A combined docosahexaenoic acid–thyroid hormone protocol upregulates rat liver β-Klotho expression and downstream components of FGF21 signaling as a potential novel approach to metabolic stress conditions

2017 ◽  
Vol 8 (11) ◽  
pp. 3980-3988 ◽  
Author(s):  
R. Vargas ◽  
B. Riquelme ◽  
J. Fernández ◽  
L. A. Videla
Keyword(s):  
Growth Factor ◽  
Thyroid Hormone ◽  
Docosahexaenoic Acid ◽  
Fibroblast Growth Factor ◽  
Metabolic Stress ◽  
Fibroblast Growth Factor 21 ◽  
Peroxisome Proliferator ◽  
Fibroblast Growth ◽  
Peroxisome Proliferator Activated Receptor ◽  
Novel Approach

We study the mechanism of how liver preconditioning by a DHA and triiodothyronine combined protocol underlies peroxisome-proliferator activated receptor α (PPARα)-fibroblast growth factor 21 (FGF21) upregulation.

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 Identification of a Domain within Peroxisome Proliferator-Activated Receptor γ Regulating Expression of a Group of Genes Containing Fibroblast Growth Factor 21 That Are Selectively Repressed by SIRT1 in Adipocytes

2007 ◽  
Vol 28 (1) ◽  
pp. 188-200 ◽  
Author(s):  
Hong Wang ◽  
Li Qiang ◽  
Stephen R. Farmer
Keyword(s):  
Amino Acid ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Constitutive Expression ◽  
Fibroblast Growth Factor 21 ◽  
Peroxisome Proliferator ◽  
Fibroblast Growth ◽  
Peroxisome Proliferator Activated Receptor ◽  
Group 2 ◽  
Pparγ Expression

ABSTRACT Peroxisome proliferator-activated receptor γ (PPARγ) activity is regulated through association with ligands that include the thiazolidinedione class of antidiabetic drugs, as well as derivatives of polyunsaturated fatty acids. Induction of PPARγ target gene expression involves ligand-dependent reconfiguration of the ligand-binding domain (LBD), followed by recruitment of specific transcriptional coactivators. In this study, we have identified an amino acid (F372) within helix 7 of the LBD that is required for the response of PPARγ to endogenous ligands. Additionally, the data show that this amino acid is also required for expression of a novel subset of adipocyte genes (group 2), including fibroblast growth factor 21 (FGF21), and that the FGF21 gene is a direct target of PPARγ. Expression of the group 2 genes is selectively repressed by the NAD-dependent deacetylase SIRT1 in mature 3T3-L1 adipocytes, since knockdown of SIRT1 through the constitutive expression of a corresponding RNA interference enhances their expression without affecting the expression of classic adipogenic genes, such as adiponectin and FABP4/aP2. It appears that many of the group 2 genes repressed by SIRT1 in mature adipocytes correspond to the same set of genes that are selectively activated by treatment of fat cells with the PPARγ ligand, troglitazone. These data support a role for helix 7 of the LBD of PPARγ in regulating adipocyte function and suggest that inhibition of SIRT1 in adipocytes induces the same insulin-sensitizing action as PPARγ ligands.

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