scholarly journals The Nuanced Metabolic Functions of Endogenous FGF21 Depend on the Nature of the Stimulus, Tissue Source, and Experimental Model

2022 ◽  
Vol 12 ◽  
Author(s):  
Redin A. Spann ◽  
Christopher D. Morrison ◽  
Laura J. den Hartigh
Keyword(s):  
Expression Patterns ◽  
Nutritional Stress ◽  
Receptor Expression ◽  
Metabolic Effects ◽  
Fibroblast Growth Factor 21 ◽  
Target Tissue ◽  
Alcoholic Fatty Liver ◽  
Metabolic Functions ◽  
Brown Adipose ◽  
Fgf21 Expression

Fibroblast growth factor 21 (FGF21) is a hormone that is involved in the regulation of lipid, glucose, and energy metabolism. Pharmacological FGF21 administration promotes weight loss and improves insulin sensitivity in rodents, non-human primates, and humans. However, pharmacologic effects of FGF21 likely differ from its physiological effects. Endogenous FGF21 is produced by many cell types, including hepatocytes, white and brown adipocytes, skeletal and cardiac myocytes, and pancreatic beta cells, and acts on a diverse array of effector tissues such as the brain, white and brown adipose tissue, heart, and skeletal muscle. Different receptor expression patterns dictate FGF21 function in these target tissues, with the primary effect to coordinate responses to nutritional stress. Moreover, different nutritional stimuli tend to promote FGF21 expression from different tissues; i.e., fasting induces hepatic-derived FGF21, while feeding promotes white adipocyte-derived FGF21. Target tissue effects of FGF21 also depend on its capacity to enter the systemic circulation, which varies widely from known FGF21 tissue sources in response to various stimuli. Due to its association with obesity and non-alcoholic fatty liver disease, the metabolic effects of endogenously produced FGF21 during the pathogenesis of these conditions are not well known. In this review, we will highlight what is known about endogenous tissue-specific FGF21 expression and organ cross-talk that dictate its diverse physiological functions, with particular attention given to FGF21 responses to nutritional stress. The importance of the particular experimental design, cellular and animal models, and nutritional status in deciphering the diverse metabolic functions of endogenous FGF21 cannot be overstated.

scholarly journals Cold-induction of afadin in brown fat supports its thermogenic capacity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Morten Lundh ◽  
Ali Altıntaş ◽  
Marco Tozzi ◽  
Odile Fabre ◽  
Tao Ma ◽  
...  
Keyword(s):  
Cold Exposure ◽  
Functional Enrichment ◽  
Activation Process ◽  
Target Tissue ◽  
Cold Stimulation ◽  
Brown Adipocytes ◽  
Protein Levels ◽  
Mrna Induction ◽  
Metabolic Functions ◽  
Brown Adipose

AbstractThe profound energy-expending nature of brown adipose tissue (BAT) thermogenesis makes it an attractive target tissue to combat obesity-associated metabolic disorders. While cold exposure is the strongest inducer of BAT activity, the temporal mechanisms tuning BAT adaptation during this activation process are incompletely understood. Here we show that the scaffold protein Afadin is dynamically regulated by cold in BAT, and participates in cold acclimation. Cold exposure acutely increases Afadin protein levels and its phosphorylation in BAT. Knockdown of Afadin in brown pre-adipocytes does not alter adipogenesis but restricts β3-adrenegic induction of thermogenic genes expression and HSL phosphorylation in mature brown adipocytes. Consistent with a defect in thermogenesis, an impaired cold tolerance was observed in fat-specific Afadin knockout mice. However, while Afadin depletion led to reduced Ucp1 mRNA induction by cold, stimulation of Ucp1 protein was conserved. Transcriptomic analysis revealed that fat-specific ablation of Afadin led to decreased functional enrichment of gene sets controlling essential metabolic functions at thermoneutrality in BAT, whereas it led to an altered reprogramming in response to cold, with enhanced enrichment of different pathways related to metabolism and remodeling. Collectively, we demonstrate a role for Afadin in supporting the adrenergic response in brown adipocytes and BAT function.

scholarly journals Physiological and metabolic differences between visceral and subcutaneous adipose tissues in Nile tilapia (Oreochromis niloticus)

2017 ◽  
Vol 313 (5) ◽  
pp. R608-R619 ◽  
Author(s):  
Ya-Wen Wang ◽  
Ji-Lei Zhang ◽  
Jian-Gang Jiao ◽  
Xiao-Xia Du ◽  
Samwel Mchele Limbu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Nile Tilapia ◽  
Lipolytic Activity ◽  
Expression Patterns ◽  
Endocrine System ◽  
Lipid Deposition ◽  
Metabolic Functions ◽  
Brown Adipose ◽  
Subcutaneous Adipose

Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SCAT) have different structures and metabolic functions and play different roles in the regulation of the mammal endocrine system. However, little is known about morphology and physiological and metabolic functions between VAT and SCAT in fish. We compared the morphological, physiological, and biochemical characteristics of VAT and SCAT in Nile tilapia and measured their functions in energy intake flux, lipolytic ability, and gene expression patterns. SCAT contained more large adipocytes and nonadipocytes than VAT in Nile tilapia. VAT had higher lipid content and was the primary site for lipid deposition. Conversely, SCAT had higher hormone-induced lipolytic activity. Furthermore, SCAT had a higher percentage of monounsaturated and lower polyunsaturated fatty acids than VAT. SCAT had higher mitochondrial DNA, gene expression for fatty acid β-oxidation, adipogenesis, and brown adipose tissue characteristics, but it also had a lower gene expression for inflammation and adipocyte differentiation than VAT. SCAT and VAT have different morphological structures, as well as physiological and metabolic functions in fish. VAT is the preferable lipid deposition tissue, whereas SCAT exhibits higher lipid catabolic activity than VAT. The physiological functions of SCAT in fish are commonly overlooked. The present study indicates that SCAT has specific metabolic characteristics that differ from VAT. The differences between VAT and SCAT should be considered in future metabolism studies using fish as models, either in biomedical or aquaculture studies.

scholarly journals Nutritional regulation of fibroblast growth factor 21: from macronutrients to bioactive dietary compounds

2016 ◽  
Vol 30 (1) ◽  
Author(s):  
Albert Pérez-Martí ◽  
Viviana Sandoval ◽  
Pedro F. Marrero ◽  
Diego Haro ◽  
Joana Relat
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Metabolic Effects ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Nutritional Regulation ◽  
Ketogenic Diets ◽  
Brown Adipose

AbstractObesity is a worldwide health problem mainly due to its associated comorbidities. Fibroblast growth factor 21 (FGF21) is a peptide hormone involved in metabolic homeostasis in healthy individuals and considered a promising therapeutic candidate for the treatment of obesity. FGF21 is predominantly produced by the liver but also by other tissues, such as white adipose tissue (WAT), brown adipose tissue (BAT), skeletal muscle, and pancreas in response to different stimuli such as cold and different nutritional challenges that include fasting, high-fat diets (HFDs), ketogenic diets, some amino acid-deficient diets, low protein diets, high carbohydrate diets or specific dietary bioactive compounds. Its target tissues are essentially WAT, BAT, skeletal muscle, heart and brain. The effects of FGF21 in extra hepatic tissues occur through the fibroblast growth factor receptor (FGFR)-1c together with the co-receptor β-klotho (KLB). Mechanistically, FGF21 interacts directly with the extracellular domain of the membrane bound cofactor KLB in the FGF21- KLB-FGFR complex to activate FGFR substrate 2α and ERK1/2 phosphorylation. Mice lacking KLB are resistant to both acute and chronic effects of FGF21. Moreover, the acute insulin sensitizing effects of FGF21 are also absent in mice with specific deletion of adipose KLB or FGFR1. Most of the data show that pharmacological administration of FGF21 has metabolic beneficial effects. The objective of this review is to compile existing information about the mechanisms that could allow the control of endogenous FGF21 levels in order to obtain the beneficial metabolic effects of FGF21 by inducing its production instead of doing it by pharmacological administration.

scholarly journals Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Robert L. Hollis ◽  
Barbara Stanley ◽  
John P. Thomson ◽  
Michael Churchman ◽  
Ian Croy ◽  
...  
Keyword(s):  
High Risk ◽  
Ovarian Carcinoma ◽  
Expression Patterns ◽  
Parp Inhibitors ◽  
Receptor Expression ◽  
Cancer Type ◽  
Sequencing Data ◽  
Molecular Features ◽  
Endometrioid Ovarian Carcinoma ◽  
Molecular Landscape

AbstractEndometrioid ovarian carcinoma (EnOC) is an under-investigated ovarian cancer type. Recent studies have described disease subtypes defined by genomics and hormone receptor expression patterns; here, we determine the relationship between these subtyping layers to define the molecular landscape of EnOC with high granularity and identify therapeutic vulnerabilities in high-risk cases. Whole exome sequencing data were integrated with progesterone and oestrogen receptor (PR and ER) expression-defined subtypes in 90 EnOC cases following robust pathological assessment, revealing dominant clinical and molecular features in the resulting integrated subtypes. We demonstrate significant correlation between subtyping approaches: PR-high (PR + /ER + , PR + /ER−) cases were predominantly CTNNB1-mutant (73.2% vs 18.4%, P < 0.001), while PR-low (PR−/ER + , PR−/ER−) cases displayed higher TP53 mutation frequency (38.8% vs 7.3%, P = 0.001), greater genomic complexity (P = 0.007) and more frequent copy number alterations (P = 0.001). PR-high EnOC patients experience favourable disease-specific survival independent of clinicopathological and genomic features (HR = 0.16, 95% CI 0.04–0.71). TP53 mutation further delineates the outcome of patients with PR-low tumours (HR = 2.56, 95% CI 1.14–5.75). A simple, routinely applicable, classification algorithm utilising immunohistochemistry for PR and p53 recapitulated these subtypes and their survival profiles. The genomic profile of high-risk EnOC subtypes suggests that inhibitors of the MAPK and PI3K-AKT pathways, alongside PARP inhibitors, represent promising candidate agents for improving patient survival. Patients with PR-low TP53-mutant EnOC have the greatest unmet clinical need, while PR-high tumours—which are typically CTNNB1-mutant and TP53 wild-type—experience excellent survival and may represent candidates for trials investigating de-escalation of adjuvant chemotherapy to agents such as endocrine therapy.

