scholarly journals Lack of Overt FGF21 Resistance in Two Mouse Models of Obesity and Insulin Resistance

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 69-80 ◽  
Author(s):  
Clarence Hale ◽  
Michelle M. Chen ◽  
Shanaka Stanislaus ◽  
Narumol Chinookoswong ◽  
Todd Hager ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Energy Homeostasis ◽  
Tissue Expression ◽  
Whole Body ◽  
Fibroblast Growth Factor 21 ◽  
Disease Models ◽  
Response Curves ◽  
Fgf Receptor ◽  
Expression Levels ◽  
Erk Phosphorylation

Circulating levels of fibroblast growth factor 21 (FGF21), a metabolic regulator of glucose, lipid, and energy homeostasis, are elevated in obese diabetic subjects, raising questions about potential FGF21 resistance. Here we report tissue expression changes in FGF21 and its receptor components, and we describe the target-organ and whole-body responses to FGF21 in ob/ob and diet-induced obese (DIO) mice. Plasma FGF21 concentrations were elevated 8- and 16-fold in DIO and ob/ob mice, respectively, paralleling a dramatic increase in hepatic FGF21 mRNA expression. Concurrently, expression levels of βKlotho, FGF receptor (FGFR)-1c, and FGFR2c were markedly down-regulated in the white adipose tissues (WAT) of ob/ob and DIO mice. However, dose-response curves of recombinant human FGF21 (rhFGF21) stimulation of ERK phosphorylation in the liver and WAT were not right shifted in disease models, although the magnitude of induction in ERK phosphorylation was partially attenuated in DIO mice. Whole-body metabolic responses were preserved in ob/ob and DIO mice, with disease models being more sensitive and responsive than lean mice to the glucose-lowering and weight-loss effects of rhFGF21. Endogenous FGF21 levels, although elevated in diseased mice, were below the half-maximal effective concentrations of rhFGF21, suggesting a state of relative deficiency. Hepatic and WAT FGF21 mRNA expression levels declined after rhFGF21 treatment in the absence of the increased expression levels of βKlotho and FGFR. We conclude that overt FGF21 resistance was not evident in the disease models, and increased hepatic FGF21 expression as a result of local metabolic changes is likely a major cause of elevated circulating FGF21 levels.

Estrogen-related receptor γ2 controls NaCl uptake to maintain ionic homeostasis

2021 ◽  
Author(s):  
Shang-Wu Shih ◽  
Jia-Jiun Yan ◽  
Yi-Hsing Wang ◽  
Yi-Ling Tsou ◽  
Ling Chiu ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Body Fluid ◽  
Whole Body ◽  
Ionic Homeostasis ◽  
Ion Regulation ◽  
Expression Levels ◽  
Morpholino Knockdown ◽  
Oryzias Melastigma ◽  
Euryhaline Teleost

Estrogen-related receptors (ERRs) are known to function in mammalian kidney as key regulators of ion transport-related genes; however, a comprehensive understanding of the physiological functions of ERRs in vertebrate body fluid ionic homeostasis is still elusive. Here, we used medaka (Oryzias melastigma), a euryhaline teleost, to investigate how ERRs are involved in ion regulation. After transferring medaka from hypertonic seawater to hypotonic freshwater (FW), the mRNA expression levels of errγ2 were highly upregulated, suggesting that ERRγ2 may play a crucial role in ion uptake. In situ hybridization and immunofluorescence staining showed that errγ2 was specifically expressed in ionocytes, the cells responsible for Na+/Cl- transport. In normal FW, ERRγ2 morpholino knockdown caused reductions in the mRNA expression of Na+/Cl- cotransporter (NCC), the number of NCC ionocytes, Na+/Cl- influxes of ionocytes, and whole-body Na+/Cl- contents. In FW with low Na+ and low Cl-, the expression levels of mRNA for Na+/H+ exchanger 3 (NHE3) and NCC were both decreased in ERRγ2 morphants. Treating embryos with DY131, an agonist of ERRγ, increased the whole-body Na+/Cl- contents and ncc mRNA expression in ERRγ2 morphants. As such, medaka ERRγ2 may control Na+/Cl- uptake by regulating ncc and/or nhe3 mRNA expression and ionocyte number, and these regulatory actions may be subtly adjusted depending on internal and external ion concentrations. These findings not only provide new insights into the underpinning mechanism of actions of ERRs, but also enhance our understanding of their roles in body fluid ionic homeostasis for adaptation to changing environments during vertebrate evolution.

scholarly journals Spinal Cord Injury Reduces Serum Levels of Fibroblast Growth Factor-21 and Impairs its Signaling Pathways in Liver and Adipose Tissue in Mice

