Adipokines identified as new downstream targets for adiponectin: lessons from adiponectin-overexpressing or -deficient mice

Abstract

Adipokines play a central role in the pathogenesis of the metabolic syndrome. Among them, adiponectin (ApN), a master regulator of immune and fuel homeostasis, is decreased. Identifying downstream adipokines targeted by ApN may help in deciphering this syndrome. We have generated transgenic mice, allowing persistent and moderate overexpression of ApN (ApNOverex) specifically in white adipose tissue (AT). We took advantage of this model to unravel the adipokine secretion profile triggered by ApN. AT was fractionated into adipocytes and stromal-vascular cells (SVC), which were cultured for 8 h. Profiling of secretory products by antibody arrays and subsequent ELISAs showed that the secretion of three proinflammatory factors (IL-17B, IL-21, TNF␣) and three hematopoietic growth factors [GF; thrombopoietin and granulocyte (macrophage) colony-stimulating-factors] was reduced in adipocytes of ApN-Overex mice compared with wild-type mice. In the SVC of these mice, besides the hematopoietic GFs, the secretion of another GF (vascular endothelial GF receptor 1), two chemokines (RANTES and ICAM-1), and two proinflammatory factors (IL-6 and IL-12p70) was reduced as well. Only one cytokine, IL-1 receptor 4, was oversecreted by SVC of ApN-Overex mice, which may exhibit antiinflammatory properties. Most of these changes in secretion were due to corresponding changes in mRNAs. A reverse profile of adipokine expression was observed in ApN-KO mice. In conclusion, ApN regulates in vivo the secretion of downstream adipokines, thereby inducing a shift of the immune balance in both adipocytes and SVC toward a less inflammatory phenotype. These downstream adipokines may be new therapeutic targets for the management of the metabolic syndrome.inflammation; adipocytes; stromal-vascular cells; secretome ADIPOSE TISSUE (AT) secretes a number of bioactive peptides, collectively named adipokines. They may exert endocrine actions on distant organs or autocrine/paracrine actions on AT. They play a central role in energy and vascular homeostasis as well as in immunity (23). Virtually all known adipokines are dysregulated in obesity, type 2 diabetes, and metabolic syndrome, leading to overproduction of deleterious adipokines and hyposecretion of defensive ones such as adiponectin (ApN). Such a dysregulation triggers the development of a low-grade proinflammatory state, which is considered to build the common soil for the development of obesity-linked disorders (23).Resetting the immunological balance in adipose tissue may be a crucial approach for the future management of the metabolic syndrome. Adipokines may be potential therapeutic targets.ApN has emerged as a master regulator of immune/inflammatory and fuel homeostasis (14). Besides its vascular protection (32), ApN exerts anti-inflammatory effects on other organs such as liver, colon, cardiac, or skeletal muscles (2,18,30,37). As yet, the autocrine and paracrine anti-inflammatory effects of ApN on its own production site have been scarcely described (1, 9, 22). Moreover, its effects on AT se...

Adiponectin: mechanistic insights and clinical implications

“…TNFα, IL-6) from adipocytes and surrounding stromal vascular cells [52,[57][58][59][60]. This demonstrates the complex interplay between local (e.g.…”

Skeletal muscle secretome in Duchenne muscular dystrophy: a pivotal anti-inflammatory role of adiponectin

“…Moreover, we also measured TNFα (RayBiotech) by ELISA, which actually escaped detection by arrays, because of the known relationships between TNFα and ApN [20] and our past experience [the background generated by non-conditioned medium may mask the low amounts of some cytokines secreted by cultured cells (such as TNFα)] [21, 22]. …”

Interactions of exercise training and high-fat diet on adiponectin forms and muscle receptors in mice

“…Hypoadiponectinemia has been associated with both MetS and various pathological states, such as obesity and diabetes. Ad deficiency in mice results in inflammation [3], insulin resistance [4–6] and heart failure [7]. In view of these observations, Ad has been suggested as a promising and easily detectable biological marker for MetS (reviewed in [8]).…”