scholarly journals Insulin Activates RSK (p90 Ribosomal S6 Kinase) to Trigger a New Negative Feedback Loop That Regulates Insulin Signaling for Glucose Metabolism

2013 ◽  
Vol 288 (43) ◽  
pp. 31165-31176 ◽  
Author(s):  
Nicolas Smadja-Lamère ◽  
Michael Shum ◽  
Paul Déléris ◽  
Philippe P. Roux ◽  
Jun-Ichi Abe ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Negative Feedback ◽  
Insulin Signaling ◽  
Feedback Loop ◽  
Negative Feedback Loop ◽  
S6 Kinase ◽  
P90 Ribosomal S6 Kinase ◽  
Ribosomal S6 Kinase

scholarly journals Balancing Akt with S6K

2004 ◽  
Vol 167 (3) ◽  
pp. 399-403 ◽  
Author(s):  
Brendan D. Manning
Keyword(s):  
Feedback Loop ◽  
Metabolic Diseases ◽  
Mammalian Target Of Rapamycin ◽  
Akt Pathway ◽  
Negative Feedback Loop ◽  
Insulin Receptor Substrate ◽  
S6 Kinase ◽  
Ribosomal S6 Kinase ◽  
Phosphoinositide 3 Kinase ◽  
Diabetes And Obesity

Proper regulation of the phosphoinositide 3-kinase–Akt pathway is critical for the prevention of both insulin resistance and tumorigenesis. Many recent studies have characterized a negative feedback loop in which components of one downstream branch of this pathway, composed of the mammalian target of rapamycin and ribosomal S6 kinase, block further activation of the pathway through inhibition of insulin receptor substrate function. These findings form a novel basis for improved understanding of the pathophysiology of metabolic diseases (e.g., diabetes and obesity), tumor syndromes (e.g., tuberous sclerosis complex and Peutz-Jegher's syndrome), and human cancers.

scholarly journals The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells

2014 ◽  
Vol 42 (22) ◽  
pp. 13799-13811 ◽  
Author(s):  
Yuan Gao ◽  
Fuju Wu ◽  
Jichun Zhou ◽  
Lei Yan ◽  
Michael J. Jurczak ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Muscle Cells ◽  
Negative Feedback Loop ◽  
Double Negative

Inhibition of the mTOR/p70S6K pathway is not involved in the insulin-sensitizing effect of AMPK on cardiac glucose uptake

2011 ◽  
Vol 301 (2) ◽  
pp. H469-H477 ◽  
Author(s):  
Audrey Ginion ◽  
Julien Auquier ◽  
Carley R. Benton ◽  
Céline Mouton ◽  
Jean-Louis Vanoverschelde ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Glucose Uptake ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Mammalian Target Of Rapamycin ◽  
Serine Phosphorylation ◽  
Negative Feedback Loop ◽  
Ribosomal S6 Kinase ◽  
Sensitizing Effect ◽  
Stimulation Of

The AMP-activated protein kinase (AMPK) is known to increase cardiac insulin sensitivity on glucose uptake. AMPK also inhibits the mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase (p70S6K) pathway. Once activated by insulin, mTOR/p70S6K phosphorylates insulin receptor substrate-1 (IRS-1) on serine residues, resulting in its inhibition and reduction of insulin signaling. AMPK was postulated to act on insulin by inhibiting this mTOR/p70S6K-mediated negative feedback loop. We tested this hypothesis in cardiomyocytes. The stimulation of glucose uptake by AMPK activators and insulin correlated with AMPK and protein kinase B (PKB/Akt) activation, respectively. Both treatments induced the phosphorylation of Akt substrate 160 (AS160) known to control glucose uptake. Together, insulin and AMPK activators acted synergistically to induce PKB/Akt overactivation, AS160 overphosphorylation, and glucose uptake overstimulation. This correlated with p70S6K inhibition and with a decrease in serine phosphorylation of IRS-1, indicating the inhibition of the negative feedback loop. We used the mTOR inhibitor rapamycin to confirm these results. Mimicking AMPK activators in the presence of insulin, rapamycin inhibited p70S6K and reduced IRS-1 phosphorylation on serine, resulting in the overphosphorylation of PKB/Akt and AS160. However, rapamycin did not enhance the insulin-induced stimulation of glucose uptake. In conclusion, although the insulin-sensitizing effect of AMPK on PKB/Akt is explained by the inhibition of the insulin-induced negative feedback loop, its effect on glucose uptake is independent of this mechanism. This disconnection revealed that the PKB/Akt/AS160 pathway does not seem to be the rate-limiting step in the control of glucose uptake under insulin treatment.

