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Second messengers Ca, IP3, cAMP, NO, cGMP, and cADP ribose are incorporated as obligatory elements into multivariable Ca-signaling system, which integrates incoming signals of hormones and neurotransmitters in white adipocytes. This cross-controlled system includes two robust generators (RGs) of rhythmic processes, involving phospholipase Cand NO-synthase-dependent signaling networks (PLC-RG and NOS-RG). Multi-loop positive feedback control of both RGs provides their robustness, multistability, signaling interplay, and extreme sensitivity to the alterations of incoming signals of acetylcholine, norepinephrine, insulin, cholecystokinin, atrial natriuretic peptide, bradykinin, and so on. Hypertrophy of cultured adipocytes and of mature cells, isolated from epididymal white adipose tissue (eWAT), results in the loss of rhythmicity and development of general hormonal signaling resistance. Preadipocytes isolated from eWAT of obese mice cannot grow and accumulate lipids in the media devoid of fatty acids. However, even low concentrations of palmitoylcarnitine in the media (1 μM) may result in drastic suppression of mRNA expressions of the proteins of Ca-signaling system, especially of NOS-RG. Similar alterations of gene expression are observed in eWAT and liver at adiposity. All this may indicate on universal background pathogenic mechanisms. Treatment modalities, which may help to restore deregulation of Ca2+-signaling system and corresponding tissues dysfunction, are discussed briefly.

Feedback Control of Second Messengers Signaling Systems in White Adipose Tissue Adipocytes in Healthy State and Its Loss at Adiposity