Diabetes Metab J.  2019 Oct;43(5):549-559. 10.4093/dmj.2019.0157.

Regulation of Systemic Glucose Homeostasis by T Helper Type 2 Cytokines

• Kang YE
• Kim HJ
• Shong M

• KMID: 2460948
• DOI: http://doi.org/10.4093/dmj.2019.0157

Abstract

Obesity results in an inflammatory microenvironment in adipose tissue, leading to the deterioration of tissue protective mechanisms. Although recent studies suggested the importance of type 2 immunity in an anti-inflammatory microenvironment in adipose tissue, the regulatory effects of T helper 2 (Th2) cytokines on systemic metabolic regulation are not fully understood. Recently, we identified the roles of the Th2 cytokine (interleukin 4 [IL-4] and IL-13)-induced adipokine, growth differentiation factor 15 (GDF15), in adipose tissue in regulating systemic glucose metabolism via signal transducer and activator of transcription 6 (STAT6) activation. Moreover, we showed that mitochondrial oxidative phosphorylation is required to maintain these macrophage-regulating autocrine and paracrine signaling pathways via Th2 cytokine-induced secretion of GDF15. In this review, we discuss how the type 2 immune response and Th2 cytokines regulate metabolism in adipose tissue. Specifically, we review the systemic regulatory roles of Th2 cytokines in metabolic disease and the role of mitochondria in maintenance of type 2 responses in adipose tissue homeostasis.

Keyword

Adipokines; Adipose tissue; Cytokines; Immunity; Metabolic diseases; Obesity

MeSH Terms

Adipokines
Adipose Tissue
Cytokines*
Glucose*
Growth Differentiation Factor 15
Homeostasis*
Metabolic Diseases
Metabolism
Mitochondria
Obesity
Oxidative Phosphorylation
Paracrine Communication
STAT6 Transcription Factor
Adipokines
Cytokines
Glucose
Growth Differentiation Factor 15
STAT6 Transcription Factor

Figure

• 

  Fig. 1 Oxidative metabolism controls polarization of macrophages. Classically activated macrophages (M1) induce an aerobic glycolytic program. The hypoxia-inducible factor 1α (HIF1α) transcription factor also becomes activated and can drive production of proinflammatory cytokines. The key functional consequences are bacterial killing, mostly through the production of reactive oxygen species (ROS) and nitric oxide (NO) from L-arginine. Inflammatory genes are also activated by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and promoted by interferon γ (IFN-γ), lipopolysaccharide (LPS), and tumor necrosis factor-α (TNF-α). Alternative activated macrophages (M2) trigger a metabolic program including the electron transport chain as well as fatty acid oxidation, which is orchestrated by signal transducer and activator of transcription 6 (STAT6) and proliferator-activated receptor-γ coactivator 1β (PGC-1β). Arginase also drives the production of polyamines and L-ornithine. IRS, insulin receptor substrate; JNK, c-Jun N-terminal kinases; IKK, IκB kinase; AP1, activator protein 1; iNOS, nitric oxide synthase; IL, interleukin; YM1, chitinase-like 3.

• 

  Fig. 2 Reduced oxidative capacity in macrophages triggers systemic insulin resistance characterized by classically activated macrophages (M1)-like polarization and adipose inflammation via T helper 2 (Th2) cytokine-growth differentiation factor 15 (GDF15) signaling. (A) Th2 cytokines, interleukin 4 (IL-4) and IL-13, alternative activated macrophages (M2)-like polarization and induced GDF15 secretion in white adipose tissue dependent on signal transducer and activator of transcription 6 (STAT6) activation. (B) Reduced oxidative capacity in macrophages impaired STAT6 activation and triggered M1-like polarization and lack of GDF15 secretion. Consequently, dysregulation of Th2 cytokine-GDF15 signaling due to dysfunction of mitochondria in adipose tissue triggers systemic insulin resistance.

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