scholarly journals Metabolic Effects of Recurrent Genetic Aberrations in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 396
Author(s):  
Timon A. Bloedjes ◽  
Guus de Wilde ◽  
Jeroen E. J. Guikema
Keyword(s):  
Multiple Myeloma ◽  
Cell Metabolism ◽  
Chromosomal Rearrangements ◽  
Chromosomal Translocations ◽  
Metabolic Effects ◽  
Aberrant Expression ◽  
Metabolic Functions ◽  
Complex Chromosomal Rearrangements ◽  
Cancer Cell Metabolism ◽  
The Many

Oncogene activation and malignant transformation exerts energetic, biosynthetic and redox demands on cancer cells due to increased proliferation, cell growth and tumor microenvironment adaptation. As such, altered metabolism is a hallmark of cancer, which is characterized by the reprogramming of multiple metabolic pathways. Multiple myeloma (MM) is a genetically heterogeneous disease that arises from terminally differentiated B cells. MM is characterized by reciprocal chromosomal translocations that often involve the immunoglobulin loci and a restricted set of partner loci, and complex chromosomal rearrangements that are associated with disease progression. Recurrent chromosomal aberrations in MM result in the aberrant expression of MYC, cyclin D1, FGFR3/MMSET and MAF/MAFB. In recent years, the intricate mechanisms that drive cancer cell metabolism and the many metabolic functions of the aforementioned MM-associated oncogenes have been investigated. Here, we discuss the metabolic consequences of recurrent chromosomal translocations in MM and provide a framework for the identification of metabolic changes that characterize MM cells.

scholarly journals DPP-4 inhibitor induces FGF21 expression via sirtuin 1 signaling and improves myocardial energy metabolism

2020 ◽  
Vol 36 (1) ◽  
pp. 136-146
Author(s):  
Nozomi Furukawa ◽  
Norimichi Koitabashi ◽  
Hiroki Matsui ◽  
Hiroaki Sunaga ◽  
Yogi Umbarawan ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Systolic Function ◽  
Cardiac Fibroblasts ◽  
Left Ventricular ◽  
Sirtuin 1 ◽  
Fibroblast Growth Factor 21 ◽  
Mouse Heart ◽  
Acid Uptake ◽  
Dipeptidyl Peptidase 4 ◽  
Fgf21 Expression

AbstractDipeptidyl peptidase-4 (DPP-4) inhibitors are widely used incretin-based therapy for the treatment of type 2 diabetes. We investigated the cardioprotective effect of a DPP-4 inhibitor, vildagliptin (vilda), on myocardial metabolism and cardiac performance under pressure overload. Mice were treated with either vehicle or vilda, followed by transverse aortic constriction (TAC). After 3 weeks of TAC, cardiac hypertrophy and impairment of systolic function were attenuated in vilda-treated mice. Pressure–volume analysis showed that vilda treatment significantly improved left-ventricular contractile efficiency in TAC heart. Myocardial energy substrate analysis showed that vilda treatment significantly increased glucose uptake as well as fatty acid uptake. Fibroblast growth factor 21 (FGF21), a peptide involved in the regulation of energy metabolism, increased in TAC heart and was further increased by vilda treatment. FGF21 was strongly expressed in cardiac fibroblasts than in cardiomyocytes in mouse heart after TAC with vilda treatment. Vilda treatment markedly induced FGF21 expression in human cardiac fibroblasts through a sirtuin (Sirt) 1-mediated pathway, suggesting that fibroblast-mediated FGF21 expression may regulate energy metabolism and exert vilda-mediated beneficial effects in stressed heart. Vilda induced a metabolic regulator, FGF21 expression in cardiac fibroblasts via Sirt1, and increased contractile efficiency in murine pressure-overloaded heart.

