on metabolic diseases are the three major topics in FGF-21 research, whereas the central metabolic effects of FGF-21 and the effects of FGF-21 on metabolic diseases are the emerging trends and may become the following hot topics in FGF-21 research.
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Affiliation(s)
- Qin-Ying She
- Department of Nephrology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Li-Juan Li
- Department of Nephrology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Ming-Hong Liu
- Department of Nephrology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Ru-Yu Tan
- Department of Nephrology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Yi-Wen Zhong
- Department of Nephrology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Jing-Fu Bao
- State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China
| | - Jie-Dong Xie
- Department of Nephrology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China
- *Correspondence: Jie-Dong Xie,
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Korkmaz D, Konya P, Demirtürk N. Investigation of the Characteristics of Crimean Congo Hemorrhagic Fever Cases Reported in Afyonkarahisar Province. TURKIYE PARAZITOLOJII DERGISI 2022; 46:224-227. [PMID: 36094125 DOI: 10.4274/tpd.galenos.2022.14633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
OBJECTIVE Crimean Congo Hemorrhagic Fever (CCHF); fever, widespread pain in the body, deterioration in liver function tests; it is a tick-borne viral infectious disease that can cause bleeding and death in the skin, mucous membranes, and sometimes internal organs. In this study, we retrospectively evaluated the clinical, laboratory, and epidemiological characteristics of CCHF cases diagnosed in Afyonkarahisar. METHODS Demographic and clinical characteristics, laboratory findings, treatments, and prognoses of patients diagnosed with CCHF in Afyonkarahisar were retrospectively analyzed. RESULTS In Afyonkarahisar, it was determined that 35 case reports were made between 2002 and November 2019, the date when the CCHF was first seen in Turkey. A history of tick attachment was detected in 31 subjects. Tick arrest cases were most common in June (12 cases; 34.3%) and July (9 cases; 2.9%). There was a history of living in rural areas in twenty-seven (77.1%) patients, close contact with animals in 12 patients, and a history of contact with animal blood in 4 patients. All the 35 cases that followed resulted in healing and no mortality was observed. CONCLUSION CCHF is an endemic disease that still maintains its importance in our country. The most important factor in the control with the disease is to prevent virus contact to prevent transmission. People living in endemic areas should be informed about the precautions to be taken against tick bites, and awareness should be raised by providing education about the disease.
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Affiliation(s)
- Derya Korkmaz
- Afyonkarahisar Sağlık Bilimleri Üniversitesi, Sağlık Uygulama ve Araştırma Merkezi, Enfeksiyon Hastalıkları ve Klinik Mikrobiyoloji Anabilim Dalı, Afyonkarahisar, Türkiye
| | - Petek Konya
- Afyonkarahisar Sağlık Bilimleri Üniversitesi, Sağlık Uygulama ve Araştırma Merkezi, Enfeksiyon Hastalıkları ve Klinik Mikrobiyoloji Anabilim Dalı, Afyonkarahisar, Türkiye
| | - Neşe Demirtürk
- Afyonkarahisar Sağlık Bilimleri Üniversitesi, Sağlık Uygulama ve Araştırma Merkezi, Enfeksiyon Hastalıkları ve Klinik Mikrobiyoloji Anabilim Dalı, Afyonkarahisar, Türkiye
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She QY, Bao JF, Wang HZ, Liang H, Huang W, Wu J, Zhong Y, Ling H, Li A, Qin SL. Fibroblast growth factor 21: A "rheostat" for metabolic regulation? Metabolism 2022; 130:155166. [PMID: 35183545 DOI: 10.1016/j.metabol.2022.155166] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 02/12/2022] [Accepted: 02/14/2022] [Indexed: 01/10/2023]
Abstract
Fibroblast growth factor 21 is an evolutionarily conserved factor that plays multiple important roles in metabolic homeostasis. During the past two decades, extensive investigations have improved our understanding of its delicate metabolic roles and identified its pharmacological potential to mitigate metabolic disorders. However, most clinical trials have failed to obtain the desired results, which raises issues regarding its clinical value. Fibroblast growth factor 21 is dynamically regulated by nutrients derived from food intake and hepatic/adipose release, which in turn act on the central nervous system, liver, and adipose tissues to influence food preference, hepatic glucose, and adipose fatty acid output. Based on this information, we propose that fibroblast growth factor 21 should not be considered merely an anti-hyperglycemia or anti-obesity factor, but rather a means of balancing of nutrient fluctuations to maintain an appropriate energy supply. Hence, the specific functions of fibroblast growth factor 21 in glycometabolism and lipometabolism depend on specific metabolic states, indicating that its pharmacological effects require further consideration.
