Interleukin-6: An Under-Appreciated Inducer of Thermogenic Adipocyte Differentiation

Abstract

Adipose tissue inflammation is a key factor leading to obesity-associated immune disorders, such as insulin resistance, beta cell loss in the pancreatic islets, meta-inflammation, and autoimmunity. Inhibiting adipose tissue inflammation is considered a straightforward approach to abrogate these diseases. However, recent findings show that certain pro-inflammatory cytokines are essential for the proper differentiation and functioning of adipocytes. Lipolysis is stimulated, and the thermogenic competence of adipocytes is unlocked by interleukin-6 (IL-6), a cytokine that was initially recognized as a key trigger of adipose tissue inflammation. Coherently, signal transducer and activator of transcription 3 (STAT3), which is a signal transducer for IL-6, is necessary for thermogenic adipocyte development. Given the impact of thermogenic adipocytes in increasing energy expenditure and reducing body adiposity, functions of IL-6 in the adipose tissue have gained attention recently. In this review, we show that IL-6 signaling may protect from excess fat accumulation by stimulating thermogenesis in adipocytes.

Keywords: adipocyte; inflammation; obesity; thermogenesis.

Figure 1

IL-6 signaling in the adipose tissue. (a) Single-cell sequencing data retrieved from Tabula Muris [35], showing cell populations of the mouse adipose tissue that express Il6 and Il6ra (encoding IL-6 receptor α). Emr1: encodes F4/80 antigen, a marker protein of murine macrophages. Adipose tissue macrophages (ATMs) are F4/80-positive cells, and hence are identified as Emr1-expressing cells in this plot. Preadipocytes are identified as Hoxc8-expressing cells. Hoxc8 encodes homeobox 8C, a protein marker of adipocyte precursors and adipocytes [36]. Il6 expression is apparent in the preadipocyte/adipocyte population, and in a lesser extent, in the ATMs. In turn, Il6ra is strongly expressed by both ATMs and preadipocytes/adipocytes, allowing IL-6 to target both cell populations. tSNE: t-distributed stochastic neighbor embedding; purple color intensity of the cell populations is proportional to expression levels of Emr1, Hoxc8, Il6 and Il6ra mRNA. (b) Simplified scheme of IL-6 signaling. In the so-called classical IL-6 signaling pathway IL-6 binds to IL-6 receptor α (IL-6Rα), which eventually forms dimers and associates with GP130 protein. The so-called trans-signaling is activated by soluble IL-6Rα (sIL-6Rα). SHC2: Src homology-2 containing protein; TYK: tyrosine kinase; JAK: Janus kinase; JNK: c-Jun terminal kinase; MAPK/ERK: mitogen-activated protein kinase/extracellular signal-regulated kinase; p38/MAPK: p38 mitogen-activated protein kinase; STAT1, 3 and 5: signal transducer and activator of transcription 1, 3 and 5; IRS1/2: insulin receptor substrate 1 and 2; PI3K-Akt: Phosphoinositide 3-kinase—Ak strain-transforming; IL-6R: IL-6 receptor complex containing IL-6, IL-6Rα and GP130 in a 2:2:2 ratio.

Figure 2

Possible effects of IL-6 signaling on energy intake and energy expenditure under non-obesogenic conditions. (a) Hypothalamic IL-6/STAT3 signaling may reduce energy intake and stimulate thermogenesis and lipolysis in adipocytes. The underlying mechanisms are still largely unexplored. (b) IL-6 is released from the skeletal muscle during exercise, which may increase lipolysis and thermogenesis in adipocytes. Tumor tissues may also secrete IL-6 into the blood stream, that can over-stimulate fat catabolism and cause excessive wasting of body fat and lead to cachexia. (c) It has been shown recently that IL-6/STAT3 signaling triggers the expression of genes required for mitochondrial biogenesis and thermogenesis in preadipocytes and adipocytes, and STAT3 is necessary for thermogenic fat development. Upstream stimulators of the locally produced IL-6 may be human milk alkylglycerols (AKGs). AKGs are metabolized by ATMs into platelet-activating factor (PAF), which is non-enzymatically converted into azelaoyl PAF (AzPAF) and stimulates IL-6 release from ATMs. AzPAF is a peroxisome proliferator-activated receptor gamma (PPARγ) ligand [21]. (d) Autocrine IL-6 signaling stimulates the transcription of mitobiogenesis and thermogenesis genes in adipocytes, especially during the early postnatal life. Upstream stimulators of IL-6 synthesis are mitochondria-derived RNA species (mtRNA), which increase IL-6 synthesis through the RIG-I/MDA5 (retinoic acid-inducible gene-1/RIG-I-like receptor dsRNA helicase) cytosolic RNA recognition pathway [31].

Figure 3

IL-6/STAT3 stimulates expression of genes necessary for mitochondrial biogenesis and thermogenesis. (a) STRING protein–protein interaction network of IL-6 [91]. A gene network required for mitochondrial biogenesis and uncoupling is strongly associated with IL-6 signaling. The gene network includes Ucp1, encoding uncoupling protein 1; Ppargc1a, encoding peroxisome proliferator activated receptor gamma coactivator 1; Cidea, encoding cell death-inducing DFFA-like effector A; Prdm16, encoding PR domain containing 16; Dio2, encoding Type II iodothyronine deiodinase; and Cox7a1, encoding cytochrome c oxidase subunit 7A1. Moreover, Lhx8 and Myod1, which encode proteins (LIM homeobox 8 and myogenic differentiation 1, respectively) involved in thermogenic adipocyte development, are also associated with the gene network [39,92]. (b) Scheme summarizing transcription binding sites upstream to promoter regions of Ucp1, Ppargc1a, Cidea, Cox7a1, Dio2, Myod1 and Lhx8. All these genes have predicted binding sites for STATs, STAT1 and STAT3. Transcription factor binding sites were predicted by Interferome 2.0 [93].

Figure 4

Summary of the possible role of IL-6 in thermogenesis in adipocytes. (a) IL-6 may be released by contracting skeletal muscle fibers and reach the adipose tissue through the bloodstream or may be released locally by ATMs and by further immune cells of the adipose tissue. IL-6 may also be produced by preadipocytes or adipocytes in response to β-adrenergic receptor (ADRB) stimulation, or cytosolic mitochondrial RNA (mtRNA), allowing autocrine IL-6 signaling. Activation of the IL-6/STAT3 pathway stimulates the transcription of genes required for mitochondrial biogenesis and thermogenesis. (b) At a systemic level, IL-6 signaling may affect adipocyte thermogenesis by various mechanisms: it may affect the hypothalamic control of energy intake and energy expenditure. Skeletal-muscle-derived IL-6 may stimulate thermogenesis in adipocytes. Adipose tissue-derived IL-6 may stimulate lipolysis and thermogenesis. All these mechanisms have the potential to increase fat loss; however, the underlying molecular mechanisms are still to be explored.