Deregulation of Ca2+-Signaling Systems in White Adipocytes, Manifested as the Loss of Rhythmic Activity, Underlies the Development of Multiple Hormonal Resistance at Obesity and Type 2 Diabetes
Abstract
:1. Introduction
- -
- short PFL based on CICR encoded by inositol-3-phosphate (IP3)-dependent Ca2+-receptor (IP3R):Ca2+ → IP3R → Ca2+
- -
- long PFL based on feedback activation of phospholipase C (PLC) by Ca2+ and subsequent activation of IP3R by the product of PLC reaction IP3:Ca2+ → PLC → IP3 → IP3R → Ca2+
2. Results
2.1. Diversity of Ca2+-Responses Evoked by Various Hormones in Cultured Adipocytes
2.1.1. Impact of Cell Size
- (1)
- in total, 10% to 15% of all cells in culture having small lipid inclusions (discernible with specific staining by Oil Red) and size (Ø) equal to or higher than 50 µM (Ø ≥ 50 µM);
- (2)
- in total, 50% to 60% of cells having several lipid droplets and Ø ≥ 100 µM;
- (3)
- the rest of the cells (15–20%) representing hypertrophied “obese” adipocytes completely filled with numerous lipid inclusions and having Ø ≥ 200 µM.
2.1.2. Impact of GPCR and RTK and Cultured Cells’ State on Switching on of PLC-G and NOS-G
2.1.3. Simplified Kinetic Model of NOS-G and PLC-G with Input Signaling Axes
2.2. Combined Synergistic Action of Hormones Implicated in Parametric Control of NOS-RG
2.2.1. Gβγ-Subunits Interplay
2.2.2. Gβγ/TK Interplay
2.2.3. Gβγ/Gα Proteins Interplay
2.2.4. Gβγ/Gs Proteins Interplay
2.3. Multi-Loop Positive Feedback Control and Robustness of NOS-G
2.4. Impact of Obesity on Cultured Adipocytes
2.4.1. Effect of Obesity on Adipocytes Lipids Accumulation and Expression of IP3R and RyR
2.4.2. Impact of Obesity on Ca2+-Signaling
3. Discussion
3.1. Positive Feedback Loops Interplay
3.2. Extreme Sensitivity of NOS-G to Input Signal and G Proteins Interplay
3.3. Over-Activation of Input Axes and Multistability of NOS-G
3.4. Positive and Negative Feedbacks’ Crosstalk
3.5. Obesity-Induced General Hormonal Signaling Resistance of Adipocytes
4. Materials and Methods
4.1. Isolation and Cultivation of Preadipocytes
4.2. The Measurement of Cytosolic Calcium Concentration ([Ca2+]i)
4.3. Immunocytochemical Method
4.4. Animal Model of Obesity and Type 2 Diabetes
4.5. Metabolite and Blood Parameters Determinations
4.6. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Conflicts of Interest
Abbreviations
[Ca2+]i | intracellular free calcium concentration |
PKB | protein kinase B |
PI3Kα, γ | lipid kinases α, γ |
eNOS | endothelial NO-synthase |
AMPKα | AMP-activated protein kinase α |
ACh | acetylcholine |
NE | norepinephrine |
BK | bradykinin |
CCK | cholecystokinin |
AngII | Angiotensin II |
Ins | Insulin |
Gβγ | G-protein βγ |
Gαq | G-protein αq |
α1,2-AR | α1,2-adrenoreceptors |
β1-3-AR | β1-3-adrenoreceptors |
eWAT | epididymal white adipose tissue |
CICR | calcium- induced calcium release |
NFL | negative feedback loop |
PFL | positive feedback loop |
m3-MR | m3-muscarinic receptors |
ANP | atrial natriuretic peptide |
NOS-G | eNOS- dependent rhythmic generator |
PLC-G | PLC- dependent rhythmic generator |
Gαs | G-protein αs |
GPCR | G-protein coupled receptors |
RTK | tyrosine kinase coupled receptors |
