Adipose Signals Regulating Distal Organ Health and Disease

Abstract

Excessive adiposity in obesity is a significant risk factor for development of type 2 diabetes (T2D), nonalcoholic fatty liver disease, and other cardiometabolic diseases. An unhealthy expansion of adipose tissue (AT) results in reduced adipogenesis, increased adipocyte hypertrophy, adipocyte hypoxia, chronic low-grade inflammation, increased macrophage infiltration, and insulin resistance. This ultimately culminates in AT dysfunction characterized by decreased secretion of antidiabetic adipokines such as adiponectin and adipsin and increased secretion of proinflammatory prodiabetic adipokines including RBP4 and resistin. This imbalance in adipokine secretion alters the physiological state of AT communication with target organs including pancreatic β-cells, heart, and liver. In the pancreatic β-cells, adipokines are known to have a direct effect on insulin secretion, gene expression, cell death, and/or dedifferentiation. For instance, impaired secretion of adipsin, which promotes insulin secretion and β-cell identity, results in β-cell failure and T2D, thus presenting a potential druggable target to improve and/or preserve β-cell function. The cardiac tissue is affected by both the classic white AT-secreted adipokines and the newly recognized brown AT (BAT)-secreted BATokines or lipokines that alter lipid deposition and ventricular function. In the liver, adipokines affect hepatic gluconeogenesis, lipid accumulation, and insulin sensitivity, underscoring the importance of adipose-liver communication in the pathogenesis of nonalcoholic fatty liver disease. In this perspective, we outline what is currently known about the effects of individual adipokines on pancreatic β-cells, liver, and the heart.

Figure 1

Adipose tissue dysfunction in a setting of obesity. Under conditions of caloric excess and metabolic stress, the AT undergoes an unhealthy expansion characterized by an array of features distinguishable from an otherwise healthy expansion. These include reduced adipogenesis, increased adipocyte hypertrophy, increased immune cell infiltration, chronic low-grade inflammation, and decreased insulin sensitivity. Adipocyte dysfunction results in an imbalance in the secretion of adipokines, with higher secretion of proinflammatory prodiabetes adipokines (red dots) and lower secretion of anti-inflammatory antidiabetes adipokines (green dots). This impairs the AT’s physiological communication to the adipokine-effector organs such as pancreatic β-cells, liver, and heart.

Figure 2

Adipokines with direct effects on pancreatic β-cells. Most adipokines bind to their receptors on the β-cell surface and signal via their cognate receptors to stimulate or inhibit insulin secretion and alter β-cell transcriptional identity, β-cell death and/or dedifferentiation. For example, C3a, the downstream active product of adipsin pathway, binds and activates its G-protein–coupled receptor C3aR1. The resulting downstream signaling pathway promotes GSIS, maintains β-cell transcriptional identity, and promotes survival by dampening both β-cell death and dedifferentiation. AdipoR1/R2, adiponectin receptor 1/receptor 2; APJ, apelin receptor; CFB, complement factor B; CFD, complement factor D (Adipsin); C3aR1, C3a receptor 1; IR, insulin receptor; Lep-R, leptin receptor; RBP4, retinol binding protein 4; STRA6, stimulated by retinoic acid 6 receptor.

Figure 3

Adipose communication to heart. In the healthy state, the WAT and the brown-like EAT mostly secrete EVs with protective cargo and anti-inflammatory cytokines, which protect against structural and electrical remodeling of the heart. The BAT secretes protective BATokines like FGF21, NRG4, and 12,13-diHOME. In the diseased state, WAT and EAT become inflamed and expand. In addition, more proinflammatory cytokines and EVs with inflammatory cargo are secreted resulting in detrimental changes to the heart that include fibrosis, electrical remodeling, and apoptosis.

Figure 4

Adipose communication to liver. AT can secrete hepatoprotective hormones in the healthy lean state, such as adiponectin, SFRP5, asprosin, NRG4, and adipsin. However, in unhealthy adipose expansion and insulin resistance, adipose dysfunction and inflammation lead to ectopic fat deposition, including hepatosteatosis and downregulation of the above hepatoprotective factors. In addition, there are increased levels of other factors that promote hepatic dysfunction and further insulin resistance, such as RBP4 and exosome-derived miRNAs. Together these illustrate the interrelatedness of obesity and liver disease due to the secretion of important regulatory factors from AT. NRG4, neuregulin 4; RBP4, retinol binding protein 4; SFRP5, secreted frizzled-related protein 5.