Adiponectin as a tissue regenerating hormone: more than a metabolic function

Abstract

The great interest that scientists have for adiponectin is primarily due to its central metabolic role. Indeed, the major function of this adipokine is the control of glucose homeostasis that it exerts regulating liver and muscle metabolism. Adiponectin has insulin-sensitizing action and leads to down-regulation of hepatic gluconeogenesis and an increase of fatty acid oxidation. In addition, adiponectin is reported to play an important role in the inhibition of inflammation. The hormone is secreted in full-length form, which can either assemble into complexes or be converted into globular form by proteolytic cleavage. Over the past few years, emerging publications reveal a more varied and pleiotropic action of this hormone. Many studies emphasize a key role of adiponectin during tissue regeneration and show that adiponectin deficiency greatly inhibits the mechanisms underlying tissue renewal. This review deals with the role of adiponectin in tissue regeneration, mainly referring to skeletal muscle regeneration, a process in which adiponectin is deeply involved. In this tissue, globular adiponectin increases proliferation, migration and myogenic properties of both resident stem cells (namely satellite cells) and non-resident muscle precursors (namely mesoangioblasts). Furthermore, skeletal muscle could be a site for the local production of the globular form that occurs in an inflamed environment. Overall, these recent findings contribute to highlight an intriguing function of adiponectin in addition to its well-recognized metabolic action.

Fig. 1

Role of adiponectin in skeletal muscle regeneration. Beyond its metabolic role, gAd exerts a significant function as a regenerating hormone in skeletal muscle. Skeletal muscle represents an autocrine circuit of fAd production, the amount of which is further increased when an injury occurs. Indeed, damage develops an inflammatory environment that leads to adiponectin production via two different mechanisms: (1) secretion of IL-6 and IFN-γ, which induces the up-regulation of adiponectin expression by skeletal muscle; (2) recruitment of activated macrophages secreting fAd that, in turn, is cleaved into gAd. gAd plays a major role in skeletal muscle regeneration, acting on different cell populations involved in tissue regeneration. gAd acts on satellite cells by inducing their activation and migration towards the damaged muscle site. gAd also acts as a chemo-attractant factor for mesoangioblasts, non-resident muscle progenitor cells, recruited to the injured region. Here, gAd promotes myogenesis of both satellite cells and mesoangioblasts, thus concurring to rebuild the damaged fibers

Fig. 2

Adiponectin participates in tissue regeneration. The figure shows the cell lines and/or the animal models used to demonstrate the involvement of adiponectin in tissue regeneration. The obtained results for each tissue are reported (detailed text in paragraph “Role of adiponectin in the regeneration of non-muscle tissues”). Both fAd and gAd play a role in tissue regeneration. gAd acts on satellite cells in skeletal muscle by inducing cell motility and myogenesis [15]; on mesoangioblasts by activating proliferation, cell motility, myogenesis, and inhibiting both apoptosis and anoikis [60]; on hemopoietic stem cells [71] and hippocampal neural stem cells by inducing cell proliferation [72]. In skeletal muscle, gAd promotes the differentiation of myoblasts into myotubes [40]. In the kidney, fAd acts by inhibiting apoptosis in podocytes and by supporting renal recovery [76]. Depletion of fAd in murine liver leads to a decrease in mass growth and hepatocyte proliferation [74] and an increase in lipid accumulation [75]. In the bone, fAd promotes the differentiation of mesenchymal progenitors into osteoblasts [77]. In the endothelium, fAd promotes the enhancement of proliferation and the migration of keratinocytes [88], ameliorates wound repair in adiponectin-deficient and diabetic db/db mice [88] and increases the recruitment of endothelial cell precursors [78]