Adipokines in Sleep Disturbance and Metabolic Dysfunction: Insights from Network Analysis

Abstract

Adipokines are a growing group of secreted proteins that play important roles in obesity, sleep disturbance, and metabolic derangements. Due to the complex interplay between adipokines, sleep, and metabolic regulation, an integrated approach is required to better understand the significance of adipokines in these processes. In the present study, we created and analyzed a network of six adipokines and their molecular partners involved in sleep disturbance and metabolic dysregulation. This network represents information flow from regulatory factors, adipokines, and physiologic pathways to disease processes in metabolic dysfunction. Analyses using network metrics revealed that obesity and obstructive sleep apnea were major drivers for the sleep associated metabolic dysregulation. Two adipokines, leptin and adiponectin, were found to have higher degrees than other adipokines, indicating their central roles in the network. These adipokines signal through major metabolic pathways such as insulin signaling, inflammation, food intake, and energy expenditure, and exert their functions in cardiovascular, reproductive, and autoimmune diseases. Leptin, AMP activated protein kinase (AMPK), and fatty acid oxidation were found to have global influence in the network and represent potentially important interventional targets for metabolic and sleep disorders. These findings underscore the great potential of using network based approaches to identify new insights and pharmaceutical targets in metabolic and sleep disorders.

Keywords: adipokine; cardiovascular disease; metabolic syndrome; network analysis; sleep disorder.

Figure 1

Representative networks and network metrics. (A) A hypothetical gene regulatory network showing nodes connected by directed edges. TF1 and TF2: Transcription factors 1 and 2. G1, G2, and G3: Genes 1, 2, and 3. (B) A hypothetical protein and protein interaction network showing nodes connected by undirected edges. P0, P1, P2, P3, and P4: Proteins 0, 1, 2, 3, and 4. (C) An example of a random network. (D) A network with the node of high degree centrality, referred as a “hub”, shown in black. (E) A network with the node of high betweenness centrality, referred as a “bottleneck”, shown in black.

Figure 2

Degree analysis of the adipokine network representing adipokines (A), physiologic perturbations (B), sleep disturbances (C), molecular targets (D), physiologic functions (E), and relevant disease processes (F). Among them, physiologic perturbations (B) and sleep disturbances (C) only have out-degree, and disease processes (F) only have in-degree. Adipokines (A), molecular targets (D), and physiologic functions (E) have in-degree, out-degree, and combined degrees. Only selected molecular targets and physiologic functions are shown.

Figure 3

Betweenness centrality of the adipokine network, representing adipokines (A), molecular targets (B), and physiologic functions (C). Only selected molecular targets and physiologic functions are shown.