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Affiliation(s)
- Qin-Ying She
- Department of Endocrinology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510999, China; Department of Nephrology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510999, China
| | - Jing-Fu Bao
- State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510515, China
| | - Hui-Zhen Wang
- State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510515, China
| | - Huixin Liang
- Department of Endocrinology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510999, China
| | - Wentao Huang
- Department of Endocrinology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510999, China
| | - Jing Wu
- Department of Nephrology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510999, China
| | - Yiwen Zhong
- Department of Nephrology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510999, China
| | - Hanxin Ling
- Department of Nephrology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510999, China
| | - Aiqing Li
- State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510515, China.
| | - Shu-Lan Qin
- Department of Endocrinology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510999, China.
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Sostre-Colón J, Gavin MJ, Santoleri D, Titchenell PM. Acute Deletion of the FOXO1-dependent Hepatokine FGF21 Does not Alter Basal Glucose Homeostasis or Lipolysis in Mice. Endocrinology 2022; 163:6550639. [PMID: 35303074 PMCID: PMC8995092 DOI: 10.1210/endocr/bqac035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Indexed: 01/07/2023]
Abstract
The hepatic transcription factor forkhead box O1 (FOXO1) is a critical regulator of hepatic and systemic insulin sensitivity. Previous work by our group and others demonstrated that genetic inhibition of FOXO1 improves insulin sensitivity both in genetic and dietary mouse models of metabolic disease. Mechanistically, this is due in part to cell nonautonomous control of adipose tissue insulin sensitivity. However, the mechanisms mediating this liver-adipose tissue crosstalk remain ill defined. One candidate hepatokine controlled by hepatic FOXO1 is fibroblast growth factor 21 (FGF21). Preclinical and clinical studies have explored the potential of pharmacological FGF21 as an antiobesity and antidiabetic therapy. In this manuscript, we performed acute loss-of-function experiments to determine the role of hepatocyte-derived FGF21 in glucose homeostasis and insulin tolerance both in control and mice lacking hepatic insulin signaling. Surprisingly, acute deletion of FGF21 did not alter glucose tolerance, insulin tolerance, or adipocyte lipolysis in either liver-specific FGF21KO mice or mice lacking hepatic AKT-FOXO1-FGF21, suggesting a permissive role for endogenous FGF21 in the regulation of systemic glucose homeostasis and insulin tolerance in mice. In addition, these data indicate that liver FOXO1 controls glucose homeostasis independently of liver-derived FGF21.
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Affiliation(s)
- Jaimarie Sostre-Colón
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Matthew J Gavin
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Dominic Santoleri
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Paul M Titchenell
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Department of Physiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Correspondence: Paul M. Titchenell, PhD, Perelman School of Medicine at the University of Pennsylvania, Smilow Center for Translational Research, 3400 Civic Center Blvd, Rm. 12-104, Philadelphia, PA 19104, USA.
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Lamb CL, Giesy SL, McGuckin MM, Perfield JW, Butterfield A, Moniruzzaman M, Haughey NJ, McFadden JW, Boisclair YR. Fibroblast growth factor-21 improves insulin action in nonlactating ewes. Am J Physiol Regul Integr Comp Physiol 2022; 322:R170-R180. [PMID: 35018810 PMCID: PMC8816633 DOI: 10.1152/ajpregu.00259.2021] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
During metabolically demanding physiological states, ruminants and other mammals coordinate nutrient use among tissues by varying the set point of insulin action. This set point is regulated in part by metabolic hormones with some antagonizing (e.g., growth hormone and TNFα) and others potentiating (e.g., adiponectin) insulin action. Fibroblast growth factor-21 (FGF21) was recently identified as a sensitizing hormone in rodent and primate models of defective insulin action. FGF21 administration, however, failed to improve insulin action in dairy cows during the naturally occurring insulin resistance of lactation, raising the possibility that ruminants as a class of animals or lactation as a physiological state are unresponsive to FGF21. To start addressing this question, we asked whether FGF21 could improve insulin action in nonlactating ewes. Gene expression studies showed that the ovine FGF21 system resembles that of other species, with liver as the major site of FGF21 expression and adipose tissue as a target tissue based on high expression of the FGF21 receptor complex and activation of p44/42 extracellular signal-regulated kinase (ERK1/2) following exogenous FGF21 administration. FGF21 treatment for 13 days reduced plasma glucose and insulin over the entire treatment period and improved glucose disposal during a glucose tolerance test. FGF21 increased plasma adiponectin by day 3 of treatment but had no effect on the plasma concentrations of total, C16:0-, or C18:0-ceramide. Overall, these data confirm that the insulin-sensitizing effects of FGF21 are conserved in ruminants and raise the possibility that lactation is an FGF21-resistant state.
