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Article

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

1
Institute of Cell Biophysics of the Russian Academy of Sciences, Federal Research Center, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, 142290 Pushchino, Russia
2
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia
*
Author to whom correspondence should be addressed.
Academic Editor: Alessandro Cannavo
Int. J. Mol. Sci. 2021, 22(10), 5109; https://doi.org/10.3390/ijms22105109
Received: 18 April 2021 / Revised: 7 May 2021 / Accepted: 8 May 2021 / Published: 12 May 2021
Various types of cells demonstrate ubiquitous rhythmicity registered as simple and complex Ca2+-oscillations, spikes, waves, and triggering phenomena mediated by G-protein and tyrosine kinase coupled receptors. Phospholipase C/IP3-receptors (PLC/IP3R) and endothelial NO-synthase/Ryanodine receptors (NOS/RyR)–dependent Ca2+ signaling systems, organized as multivariate positive feedback generators (PLC-G and NOS-G), underlie this rhythmicity. Loss of rhythmicity at obesity may indicate deregulation of these signaling systems. To issue the impact of cell size, receptors’ interplay, and obesity on the regulation of PLC-G and NOS-G, we applied fluorescent microscopy, immunochemical staining, and inhibitory analysis using cultured adipocytes of epididumal white adipose tissue of mice. Acetylcholine, norepinephrine, atrial natriuretic peptide, bradykinin, cholecystokinin, angiotensin II, and insulin evoked complex [Ca2+]i responses in adipocytes, implicating NOS-G or PLC-G. At low sub-threshold concentrations, acetylcholine and norepinephrine or acetylcholine and peptide hormones (in paired combinations) recruited NOS-G, based on G proteins subunits interplay and signaling amplification. Rhythmicity was cell size- dependent and disappeared in hypertrophied cells filled with lipids. Contrary to control cells, adipocytes of obese hyperglycemic and hypertensive mice, growing on glucose, did not accumulate lipids and demonstrated hormonal resistance being non responsive to any hormone applied. Preincubation of preadipocytes with palmitoyl-L-carnitine (100 nM) provided accumulation of lipids, increased expression and clustering of IP3R and RyR proteins, and partially restored hormonal sensitivity and rhythmicity (5–15% vs. 30–80% in control cells), while adipocytes of diabetic mice were not responsive at all. Here, we presented a detailed kinetic model of NOS-G and discussed its control. Collectively, we may suggest that universal mechanisms underlie loss of rhythmicity, Ca2+-signaling systems deregulation, and development of general hormonal resistance to obesity. View Full-Text
Keywords: murine white adipocytes; G proteins interplay; feedback control of Ca2+ signaling systems; Ca2+ oscillations and triggering phenomena; NO and protein kinase G; loss of rhythmicity and general hormonal resistance to obesity murine white adipocytes; G proteins interplay; feedback control of Ca2+ signaling systems; Ca2+ oscillations and triggering phenomena; NO and protein kinase G; loss of rhythmicity and general hormonal resistance to obesity
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MDPI and ACS Style

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

AMA Style

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 Style

Turovsky, 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

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