2021 ◽  
Author(s):  
Xin-Hua Liu ◽  
Zachary A. Graham ◽  
Lauren Harlow ◽  
Jiangping Pan ◽  
Daniella Azulai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Adipose Tissue ◽  
Mrna Expression ◽  
Serum Levels ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Fgf Receptor ◽  
Cord Injury ◽  
Fgf21 Expression

AbstractSpinal cord injury (SCI) results in dysregulation of carbohydrate and lipid metabolism; the underlying cellular and physiological mechanisms remain unclear. Fibroblast growth factor 21 (FGF21) is a circulating protein primarily secreted by the liver that lowers blood glucose levels, corrects abnormal lipid profiles, and mitigates non-alcoholic fatty liver disease. FGF21 acts via activating FGF receptor 1 and ß-klotho in adipose tissue and stimulating release of adiponectin from adipose tissue which in turn signals in the liver and skeletal muscle. We examined FGF21/adiponectin signaling after spinal cord transection in mice fed a high fat diet (HFD) or a standard mouse chow. Tissues were collected at 84 days after spinal cord transection or a sham SCI surgery. SCI reduced serum FGF21 levels and hepatic FGF21 expression, as well as β-klotho and FGF receptor-1 (FGFR1) mRNA expression in adipose tissue. SCI also reduced serum levels and adipose tissue mRNA expression of adiponectin and leptin, two major adipokines. In addition, SCI suppressed hepatic type 2 adiponectin receptor (AdipoR2) mRNA expression and PPARα activation in the liver. Post-SCI mice fed a HFD had further suppression of serum FGF21 levels and hepatic FGF21 expression. Elevated serum free fatty acid (FFA) levels after HFD feeding were observed in post-SCI mice but not in shammice, suggesting defective FFA uptake after SCI. Moreover, after SCI several genes that are implicated in insulin’s action had reduced expression in tissues of interest. These findings suggest that downregulated FGF21/adiponectin signaling and impaired responsiveness of adipose tissues to FGF21 may, at least in part, contribute to the overall picture of metabolic dysfunction after SCI.

scholarly journals First-Line Gemcitabine Plus Cisplatin in Nonsmall Cell Lung Cancer Patients

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Ying Li ◽  
Lin Run Wang ◽  
Jian Chen ◽  
Yan Lou ◽  
Guo Bing Zhang
Keyword(s):  
Mrna Expression ◽  
Peripheral Blood ◽  
Tumor Tissue ◽  
Nonsmall Cell Lung Cancer ◽  
Tissue Expression ◽  
Expression Levels ◽  
Lung Cancer Patients ◽  
Nsclc Patients ◽  
Linear Correlations ◽  
Gemcitabine And Cisplatin

Aim. To evaluate the predictive value of RRM1, ERCCl, and BRCA1 expression in Chinese NSCLC patients treated with gemcitabine and cisplatin.Methods. Real-time fluorescent quantitative PCR was used to determine the RRM1, ERCC1, and BRCA1 mRNA expression levels of peripheral blood in late-stage NSCLC patients. The relationship between peripheral blood and mRNA expression in tumor tissues was analyzed further.Results. In terms of the tumor susceptibility to chemotherapy, the response rate in the low-RRM1-expression group was significantly greater than in the high-expression group (52.9% versus 5.9%,χ2test,P=0.007). Subjects with low peripheral blood RRM1 expression survived longer than those with high RRM1 expression (15.5 versus 12.0 months, logrank 3.980,P=0.046). Linear correlations were observed between peripheral blood and tumor tissue expression levels for RRM1(R2=0.045,  P=0.048) and BRCA1(R2=0.021,  P=0.001).Conclusion. Our study demonstrates increased survival and superior efficacy of gemcitabine and cisplatin combination chemotherapy in the treatment of NSCLC patients with low peripheral blood RRM1 expression. The linear correlations of the relative expression of mRNA were observed between peripheral blood and tumor tissue expression levels for RRM1 and BRCA1. RRM1 gene expression may contribute to chemotherapy sensitivity and may be an indicator of survival. It was significant to individual chemotherapy of patients with advanced NSCLC who do not have sufficient tumor tissue.

scholarly journals Ghrelin O-Acyl Transferase: Bridging Ghrelin and Energy Homeostasis

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Andrew Shlimun ◽  
Suraj Unniappan
Keyword(s):  
Energy Homeostasis ◽  
Expression Patterns ◽  
Tissue Expression ◽  
Whole Body ◽  
Acyl Transferase ◽  
Glucose Levels ◽  
Metabolic Functions ◽  
Blood Glucose Levels ◽  
Body Energy ◽  
Metabolic Hormone