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Affiliation(s)
| | - Sarah L. Giesy
- 1Department of Animal Science, Cornell University, Ithaca, New York
| | | | - James W. Perfield
- 2Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
| | | | - Mohammed Moniruzzaman
- 3Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Norman J. Haughey
- 3Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Hua S, Liu Q, Li J, Fan M, Yan K, Ye D. Beta-klotho in type 2 diabetes mellitus: From pathophysiology to therapeutic strategies. Rev Endocr Metab Disord 2021; 22:1091-1109. [PMID: 34120289 DOI: 10.1007/s11154-021-09661-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/28/2021] [Indexed: 10/21/2022]
Abstract
Type 2 diabetes mellitus (T2DM) has become a global health problem with no cure. Despite lifestyle modifications and various pharmaceutical options, the achievement of stable and durable glucose control along with effective prevention of T2DM-related cardiovascular complications remains a challenging task in clinical management. With its selective high abundance in metabolic tissues (adipose tissue, liver, and pancreas), β-Klotho is the essential component of fibroblast growth factor (FGF) receptor complexes. It is essential for high-affinity binding of endocrine FGF19 and FGF21 to evoke the signaling cascade actively involved in homeostatic maintenance of glucose metabolism and energy expenditure. In this Review, we discuss the biological function of β-Klotho in the regulation of glucose metabolism and offer mechanistic insights into its involvement in the pathophysiology of T2DM. We review our current understanding of the endocrine axis comprised of β-Klotho and FGFs (FGF19 and FGF21) and its regulatory effects on glucose metabolism under physiological and T2DM conditions. We also highlight advances in the development and preclinical validation of pharmacological compounds that target β-Klotho and/or the β-Klotho-FGFRs complex for the treatment of T2DM. Given the remarkable advances in this field, we also discuss outstanding research questions and the many challenges in the clinical development of β-Klotho-based therapies.
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Affiliation(s)
- Shuang Hua
- Key Laboratory of Glucolipid Metabolic Diseases of The Ministry of Education, Guangzhou, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Qianying Liu
- Key Laboratory of Glucolipid Metabolic Diseases of The Ministry of Education, Guangzhou, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jufei Li
- Key Laboratory of Glucolipid Metabolic Diseases of The Ministry of Education, Guangzhou, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Mengqi Fan
- Key Laboratory of Glucolipid Metabolic Diseases of The Ministry of Education, Guangzhou, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Kaixuan Yan
- Key Laboratory of Glucolipid Metabolic Diseases of The Ministry of Education, Guangzhou, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Dewei Ye
- Key Laboratory of Glucolipid Metabolic Diseases of The Ministry of Education, Guangzhou, China.
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China.
