Adipose Tissue-Derived Signatures for Obesity and Type 2 Diabetes: Adipokines, Batokines and MicroRNAs

Abstract

: Obesity is one of the main risk factors for type 2 diabetes mellitus (T2DM). It is closely related to metabolic disturbances in the adipose tissue that primarily functions as a fat reservoir. For this reason, adipose tissue is considered as the primary site for initiation and aggravation of obesity and T2DM. As a key endocrine organ, the adipose tissue communicates with other organs, such as the brain, liver, muscle, and pancreas, for the maintenance of energy homeostasis. Two different types of adipose tissues-the white adipose tissue (WAT) and brown adipose tissue (BAT)-secrete bioactive peptides and proteins, known as "adipokines" and "batokines," respectively. Some of them have beneficial anti-inflammatory effects, while others have harmful inflammatory effects. Recently, "exosomal microRNAs (miRNAs)" were identified as novel adipokines, as adipose tissue-derived exosomal miRNAs can affect other organs. In the present review, we discuss the role of adipose-derived secretory factors-adipokines, batokines, and exosomal miRNA-in obesity and T2DM. It will provide new insights into the pathophysiological mechanisms involved in disturbances of adipose-derived factors and will support the development of adipose-derived factors as potential therapeutic targets for obesity and T2DM.

Keywords: adipokines; batokines; exosomal miRNAs; obesity; potential therapeutic targets; type 2 diabetes mellitus.

Figure 1

The role of adipose-derived factors (adipokines, batokines, and miRNAs) in the maintenance of energy homeostasis. The adipose tissue (AT) is classified into visceral white adipose tissues (vWAT), subcutaneous white adipose tissues (sWAT), and brown adipose tissue (BAT). The AT secretes adipokines, batokines, and miRNAs into the blood. These adipose-derived factors act like hormones and regulate energy metabolism in tissues, including the brain, liver, AT, muscle, and pancreas.

Figure 2

Classification of adipokines and anti-inflammatory adipokines. (A) Adipokines are categorized into anti-inflammatory adipokines and inflammatory adipokines, based on their expression in obesity and type 2 diabetes mellitus. (B) Anti-inflammatory adipokines, adiponectin, omentin-1, SFRP5, and cardiotrophin-1 improve energy metabolism in the liver, skeletal muscle, and pancreas as well as the adipose tissue itself. Abbreviations: SFRP5, secreted frizzled-related protein 5; FABP-4, fatty acid binding protein 4; ASP, acylation-stimulating protein; RBP4, retinol-binding protein 4; mTOR, mammalian target of rapamycin; IRS, insulin receptor substrate; Wnt5a, wingless-type MMTV integration site family member 5A; AT, adipose tissue; AdipoR, adiponectin receptor; AMPK, AMP-activated protein kinase; PPARα, peroxisome proliferator-activated receptor alpha; GSIS, glucose-stimulated insulin secretion.

Figure 3

The role of inflammatory adipokines in obesity and type 2 diabetes mellitus (T2DM). There are increased inflammatory adipokines depending on adiposity or obesity. They exacerbate inflammation, insulin resistance, and glucose/insulin metabolism in adipose tissues and other peripheral tissues such as the liver, muscle, pancreas, and blood vessels. In particular, FABP, ASP, RBP4, and lipocalin-2 are correlated with inflammation, obesity, and insulin resistance. Although its levels are increased in obesity and T2DM, vaspin has metabolically beneficial effects as it is thought to compensate for obesity and T2DM. Additionally, leptin, a well-known inflammatory adipokine, exhibits an inflammatory phenotype in adipocytes and inflammatory cells, while administration of leptin improves hyperinsulinemia, hyperglycemia, insulin resistance, glucose/lipid metabolism. Abbreviations: FABP-4, fatty acid binding protein 4; RBP4, retinol-binding protein 4; ASP, acylation-stimulating protein; LPS, lipopolysaccharides; IL, interleukin; NF-κB, nuclear factor kappa light chain enhancer of activated B cells; C/EBP, CCAAT-enhancer-binding protein; TNF, tumor necrosis factor; NMN, nicotinamide mononucleotide; AMPK, AMP-activated protein kinase; GSIS, glucose-stimulated insulin secretion; BMP4, bone morphogenetic protein 4.

Figure 4

Batokines secreted from BAT and beige AT. Batokines secreted from BAT and beige AT contribute to the regulation of various functions such as thermogenic activity, immune activity, vascularization, substrate utilization, and other functions. Abbreviations: Mtrnl, meteorin-Like; IGF-1, insulin growth factor-1; IL-6, interleukin-6; CXCL14, chemokine (C-X-C motif) ligand 14; BMPs, bone morphogenetic proteins; PM20D1, peptidase M20 domain containing 1; bFGF, basic fibroblast growth factor; WNT10b, wingless-Related MMTV Integration Site 10b; RBP4, retinol-binding protein-4; IGFBP2, insulin-like growth factor-binding protein-2; NGF, nerve growth factor; 12,13-diHOME, 12,13-dihydroxy-9Z-octadecenoic acid; FGF21, fibroblast browth factor 21; T3, triiodothyronine; sLR11, soluble form of the low-density lipoprotein receptor relative LR11; GDF8, growth differentiation factor-8; ANGPTL8, angiopoietin-like8; VEGF-A, vascular endothelial growth factor A; NO, nitric oxide; H₂O₂, hydrogen peroxide; NRG4, neuregulin-4.

Figure 5

Adipose tissue-derived exosomal microRNAs. Recipient organs and target mRNAs of exosomal microRNAs. Brown fat-derived miR-99b suppresses Fgf-21 expression in the liver, which regulates the systemic homeostasis. The circulating mIR-130b is correlated with BMI. In a mouse obesity model, adipose tissue-derived miR-130b downregulated Pgc-1α expression in the muscle cell. The expression and secretion of miR-200a are increased by rosiglitazone treatment. Exosomal miR-200a derived from adipocytes stimulates mTOR signaling by decreasing TSC1 expression, which leads to cardiomyocyte hypertrophy. Exosomal miR-450a functions in an autocrine manner to increase adipogenesis through the downregulation of WISP2. Abbreviations: FGF21, fibroblast growth factor 21; BMI, body mass index; PGC-1α, peroxisome proliferator–activated receptor gamma coactivator-1 alpha; mTOR, mammalian target of rapamycin; TSC1, tuberous sclerosis 1; WISP2, WNT1-inducible-signaling pathway protein 2.