scholarly journals Eicosapentaenoic Acid Increases Browning Markers in Subcutaneous Adipose Tissue and Primary Adipocytes from Wild Type and UCP-1 Deficient Mice (P15-007-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Shasika Jayarathne ◽  
Mandana Pahlavani ◽  
Latha Ramalingam ◽  
Shane Scoggin ◽  
Naima Moustaid-Moussa
Keyword(s):  
Adipose Tissue ◽  
Eicosapentaenoic Acid ◽  
Subcutaneous Adipose Tissue ◽  
Uncoupling Protein ◽  
Fibroblast Growth Factor 21 ◽  
Chow Diet ◽  
Mrna Levels ◽  
Wild Type ◽  
Brown Adipose ◽  
Subcutaneous Adipose

Abstract Objectives Brown adipose tissue (BAT) regulates energy balance through thermogenesis, in part via uncoupling protein -1 (UCP-1). White adipose tissue (WAT), namely subcutaneous adipose tissue (SAT) can convert to a beige/brite adipose tissue phenotype (browning) under thermogenic conditions such as cold. We previously reported that eicosapentaenoic acid (EPA) reduced obesity and glucose intolerance, and increased UCP-1 in BAT of B6 mice at ambient temperature (22°C); and these effects were attenuated at thermoneutral environment (28–30°C). We hypothesized that EPA exerts anti-obesity effects on SAT, including increased browning, adipocyte hypotrophy; and these effects require UCP-1. Methods Six-week-old B6 wild type (WT) and UCP-1 knock-out (KO) male mice were maintained at thermoneutral environment and fed high fat diet (HF) with or without 36 g/kg of AlaskOmega EPA-enriched fish oil (800 mg/g) for 14 weeks; and SAT was collected for histological, gene and protein analyses. SAT was also prepared from chow diet-fed WT and KO mice at ambient environment to prepare stroma vascular cells, which were differentiated into adipocytes, treated with 100uM EPA for 48 hours then harvested for mRNA and protein analyses. Results KO mice fed HF diets had the highest body weight (P < 0.05) among all groups. EPA reduced fat cell size in both WT and KO mice fed the EPA diet. mRNA levels of fibroblast growth factor-21 (FGF-21) were higher in SAT of WT mice fed EPA compared to WT mice fed HF (P < 0.05), with no differences between the KO genotype. KO mice fed HF diets had lower levels of UCP-3 in SAT compared to WT mice fed HF (P < 0.05), which was rescued only in the KO mice fed EPA (P < 0.05). UCP-1 protein levels were very low in SAT tissues, and UCP-2 mRNA levels were similar across all groups in SAT. Interestingly, EPA significantly (P < 0.05) increased mRNA expression of UCP-2, UCP-3 and FGF21 in differentiated SAT adipocytes from both WT and KO compared to control. Furthermore, UCP-1 mRNA levels were significantly higher in WT adipocytes treated with EPA, compared to non-treated cells (P < 0.05). Additional mechanistic studies are currently underway to further dissect adipose depot differences in EPA effects in WT vs. KO mice. Conclusions Our data suggest that EPA increases SAT browning, independently of UCP-1. Funding Sources NIH/NCCIH.

scholarly journals Exercise, heat shock proteins and insulin resistance

2017 ◽  
Vol 373 (1738) ◽  
pp. 20160529 ◽  
Author(s):  
Ashley E. Archer ◽  
Alex T. Von Schulze ◽  
Paige C. Geiger
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Metabolic Effects ◽  
Diabetic Patients ◽  
Alcoholic Fatty Liver ◽  
Insulin Resistant ◽  
Exercise Induced ◽  
Shock Proteins

Best known as chaperones, heat shock proteins (HSPs) also have roles in cell signalling and regulation of metabolism. Rodent studies demonstrate that heat treatment, transgenic overexpression and pharmacological induction of HSP72 prevent high-fat diet-induced glucose intolerance and skeletal muscle insulin resistance. Overexpression of skeletal muscle HSP72 in mice has been shown to increase endurance running capacity nearly twofold and increase mitochondrial content by 50%. A positive correlation between HSP72 mRNA expression and mitochondrial enzyme activity has been observed in human skeletal muscle, and HSP72 expression is markedly decreased in skeletal muscle of insulin resistant and type 2 diabetic patients. In addition, decreased levels of HSP72 correlate with insulin resistance and non-alcoholic fatty liver disease progression in livers from obese patients. These data suggest the targeted induction of HSPs could be a therapeutic approach for preventing metabolic disease by maintaining the body's natural stress response. Exercise elicits a number of metabolic adaptations and is a powerful tool in the prevention and treatment of insulin resistance. Exercise training is also a stimulus for increased HSP expression. Although the underlying mechanism(s) for exercise-induced HSP expression are currently unknown, the HSP response may be critical for the beneficial metabolic effects of exercise. Exercise-induced extracellular HSP release may also contribute to metabolic homeostasis by actively restoring HSP72 content in insulin resistant tissues containing low endogenous levels of HSPs. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.

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