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Tillman EJ, Brock WJ, Rolph T. Efruxifermin, a long-acting Fc-fusion FGF21 analogue, reduces body weight gain but does not increase sympathetic tone or urine volume in Sprague Dawley rats. Br J Pharmacol 2021; 179:1384-1394. [PMID: 34773249 PMCID: PMC9306736 DOI: 10.1111/bph.15725] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 10/04/2021] [Accepted: 10/23/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND AND PURPOSE Analogues of fibroblast growth factor 21 (FGF21) demonstrate diverse metabolic benefits in preclinical models of type 2 diabetes, dyslipidaemia, and non-alcoholic steatohepatitis (NASH), but clinical responses with different analogues are inconsistent. Efruxifermin is an Fc-FGF21 fusion protein with prolonged half-life and enhanced receptor affinity compared to native human FGF21. Efruxifermin is in clinical trials for the treatment of NASH. EXPERIMENTAL APPROACH Efruxifermin was administered weekly to male and female Sprague Dawley rats for 4 or 26 weeks. Body and organ weights, macro- and microscopic pathology, clinical chemistry, blood cytology, and serum and urine biomarkers were analysed to characterise the pharmacodynamics of efruxifermin, and to investigate potential nonclinical toxicities following chronic administration of supra-pharmacological doses of efruxifermin. KEY RESULTS Efruxifermin significantly reduced body weight gain after 4 and 26 weeks, despite increasing food intake. Changes in tissue pathology, clinical chemistry and serum biomarkers generally appeared to be associated with weight loss, except for a significant decrease in urine volume in both males and females without perturbed electrolyte balance. Markers of sympathetic activation, urinary corticosterone, and ratio of adrenal-to-body weight were unchanged. CONCLUSION AND IMPLICATIONS Efruxifermin attenuated body weight gain, consistent with other FGF21 analogues. In contrast to at least one other FGF21 analogue, efruxifermin decreased rather than increased urine volume. The absence of an increase in sympathetic tone in rats mirrors the unchanged salivary cortisol and systemic blood pressure following efruxifermin treatment in humans.
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Affiliation(s)
| | - William J Brock
- Brock Scientific Consulting, LLC, Montgomery Village, MD, USA
| | - Tim Rolph
- Akero Therapeutics, South San Francisco, CA, USA
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Foresight regarding drug candidates acting on the succinate-GPR91 signalling pathway for non-alcoholic steatohepatitis (NASH) treatment. Biomed Pharmacother 2021; 144:112298. [PMID: 34649219 DOI: 10.1016/j.biopha.2021.112298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/29/2021] [Accepted: 10/05/2021] [Indexed: 11/24/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and it is a liver manifestation of metabolic syndrome, with a histological spectrum from simple steatosis to non-alcoholic steatohepatitis (NASH). NASH can evolve into progressive liver fibrosis and eventually lead to liver cirrhosis. The pathological mechanism of NASH is multifactorial, involving a series of metabolic disorders and changes that trigger low-level inflammation in the liver and other organs. In the pathogenesis of NASH, the signal transduction pathway involving succinate and the succinate receptor (G-protein-coupled receptor 91, GPR91) regulates inflammatory cell activation and liver fibrosis. This review describes the mechanism of the succinate-GPR91 signalling pathway in NASH and summarizes the drugs that act on this pathway, with the aim of providing a new approach to NASH treatment.
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Shao W, Jin T. Hepatic hormone FGF21 and its analogues in clinical trials. Chronic Dis Transl Med 2021; 8:19-25. [PMID: 35620160 PMCID: PMC9126297 DOI: 10.1016/j.cdtm.2021.08.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 08/26/2021] [Indexed: 12/30/2022] Open
Abstract
Fibroblast growth factor 21 (FGF21) is a fasting or stress inducible metabolic hormone produced mainly in the liver. It plays important roles in regulating both glucose and lipid homeostasis via interacting with a heterodimeric receptor complex comprising FGF receptor 1 (FGFR1) and β‐klotho (KLB). For the past decade, great effort has been made on developing FGF21 derivatives or specific FGF21 receptor agonists into therapeutic agents for various metabolic disorders including type 2 diabetes (T2D), obesity, and more importantly, nonalcoholic fatty liver disease (NAFLD). Here we have reviewed FGF21 gene and protein structures, its expression pattern, cellular signaling cascades that mediate FGF21 production and function. We have then summarized the six clinical trials utilizing four FGF21 analogues. Finally, two recent literatures on the development of GLP‐1 and FGF21 dual agonists were presented briefly.