Ghrelin O-acyl transferase (GOAT) is a recently identified enzyme responsible for the unique n-acyl modification of ghrelin, a multifunctional metabolic hormone. GOAT structure and activity appears to be conserved from fish to man. Since the acyl modification is critical for most of the biological actions of ghrelin, especially metabolic functions, GOAT emerged as a very important molecule of interest. The research on GOAT is on the rise, and several important results reiterating its significance have been reported. Notable among these discoveries are the identification of GOAT tissue expression patterns, effects on insulin secretion, blood glucose levels, feeding, body weight, and metabolism. Several attempts have been made to design and test synthetic compounds that can modulate endogenous GOAT, which could turn beneficial in favorably regulating whole body energy homeostasis. This paper will focus to provide an update on recent advances in GOAT research and its broader implications in the regulation of energy balance.

scholarly journals Hepatic CREB3L3 Controls Whole-Body Energy Homeostasis and Improves Obesity and Diabetes

Endocrinology ◽  
2014 ◽  
Vol 155 (12) ◽  
pp. 4706-4719 ◽  
Author(s):  
Yoshimi Nakagawa ◽  
Aoi Satoh ◽  
Sachiko Yabe ◽  
Mika Furusawa ◽  
Naoko Tokushige ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Energy Homeostasis ◽  
Binding Protein ◽  
Whole Body ◽  
Fibroblast Growth Factor 21 ◽  
Peroxisome Proliferator ◽  
Fibroblast Growth ◽  
Peroxisome Proliferator Activated Receptor ◽  
Obesity And Diabetes

Transcriptional regulation of metabolic genes in the liver is the key to maintaining systemic energy homeostasis during starvation. The membrane-bound transcription factor cAMP-responsive element-binding protein 3-like 3 (CREB3L3) has been reported to be activated during fasting and to regulate triglyceride metabolism. Here, we show that CREB3L3 confers a wide spectrum of metabolic responses to starvation in vivo. Adenoviral and transgenic overexpression of nuclear CREB3L3 induced systemic lipolysis, hepatic ketogenesis, and insulin sensitivity with increased energy expenditure, leading to marked reduction in body weight, plasma lipid levels, and glucose levels. CREB3L3 overexpression activated gene expression levels and plasma levels of antidiabetic hormones, including fibroblast growth factor 21 and IGF-binding protein 2. Amelioration of diabetes by hepatic activation of CREB3L3 was also observed in several types of diabetic obese mice. Nuclear CREB3L3 mutually activates the peroxisome proliferator-activated receptor (PPAR) α promoter in an autoloop fashion and is crucial for the ligand transactivation of PPARα by interacting with its transcriptional regulator, peroxisome proliferator-activated receptor gamma coactivator-1α. CREB3L3 directly and indirectly controls fibroblast growth factor 21 expression and its plasma level, which contributes at least partially to the catabolic effects of CREB3L3 on systemic energy homeostasis in the entire body. Therefore, CREB3L3 is a therapeutic target for obesity and diabetes.

scholarly journals Spinal Cord Injury Reduces Serum Levels of Fibroblast Growth Factor-21 and Impairs Its Signaling Pathways in Liver and Adipose Tissue in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin-Hua Liu ◽  
Zachary A. Graham ◽  
Lauren Harlow ◽  
Jiangping Pan ◽  
Daniella Azulai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Adipose Tissue ◽  
Mrna Expression ◽  
Serum Levels ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Fgf Receptor ◽  
Cord Injury ◽  
Fgf21 Expression

Spinal cord injury (SCI) results in dysregulation of carbohydrate and lipid metabolism; the underlying cellular and physiological mechanisms remain unclear. Fibroblast growth factor 21 (FGF21) is a circulating protein primarily secreted by the liver that lowers blood glucose levels, corrects abnormal lipid profiles, and mitigates non-alcoholic fatty liver disease. FGF21 acts via activating FGF receptor 1 and ß-klotho in adipose tissue and stimulating release of adiponectin from adipose tissue which in turn signals in the liver and skeletal muscle. We examined FGF21/adiponectin signaling after spinal cord transection in mice fed a high fat diet (HFD) or a standard mouse chow. Tissues were collected at 84 days after spinal cord transection or a sham SCI surgery. SCI reduced serum FGF21 levels and hepatic FGF21 expression, as well as β-klotho and FGF receptor-1 (FGFR1) mRNA expression in adipose tissue. SCI also reduced serum levels and adipose tissue mRNA expression of adiponectin and leptin, two major adipokines. In addition, SCI suppressed hepatic type 2 adiponectin receptor (AdipoR2) mRNA expression and PPARα activation in the liver. Post-SCI mice fed a HFD had further suppression of serum FGF21 levels and hepatic FGF21 expression. Elevated serum free fatty acid (FFA) levels after HFD feeding were observed in post-SCI mice but not in sham-mice, suggesting defective FFA uptake after SCI. Moreover, after SCI several genes that are implicated in insulin’s action had reduced expression in tissues of interest. These findings suggest that downregulated FGF21/adiponectin signaling and impaired responsiveness of adipose tissues to FGF21 may, at least in part, contribute to the overall picture of metabolic dysfunction after SCI.

