Obesity, Fat Mass and Immune System: Role for Leptin

Vera Francisco, Jesús Pino, Victor Campos-Cabaleiro, Clara Ruiz-Fernández, Antonio Mera, Miguel A Gonzalez-Gay, Rodolfo Gómez, Oreste Gualillo, Vera Francisco, Jesús Pino, Victor Campos-Cabaleiro, Clara Ruiz-Fernández, Antonio Mera, Miguel A Gonzalez-Gay, Rodolfo Gómez, Oreste Gualillo

Abstract

Obesity is an epidemic disease characterized by chronic low-grade inflammation associated with a dysfunctional fat mass. Adipose tissue is now considered an extremely active endocrine organ that secretes cytokine-like hormones, called adipokines, either pro- or anti-inflammatory factors bridging metabolism to the immune system. Leptin is historically one of most relevant adipokines, with important physiological roles in the central control of energy metabolism and in the regulation of metabolism-immune system interplay, being a cornerstone of the emerging field of immunometabolism. Indeed, leptin receptor is expressed throughout the immune system and leptin has been shown to regulate both innate and adaptive immune responses. This review discusses the latest data regarding the role of leptin as a mediator of immune system and metabolism, with particular emphasis on its effects on obesity-associated metabolic disorders and autoimmune and/or inflammatory rheumatic diseases.

Keywords: Type 2 diabetes mellitus (T2DM); adipokines; adipose tissue; immunometabolism; leptin; metabolism; rheumatic diseases; rheumatoid arthritis.

Figures

FIGURE 1
FIGURE 1
Leptin receptors and intracellular leptin signaling pathways. Leptin binds to its receptor (LEPR) isoforms: the soluble isoform (not shown), the short isoform and the long isoform. Binding of leptin to the long form of LEPR results in its dimerization and prompts Janus kinase 2 (JAK2) autophosphorylation, which phosphorylates cytoplasmatic domain of LEPR in tyrosine residues (Tyr974, Tyr985, Tyr1077, Tyr1138), each one functioning as docking sites for cytoplasmic adaptors. LEPR-phosphorylated Tyr1138 mediates the interaction with signaling transducer and activator of transcription 3 (STAT3), which dimerize and translocate to the nucleus to activate gene transcription of target genes, such as suppressor of cytokine signaling 3 (SOCS3) that acts as a negative feedback signaling. Additionally, leptin induces the activation of SHP2, which then recruits the adaptor protein Grb2 to prompt activation of Ras/Raf/MAPK signaling cascade. Leptin also mediated phosphatidylinositol-3-kinase (PI3K)/Akt activation via insulin receptor substrate 1/2 (IRS1/2) and protein tyrosine phosphatase 1B (PTP1B) acts as a negative regulator of leptin signaling through JAK2 dephosphorylation.
FIGURE 2
FIGURE 2
Pleiotropic nature of leptin. Since its discovery in 1994, several physiological functions have been attributed to leptin, such as modulation of vascular function, reproduction, bone metabolism, inflammation, infection, and immune responses, behind central regulation of food intake, energy expenditure and hormone regulation, via activation of leptin receptor (LEPR).
FIGURE 3
FIGURE 3
Leptin effects on innate and adaptive immunity. Leptin regulates both innate and adaptive responses through modulation of immune cells survival and proliferation as well as its activity. In innate immunity, leptin increases the cytotoxicity of natural killer (NK) cells and promotes the activation of granulocytes, macrophages and DCs. Leptin also regulates the M1- or M2-phenotype polarization and modulates DCs, licensing them towards type 1 T helper cells (Th1) priming. In adaptive immunity, leptin increases the proliferation of naïve T cells and B cells while it reduces that of regulatory T cells (Treg). Leptin promotes the switch towards a pro-inflammatory Th1 (which secretes IFNγ) rather than anti-inflammatory Th2 (which secretes IL-4) phenotype, and facilitates Th17 responses. Finally, leptin activates B cells to secrete cytokines and modulates B cell development.
FIGURE 4
FIGURE 4
Effects of adipose tissue-derived leptin on osteoarthritis and rheumatoid arthritis. Body weight gain, accompanied by white adipose tissue expansion, lead to obesity and subsequent increase of mechanical load, resulting in cartilage degradation and osteoarthritis onset. Adipose tissue-derived leptin causes osteoblast dysregulation in subchondral bone, thus promoting joint destruction. Additionally, leptin induces pro-inflammatory cytokine release from innate and adaptive immune cells, generating an inflammatory environment that prompts cartilage damage and rheumatoid arthritis.

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