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Abstract
Fibroblast growth factors (FGFs) are cell-signaling proteins with diverse functions in cell development, repair, and metabolism. The human FGF family consists of 22 structurally related members, which can be classified into three separate groups based on their action of mechanisms, namely: intracrine, paracrine/autocrine, and endocrine FGF subfamilies. FGF19, FGF21, and FGF23 belong to the hormone-like/endocrine FGF subfamily. These endocrine FGFs are mainly associated with the regulation of cell metabolic activities such as homeostasis of lipids, glucose, energy, bile acids, and minerals (phosphate/active vitamin D). Endocrine FGFs function through a unique protein family called klotho. Two members of this family, α-klotho, or β-klotho, act as main cofactors which can scaffold to tether FGF19/21/23 to their receptor(s) (FGFRs) to form an active complex. There are ongoing studies pertaining to the structure and mechanism of these individual ternary complexes. These studies aim to provide potential insights into the physiological and pathophysiological roles and therapeutic strategies for metabolic diseases. Herein, we provide a comprehensive review of the history, structure–function relationship(s), downstream signaling, physiological roles, and future perspectives on endocrine FGFs.
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Kumar V, Xin X, Ma J, Tan C, Osna N, Mahato RI. Therapeutic targets, novel drugs, and delivery systems for diabetes associated NAFLD and liver fibrosis. Adv Drug Deliv Rev 2021; 176:113888. [PMID: 34314787 PMCID: PMC8440458 DOI: 10.1016/j.addr.2021.113888] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/12/2021] [Accepted: 07/18/2021] [Indexed: 02/08/2023]
Abstract
Type 2 diabetes mellitus (T2DM) associated non-alcoholic fatty liver disease (NAFLD) is the fourth-leading cause of death. Hyperglycemia induces various complications, including nephropathy, cirrhosis and eventually hepatocellular carcinoma (HCC). There are several etiological factors leading to liver disease development, which involve insulin resistance and oxidative stress. Free fatty acid (FFA) accumulation in the liver exerts oxidative and endoplasmic reticulum (ER) stresses. Hepatocyte injury induces release of inflammatory cytokines from Kupffer cells (KCs), which are responsible for activating hepatic stellate cells (HSCs). In this review, we will discuss various molecular targets for treating chronic liver diseases, including homeostasis of FFA, lipid metabolism, and decrease in hepatocyte apoptosis, role of growth factors, and regulation of epithelial-to-mesenchymal transition (EMT) and HSC activation. This review will also critically assess different strategies to enhance drug delivery to different cell types. Targeting nanocarriers to specific liver cell types have the potential to increase efficacy and suppress off-target effects.
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Affiliation(s)
- Virender Kumar
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Xiaofei Xin
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Jingyi Ma
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Chalet Tan
- Department of Pharmaceutics and Drug Delivery, University of Mississippi, University, MS 38677, USA
| | - Natalia Osna
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Ram I Mahato
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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Gao J, Liu J, Meng Z, Li Y, Hong Y, Wang L, He L, Hu B, Zheng Y, Li T, Cui D, Shen E. Ultrasound-assisted C 3F 8-filled PLGA nanobubbles for enhanced FGF21 delivery and improved prophylactic treatment of diabetic cardiomyopathy. Acta Biomater 2021; 130:395-408. [PMID: 34129954 DOI: 10.1016/j.actbio.2021.06.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 06/04/2021] [Accepted: 06/08/2021] [Indexed: 12/26/2022]
Abstract
Diabetic cardiomyopathy (DCM) is a serious cardiac complication of diabetes that currently lacks specific treatment. Fibroblast growth factor 21 (FGF21) has been proved to have cardioprotective effect in DCM. However, the insufficient cardiac delivery effect of FGF21 limits its application in DCM. Therefore, to improve the therapeutic efficacy of FGF21 in DCM, an effective drug delivery system is urgently required. In this study, perfluoropropane (C3F8) and polyethylenimine (PEI)-doped poly (lactic-co-glycolic acid) (PLGA) nanobubbles (CPPNBs) were synthesized via double-emulsion evaporation and FGF21 was efficiently absorbed (CPPNBs@FGF21) via the electrostatic incorporation effect. CPPNBs@FGF21 could effectively deliver FGF21 to the myocardial tissue through the cavitation effect under low-frequency ultrasound (LFUS). The as-prepared CPPNBs@FGF21 could efficiently load FGF21 after doping with the cationic polymer PEI, and displayed uniform dispersion and favorable biosafety. After filling with C3F8, CPPNBs@FGF21 could be used for distribution monitoring through ultrasound imaging. Moreover, CPPNBs@FGF21 significantly downregulated the expression of ANP, CTGF, and caspase-3 mRNA via the action of LFUS owing to increased FGF21 release, therefore exhibiting enhanced inhibition of myocardial hypertrophy, apoptosis, and interstitial fibrosis in DCM mice. In conclusion, we established an effective protein delivery nanocarrier for the diagnosis and prophylactic treatment of DCM. STATEMENT OF SIGNIFICANCE: Diabetic cardiomyopathy (DCM) is a serious cardiac complication of diabetes that currently lacks effective clinical treatments. Fibroblast growth factor 21 (FGF21) can protect cardiomyocytes from diabetic damage, but insufficient cardiac drug delivery limits the application of FGF21 in DCM. In this study, perfluoropropane (C3F8) and polyethylenimine (PEI)-doped poly (lactic-co-glycolic acid) (PLGA) nanobubbles loaded with FGF21 (CPPNBs@FGF21) were developed for the prophylactic treatment of DCM. CPPNBs@FGF21 could effectively deliver the FGF21 to the myocardial tissue through the cavitation effect of low-frequency ultrasound (LFUS). Our results indicated that CPPNBs@FGF21 combined with LFUS could significantly down-regulate the expressions of ANP, CTGF, and caspase-3 mRNA, and as a result, it prevented the myocardial hypertrophy, apoptosis, and interstitial fibrosis of DCM mice. Overall, we established an effective protein delivery nanocarrier for the diagnosis and prophylactic treatment of DCM.