scholarly journals Tissue-specific Nutrient Metabolism in the Liver and Muscle of Juvenile Blunt Snout Bream (Megalobrama Amblycephala) in Response to Dietary Methionine Levels

2021 ◽  
Author(s):  
Ke Ji ◽  
Hualiang Liang ◽  
Mingchun Ren ◽  
Xianping Ge ◽  
Lu Zhang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Mrna Expression ◽  
Binding Protein ◽  
Whole Body ◽  
Megalobrama Amblycephala ◽  
Mrna Levels ◽  
Nutrient Metabolism ◽  
Tissue Specific ◽  
Expression Levels ◽  
Mrna Expression Levels

Abstract BackgroundMethionine is an essential amino acid, that affects the metabolism of protein, lipid and glucose. However, the metabolic polytrophic response in the liver and muscle of juvenile Megalobrama amblycephala to dietary methionine levels is unclear.ResultsThe 0.84% methionine diet significantly improved the growth performance compared with the 0.40% diet. Dietary methionine levels had no marked effects on plasma parameters or whole body composition of juveniles. The protein levels of phospho-phosphatidylinositol 3-kinase, protein kinase B, phospho-eukaryotic initiation factor 4E binding protein-1 (p-4E-BP1), 4E-BP1 and ribosomal protein S6 kinase 1, in the liver of fish fed the 0.84% diet were higher than those in fish fed the 0.40% diet. While in muscle, these proteins showed the opposite trend. The mRNA levels of the muscular lipid synthesis associated genes: sterol regulatory element-binding protein 1 (SREBP1), fatty acid synthetase (FAS) and acetyl-CoA carboxylase (ACC), were significantly upregulated by the 1.28% methionine diet; while hepatic SREBP1, FAS and ACC mRNA expression levels were increased by 0.40% methionine. In addition, 1.28% dietary methionine significantly induced fatty acid β-oxidation and lipolysis of the liver and muscle via increased carnitine palmitoyl transferase 1, peroxisome proliferator activated receptor alpha, lipoprotein lipase and lipase expression levels. Compared with 0.40% dietary methionine, 1.28% methionine enhanced the mRNA levels of the hepatic gluconeogenesis related genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, and the muscular glycolysis related genes phosphofructokinase (PFK) and pyruvate kinase (PK). The mRNA expression levels of hepatic PFK, PK and glucokinase were markedly upregulated by the 0.84% methionine diet compared with the 1.28% diet. In addition, muscular PEPCK and glycogen synthase, and hepatic glucose transporters 2 mRNA levels were induced by 1.28% methionine. ConclusionThe study showed that optimal methionine levels could enhance the growth of juvenile Megalobrama amblycephala, and the nutrient metabolism response to dietary methionine in the liver and muscle was tissue-specific.

scholarly journals DsbA-L deficiency in T cells promotes diet-induced thermogenesis through suppressing IFN-γ production

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Haiyan Zhou ◽  
Xinyi Peng ◽  
Jie Hu ◽  
Liwen Wang ◽  
Hairong Luo ◽  
...  
Keyword(s):  
T Cells ◽  
Adipose Tissue ◽  
T Cell ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Whole Body ◽  
Brown Adipose ◽  
Ifn Γ ◽  
Diet Induced Thermogenesis

AbstractAdipose tissue-resident T cells have been recognized as a critical regulator of thermogenesis and energy expenditure, yet the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding greatly suppresses the expression of disulfide-bond A oxidoreductase-like protein (DsbA-L), a mitochondria-localized chaperone protein, in adipose-resident T cells, which correlates with reduced T cell mitochondrial function. T cell-specific knockout of DsbA-L enhances diet-induced thermogenesis in brown adipose tissue (BAT) and protects mice from HFD-induced obesity, hepatosteatosis, and insulin resistance. Mechanistically, DsbA-L deficiency in T cells reduces IFN-γ production and activates protein kinase A by reducing phosphodiesterase-4D expression, leading to increased BAT thermogenesis. Taken together, our study uncovers a mechanism by which T cells communicate with brown adipocytes to regulate BAT thermogenesis and whole-body energy homeostasis. Our findings highlight a therapeutic potential of targeting T cells for the treatment of over nutrition-induced obesity and its associated metabolic diseases.

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