scholarly journals Smad2/3 Activation Regulates Smad1/5/8 Signaling via a Negative Feedback Loop to Inhibit 3T3-L1 Adipogenesis

2021 ◽  
Vol 22 (16) ◽  
pp. 8472
Author(s):  
Senem Aykul ◽  
Jordan Maust ◽  
Vijayalakshmi Thamilselvan ◽  
Monique Floer ◽  
Erik Martinez-Hackert
Keyword(s):  
Negative Feedback ◽  
Feedback Loop ◽  
Negative Feedback Loop ◽  
Adipose Tissues ◽  
Family Growth ◽  
Simultaneous Activation ◽  
Adipocyte Hypertrophy ◽  
Adipocyte Development ◽  
Energy Surplus

Adipose tissues (AT) expand in response to energy surplus through adipocyte hypertrophy and hyperplasia. The latter, also known as adipogenesis, is a process by which multipotent precursors differentiate to form mature adipocytes. This process is directed by developmental cues that include members of the TGF-β family. Our goal here was to elucidate, using the 3T3-L1 adipogenesis model, how TGF-β family growth factors and inhibitors regulate adipocyte development. We show that ligands of the Activin and TGF-β families, several ligand traps, and the SMAD1/5/8 signaling inhibitor LDN-193189 profoundly suppressed 3T3-L1 adipogenesis. Strikingly, anti-adipogenic traps and ligands engaged the same mechanism of action involving the simultaneous activation of SMAD2/3 and inhibition of SMAD1/5/8 signaling. This effect was rescued by the SMAD2/3 signaling inhibitor SB-431542. By contrast, although LDN-193189 also suppressed SMAD1/5/8 signaling and adipogenesis, its effect could not be rescued by SB-431542. Collectively, these findings reveal the fundamental role of SMAD1/5/8 for 3T3-L1 adipogenesis, and potentially identify a negative feedback loop that links SMAD2/3 activation with SMAD1/5/8 inhibition in adipogenic precursors.

scholarly journals p90 ribosomal S6 kinase 3 contributes to cardiac insufficiency in α-tropomyosin Glu180Gly transgenic mice

2013 ◽  
Vol 305 (7) ◽  
pp. H1010-H1019 ◽  
Author(s):  
Catherine L. Passariello ◽  
Marjorie Gayanilo ◽  
Michael D. Kritzer ◽  
Hrishikesh Thakur ◽  
Zoharit Cozacov ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Interstitial Fibrosis ◽  
Cardiac Insufficiency ◽  
S6 Kinase ◽  
Transgenic Expression ◽  
P90 Ribosomal S6 Kinase ◽  
Ribosomal S6 Kinase

Myocardial interstitial fibrosis is an important contributor to the development of heart failure. Type 3 p90 ribosomal S6 kinase (RSK3) was recently shown to be required for concentric myocyte hypertrophy under in vivo pathological conditions. However, the role of RSK family members in myocardial fibrosis remains uninvestigated. Transgenic expression of α-tropomyosin containing a Glu180Gly mutation (TM180) in mice of a mixed C57BL/6:FVB/N background induces a cardiomyopathy characterized by a small left ventricle, interstitial fibrosis, and diminished systolic and diastolic function. Using this mouse model, we now show that RSK3 is required for the induction of interstitial fibrosis in vivo. TM180 transgenic mice were crossed to RSK3 constitutive knockout ( RSK3−/−) mice. Although RSK3 knockout did not affect myocyte growth, the decreased cardiac function and mild pulmonary edema associated with the TM180 transgene were attenuated by RSK3 knockout. The improved cardiac function was consistent with reduced interstitial fibrosis in the TM180; RSK3−/− mice as shown by histology and gene expression analysis, including the decreased expression of collagens. The specific inhibition of RSK3 should be considered as a potential novel therapeutic strategy for improving cardiac function and the prevention of sudden cardiac death in diseases in which interstitial fibrosis contributes to the development of heart failure.

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