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Affiliation(s)
- Jiameng Gao
- Department of Ultrasound in Medicine, Shanghai Institute of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, PR China.; Shanghai Engineering Research Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Institute of Nano Biomedicine and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
| | - Jingjing Liu
- Shanghai Engineering Research Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Institute of Nano Biomedicine and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China; Department of Interventional Radiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, PR China
| | - Zheying Meng
- Department of Ultrasound in Medicine, Shanghai Institute of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, PR China
| | - Yanming Li
- Department of Ultrasound in Medicine, Shanghai Institute of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, PR China
| | - Yuping Hong
- Shanghai Engineering Research Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Institute of Nano Biomedicine and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
| | - Lirui Wang
- Shanghai Engineering Research Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Institute of Nano Biomedicine and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
| | - Lan He
- Department of Ultrasound in Medicine, Shanghai Eighth People's Hospital, 8 Caobao Road, Shanghai 200235, PR China
| | - Bing Hu
- Department of Ultrasound in Medicine, Shanghai Institute of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, PR China.; Department of Ultrasound in Medicine, Shanghai Eighth People's Hospital, 8 Caobao Road, Shanghai 200235, PR China
| | - Yuanyi Zheng
- Department of Ultrasound in Medicine, Shanghai Institute of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, PR China
| | - Tianliang Li
- Shanghai Engineering Research Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Institute of Nano Biomedicine and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China.
| | - Daxiang Cui
- Shanghai Engineering Research Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Institute of Nano Biomedicine and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China.
| | - E Shen
- Department of Ultrasound in Medicine, Shanghai Institute of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, PR China.; Department of Ultrasound in Medicine, Shanghai Eighth People's Hospital, 8 Caobao Road, Shanghai 200235, PR China.
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Nauck MA, Wefers J, Meier JJ. Treatment of type 2 diabetes: challenges, hopes, and anticipated successes. Lancet Diabetes Endocrinol 2021; 9:525-544. [PMID: 34181914 DOI: 10.1016/s2213-8587(21)00113-3] [Citation(s) in RCA: 149] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 12/12/2022]
Abstract
Despite the successful development of new therapies for the treatment of type 2 diabetes, such as glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 inhibitors, the search for novel treatment options that can provide better glycaemic control and at reduce complications is a continuous effort. The present Review aims to present an overview of novel targets and mechanisms and focuses on glucose-lowering effects guiding this search and developments. We discuss not only novel developments of insulin therapy (eg, so-called smart insulin preparation with a glucose-dependent mode of action), but also a group of drug classes for which extensive research efforts have not been rewarded with obvious clinical impact. We discuss the potential clinical use of the salutary adipokine adiponectin and the hepatokine fibroblast growth factor (FGF) 21, among others. A GLP-1 peptide receptor agonist (semaglutide) is now available for oral absorption, and small molecules activating GLP-1 receptors appear on the horizon. Bariatric surgery and its accompanying changes in the gut hormonal milieu offer a background for unimolecular peptides interacting with two or more receptors (for GLP-1, glucose-dependent insulinotropic polypeptide, glucagon, and peptide YY) and provide more substantial glycaemic control and bodyweight reduction compared with selective GLP-1 receptor agonists. These and additional approaches will help expand the toolbox of effective medications needed for optimising the treatment of well delineated subgroups of type 2 diabetes or help develop personalised approaches for glucose-lowering drugs based on individual characteristics of our patients.
