S100 proteins in obesity: liaisons dangereuses

Abstract

Obesity is an endemic pathophysiological condition and a comorbidity associated with hypercholesterolemia, hypertension, cardiovascular disease, type 2 diabetes mellitus, and cancer. The adipose tissue of obese subjects shows hypertrophic adipocytes, adipocyte hyperplasia, and chronic low-grade inflammation. S100 proteins are Ca²⁺-binding proteins exclusively expressed in vertebrates in a cell-specific manner. They have been implicated in the regulation of a variety of functions acting as intracellular Ca²⁺ sensors transducing the Ca²⁺ signal and extracellular factors affecting cellular activity via ligation of a battery of membrane receptors. Certain S100 proteins, namely S100A4, the S100A8/S100A9 heterodimer and S100B, have been implicated in the pathophysiology of obesity-promoting macrophage-based inflammation via toll-like receptor 4 and/or receptor for advanced glycation end-products ligation. Also, serum levels of S100A4, S100A8/S100A9, S100A12, and S100B correlate with insulin resistance/type 2 diabetes, metabolic risk score, and fat cell size. Yet, secreted S100B appears to exert neurotrophic effects on sympathetic fibers in brown adipose tissue contributing to the larger sympathetic innervation of this latter relative to white adipose tissue. In the present review we first briefly introduce S100 proteins and then critically examine their role(s) in adipose tissue and obesity.

Keywords: Adipocyte; Brown adipose tissue; Cytokine; Inflammation; Macrophage; Receptor; Transdifferentiation; White adipose tissue.

Fig. 1

Proposed function(s) of S100A8/S100A9 in WAT. In normal physiological conditions ATMs are low in number and express low S100A8/S100A9 levels likely in part due to circulating GIP that selectively restrains S100A8/S100A9 expression in ATMs [89]; the combination of low ATM numbers and low S100A8/S100A9 levels concurs to create a condition of essentially no inflammation. Excess food intake enhances GIP secretion from EECs leading to increased fat storage (1) but reduced S100A8/S100A9 expression in ATMs (2) [89]. However, high fat diet leading to obesity results in the suffering and/or death of adipocytes (3) consequent to insufficient blood supply and liberation of DAMPs (including S100A8/S100A9?) that recruit and activate ATMs to release TNF-α and IL-1β (4) [6, 10, 14, 17, 18]. TNF-α and IL-1β stimulate S100A8/S100A9 release from stromal vascular cells (5) and likely hypertrophic adipocytes with ensuing S100A8/S100A9-dependent recruitment of macrophages and fueling of ATM-dependent inflammation [80, 83]. However, inflammation of the obese adipose tissue is low-grade because of GIPdependent restraint of S100A8/S100A9 expression in ATM [89]. Unrestrained S100A8/S100A9 expression in and release from ATMs (and likely stromal vascular cells) lead to defective cold acclimation in WAT (6) [89]

Fig. 2

S100B might function as an adipokine in the interaction between adipocytes and macrophages. In the contest of obesity hypertrophic adipocytes might release S100B (1) [135] that upregulates TNF-α in ATMs [136] in a RAGE-mediated manner (2). TNF-α can stimulate S100B release from adipocytes (3) [136] thereby fueling inflammation via stimulation of ATMs. S100B is found in both hypertrophic adipocytes and ATMs [137] which makes it possible that ATM-derived S100B might participate in adipose tissue inflammation as well (4)

Fig. 3

Complex role of S100B in brown and white adipocytes, and proliferating myoblasts. a S100B secreted from brown adipocyte acts as a neurotrophic factor participating in the larger sympathetic innervation of BAT relative to WAT and WAT acclimation to cold. Exposure to cold leads to sympathetic stimulation of brown adipocytes that release S100B (1) exerting neurotrophic effects on BAT sympathetic innervation (2) [142]. b Cold exposure induces upregulation of S100B in inguinal adipocytes likely via sympathetic stimulation (?) [142]. Upregulated S100B might induce beiging (browning?) of white adipocytes [142] probably via upregulation of PRDM16 leading to UCP1 expression [117]. Whether beige (brown?) adipocytes release S100B to support sympathetic innervation of WAT and/or perform other still unknown activities remains to be established. c Oxidative stress in proliferating (MyoD⁺) myoblasts activates NF-κB to upregulate S100B [145] which inhibits the differentiation of myoblasts to fusion-competent myocytes via NF-κB-dependent repression of MyoD expression leading to inhibition of formation of myotubes [170], the precursors of skeletal myofibers. Upregulated S100B also activates an NF-κB/YY1 axis leading to reduced expression levels of miR-133, a promyogenic factor that represses PRDM16, and to upregulation and secretion of BMP-7 [145], that in turn upregulates S100b and Prdm16 leading to induction of UCP1 (that is to transdifferentiation of myoblasts into brown adipocytes) [145]