T2D | type 2 diabetes |
VP | vasopressin |
ANP | atrial natriuretic peptide |
ET-1 | endothelin-1 |
PE | phenylephrine |
SERCA | Ca2+-ATPase of endoplasmic reticulum |
PMCA | Ca2+-ATPase of plasmalemma |
AC | adenylate cyclase |
PKA | protein kinase A |
VEGF | vascular endothelial growth factor |
CCK | cholecystokinin |
BA | Bile acids |
IP3R1,2 | inositol 1,4,5-trisphosphate receptors subtypes 1,2 |
CaMKIIβ | Ca2+/calmodulin-dependent protein kinase IIβ |
CaMKK | Ca2+/calmodulin-dependent kinase kinase |
IP3 | inositol 1,4,5-trisphosphate |
PLCβ,γ | phospholipase C β,γ |
sGC | soluble guanylate cyclase |
PKG1 | cGMP-dependent protein kinase 1 |
CD38 | ectoenzyme ADP-ribosyl cyclase |
PKB | protein kinase B |
ARC | ADP-ribosyl cyclase |
cADPr | cyclic ADP-ribose |
TK | membrane tyrosine kinase |
cSrc | cytosolic tyrosine kinase |
RyR2,3 | ryanodine receptors subtypes 2,3 |
RGS | Regulator of G protein signaling |
IRAG | IP3R-associiated protein kinase G substrate |
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Agonists and Their Concentrations | |||||||
---|---|---|---|---|---|---|---|
ACh 1–5 µM | NE 1–5 µM | ANP 1–10 µM | CCK 3–20 nM | ANGII 0.2– 1 µM | BK 0.3–10 µM | Ins 3–20 nM | |
Receptors and proteins | m3 Gβγ | α1 Gαq | NPR-A Gα | CCK-B Gαq, Gβγ | AT-1 Gαq, Gβγ | B2R Gαq, Gβγ | RTK TK, cSrc |
PLC-G, % of cells with rhythmic activity | – | 30–40 | – | 25–40 | 25–40 | 30–40 | 20–30 |
NOS-G, % of cells with rhythmic activity | 70–80 | – | 30–40 | 20–40 | 30–35 | 25–30 | 15–25 |
Periods of Ca2+-oscillations (s) | 5–60 100–300 | 20–75 100–300 | 20–50 200–300 | 25–30 300–500 | 20–50 75–200 | 10–30 200–500 | 20–30 50–150 |
Age (Month) | Weight (g) | Glucose (mM) | Insulin (ng/mL) | Cholest (mM) | TG (mM) | FFA (mM) | Blood Pressure (mmHg) |
2 | 24.4 ± 0.56 | 6.4 ± 0.15 | 0.51 ± 0.04 | 2.35 ± 0.09 | 1.48 ± 0.08 | 1.14 ± 0.11 | 121 ± 2.4 |
7 | 42.5 ± 0.72 | 8.01 ± 0.21 | 1.95 ± 0.11 | 3.5 ± 0.13 | 1.92 ± 0.15 | 1.82 ± 0.12 | 143 ± 1.53 |
10 | 56.4 ± 1.42 | 11.9 ± 0.41 | 3.39 ± 0.13 | 4.33 ± 0.18 | 2.62 ± 0.21 | 1.84 ± 0.16 | 177 ± 2.96 |
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Turovsky, E.A.; Turovskaya, M.V.; Dynnik, V.V. Deregulation of Ca2+-Signaling Systems in White Adipocytes, Manifested as the Loss of Rhythmic Activity, Underlies the Development of Multiple Hormonal Resistance at Obesity and Type 2 Diabetes. Int. J. Mol. Sci. 2021, 22, 5109. https://doi.org/10.3390/ijms22105109
Turovsky EA, Turovskaya MV, Dynnik VV. Deregulation of Ca2+-Signaling Systems in White Adipocytes, Manifested as the Loss of Rhythmic Activity, Underlies the Development of Multiple Hormonal Resistance at Obesity and Type 2 Diabetes. International Journal of Molecular Sciences. 2021; 22(10):5109. https://doi.org/10.3390/ijms22105109
Chicago/Turabian StyleTurovsky, Egor A., Maria V. Turovskaya, and Vladimir V. Dynnik. 2021. "Deregulation of Ca2+-Signaling Systems in White Adipocytes, Manifested as the Loss of Rhythmic Activity, Underlies the Development of Multiple Hormonal Resistance at Obesity and Type 2 Diabetes" International Journal of Molecular Sciences 22, no. 10: 5109. https://doi.org/10.3390/ijms22105109