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Affiliation(s)
- Michael A Nauck
- Diabetes Division, Katholisches Klinikum Bochum, St Josef Hospital, Ruhr University Bochum, Bochum, Germany.
| | - Jakob Wefers
- Diabetes Division, Katholisches Klinikum Bochum, St Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Juris J Meier
- Diabetes Division, Katholisches Klinikum Bochum, St Josef Hospital, Ruhr University Bochum, Bochum, Germany
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Trivedi N, Kumar D. Fibroblast growth factor and kidney disease: Updates for emerging novel therapeutics. J Cell Physiol 2021; 236:7909-7925. [PMID: 34196395 DOI: 10.1002/jcp.30497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/04/2021] [Accepted: 05/28/2021] [Indexed: 01/01/2023]
Abstract
The discovery of fibroblast growth factors (FGFs) and fibroblast growth factor receptors (FGFRs) provided a profound new insight into physiological and metabolic functions. FGF has a large family by having divergent structural elements and enable functional divergence and specification. FGF and FGFRs are highly expressed during kidney development. Signals from the ureteric bud regulate morphogenesis, nephrogenesis, and nephron progenitor survival. Thus, FGF signaling plays an important role in kidney progenitor cell aggregation at the sites of new nephron formation. This review will summarize the current knowledge about functions of FGF signaling in kidney development and their ability to promote regeneration in injured kidneys and its use as a biomarker and therapeutic target in kidney diseases. Further studies are essential to determine the predictive significance of the various FGF/FGFR deviations and to integrate them into clinical algorithms.
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Affiliation(s)
- Neerja Trivedi
- Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Devendra Kumar
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA
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Manandhar M, Chun E, Romesberg FE. Genetic Code Expansion: Inception, Development, Commercialization. J Am Chem Soc 2021; 143:4859-4878. [DOI: 10.1021/jacs.0c11938] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Miglena Manandhar
- Synthorx, a Sanofi Company, La Jolla, California 92037, United States
| | - Eugene Chun
- Synthorx, a Sanofi Company, La Jolla, California 92037, United States
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Rühlmann C, Dannehl D, Brodtrück M, Adams AC, Stenzel J, Lindner T, Krause BJ, Vollmar B, Kuhla A. Neuroprotective Effects of the FGF21 Analogue LY2405319. J Alzheimers Dis 2021; 80:357-369. [PMID: 33554901 DOI: 10.3233/jad-200837] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND To date, there are no effective treatments for Alzheimer's disease (AD). Thus, a significant need for research of therapies remains. OBJECTIVE One promising pharmacological target is the hormone fibroblast growth factor 21 (FGF21), which is thought to be neuroprotective. A clinical candidate for medical use could be the FGF21 analogue LY2405319 (LY), which has a specificity and potency comparable to FGF21. METHODS The present study investigated the potential neuroprotective effect of LY via PPARγ/apoE/abca1 pathway, which is known to degrade amyloid-β (Aβ) plaques by using primary glial cells and hippocampal organotypic brain slice cultures (OBSCs) from 30- and 50-week-old transgenic APPswe/PS1dE9 (tg) mice. By LY treatment of 52-week-old tg mice with advanced Aβ deposition, we further aimed to elaborate the effect of LY on AD pathology in vivo. RESULTS LY application to primary glial cells caused an upregulation of pparγ, apoE, and abca1 mRNA expression and significantly decreased number and area of Aβ plaques in OBSCs. LY treatment in tg mice increased cerebral [18F] FDG uptake and N-acetylaspartate/creatine ratio indicating enhanced neuronal activity and integrity. Although LY did not reduce the number of Aβ plaques in tg mice, the number of iba1-positive cells was significantly decreased indicating reduced microgliosis. CONCLUSION These data identified LY in vitro as an activator of Aβ degrading genes leading to cerebral Aβ load amelioration in early and late AD pathology. Although Aβ plaque reduction by LY failed in vivo, LY may be used as therapeutic agent to treat AD-related neuroinflammation and impaired neuronal integrity.
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Affiliation(s)
- Claire Rühlmann
- Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - David Dannehl
- Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Marcus Brodtrück
- Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Andrew C Adams
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Jan Stenzel
- Core Facility Multimodal Small Animal Imaging, Rostock University Medical Center, Rostock, Germany
| | - Tobias Lindner
- Core Facility Multimodal Small Animal Imaging, Rostock University Medical Center, Rostock, Germany
| | - Bernd J Krause
- Core Facility Multimodal Small Animal Imaging, Rostock University Medical Center, Rostock, Germany.,Department of Nuclear Medicine, Rostock University Medical Center, Rostock, Germany
| | - Brigitte Vollmar
- Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany.,Core Facility Multimodal Small Animal Imaging, Rostock University Medical Center, Rostock, Germany
| | - Angela Kuhla
- Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
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Xue B, Xiao X, Yu T, Xiao X, Xie J, Ji Q, Wang L, Na T, Meng S, Qian L, Duan H. Mesenchymal stem cells modified by FGF21 and GLP1 ameliorate lipid metabolism while reducing blood glucose in type 2 diabetic mice. Stem Cell Res Ther 2021; 12:133. [PMID: 33588950 PMCID: PMC7885588 DOI: 10.1186/s13287-021-02205-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 02/01/2021] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE The purpose of this study was to investigate the therapeutic effects of genetically modified mesenchymal stem cells (MSCs) in the treatment of type 2 diabetes mellitus (T2DM) in order to identify a new method for treating diabetes that differs from traditional medicine and to provide a new means by which to fundamentally improve or treat diabetes. METHODS MSCs derived from adipose tissue were modified to overexpress FGF21 and GLP1, which was achieved through lentiviral particle transduction. The cells were transplanted into BKS.Cg-Dock7m+/+Leprdb/Nju mice (T2DM mouse model). Injections of physiological saline (0.1 mL) and liraglutide (0.5 mg/kg) were used as negative and positive controls, respectively. ELISA or Western blotting was used for protein analysis, and quantitative real-time PCR was used for gene expression analysis. RESULTS Genetic modification had no effects on the morphology, differentiation ability, or immunophenotype of MSCs. Moreover, MSC-FGF21+GLP1 cells exhibited significantly increased secretion of FGF21 and GLP1. In the T2DM mouse model, the transplantation of MSC-FGF21+GLP1 cells ameliorated the changes in blood glucose and weight, promoted the secretion of insulin, enhanced the recovery of liver structures, and improved the profiles of lipids. Moreover, FGF21 and GLP1 exerted synergistic effects in the regulation of glucolipid metabolism by controlling the expression of insulin, srebp1, and srebp2. CONCLUSION Stem cell treatment based on MSCs modified to overexpress the FGF21 and GLP1 genes is an effective approach for the treatment of T2DM.
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Affiliation(s)
- Binghua Xue
- Department of Military Cognitive and Stress Medicine, Institute of Military Cognitive and Brain Sciences, Academy of Military Sciences, Beijing, 100850, China
| | - Xiuxiao Xiao
- Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Academy of Military Sciences, Beijing, 100850, China
| | - Tingting Yu
- Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Academy of Military Sciences, Beijing, 100850, China
| | - Xinhua Xiao
- Department of Endocrinology, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Jing Xie
- Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Academy of Military Sciences, Beijing, 100850, China
| | - Qiuhe Ji
- Department of Endocrinology and Metabolism, Xijing Hospital of Airforce Medical University, Xi'an, 710032, Shanxi, China
| | - Li Wang
- Department of Endocrinology and Metabolism, Xijing Hospital of Airforce Medical University, Xi'an, 710032, Shanxi, China
| | - Tao Na
- The Cell Collection and Research Center, Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, National Institutes for Food and Drug Control, Beijing, 100050, China
| | - Shufang Meng
- The Cell Collection and Research Center, Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, National Institutes for Food and Drug Control, Beijing, 100050, China
| | - Lingjia Qian
- Department of Military Cognitive and Stress Medicine, Institute of Military Cognitive and Brain Sciences, Academy of Military Sciences, Beijing, 100850, China.
| | - Haifeng Duan
- Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Academy of Military Sciences, Beijing, 100850, China.
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