Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications

Abstract

Obesity is a critical risk factor for the development of type 2 diabetes (T2D), and its prevalence is rising worldwide. White adipose tissue (WAT) has a crucial role in regulating systemic energy homeostasis. Adipose tissue expands by a combination of an increase in adipocyte size (hypertrophy) and number (hyperplasia). The recruitment and differentiation of adipose precursor cells in the subcutaneous adipose tissue (SAT), rather than merely inflating the cells, would be protective from the obesity-associated metabolic complications. In metabolically unhealthy obesity, the storage capacity of SAT, the largest WAT depot, is limited, and further caloric overload leads to the fat accumulation in ectopic tissues (e.g., liver, skeletal muscle, and heart) and in the visceral adipose depots, an event commonly defined as "lipotoxicity." Excessive ectopic lipid accumulation leads to local inflammation and insulin resistance (IR). Indeed, overnutrition triggers uncontrolled inflammatory responses in WAT, leading to chronic low-grade inflammation, therefore fostering the progression of IR. This review summarizes the current knowledge on WAT dysfunction in obesity and its associated metabolic abnormalities, such as IR. A better understanding of the mechanisms regulating adipose tissue expansion in obesity is required for the development of future therapeutic approaches in obesity-associated metabolic complications.

Keywords: adipogenesis; adipose tissue; adipose tissue dysfunction; diabetes; ectopic lipid deposition; hypertrophic obesity; inflammation; insulin resistance; lipotoxicity; obesity.

Figure 1

White adipose tissue expansion in obesity. White adipose tissue responds to caloric excess through a healthy or unhealthy expansion. Healthy expansion through adipocyte hyperplasia protects against the metabolic complications of obesity. Unhealthy expansion through adipocyte hypertrophy promotes the obesity-associated metabolic complications. WAT, white adipose tissue; T2D, type 2 diabetes; NAFLD, non-alcoholic fatty liver disease; CVD, cardiovascular disease.

Figure 2

Molecular mechanisms of adipogenesis. Adipogenesis can be divided into two phases: commitment and terminal differentiation. Bone morphogenetic protein 4 (BMP4) induces mesenchymal progenitor cells to the adipocyte lineage as part of the adipogenic commitment. As a result of BMP4 signaling pathways, committed preadipocytes express the transcriptional activator zinc-finger protein 423 (ZNF423), a fundamental determinant of preadipocyte cell fate. The commitment phase also requires coordinated inhibition of several pathways [e.g., wingless-type mouse mammary tumor virus integration site family (WNT) and wnt1-inducible-signalling pathway protein 2 (WISP2)]. During terminal differentiation phase, committed preadipocytes arrest their growth and activate early differentiation markers, including peroxisome proliferator-activated receptor-γ (PPARγ) and transcription co-activators CCAAT/enhancer-binding protein α (C/EBPα). C/EBPα and PPARγ induce and maintain the expression of key adipogenic genes (GLUT4, AP2, and ADIPOQ), which are necessary for normal adipocyte function. WISP2, WNT1-inducible signaling pathway protein 2; DKK1, proadipogenic factors Dickkopf 1. LRP5/6, lipoprotein-receptor-related protein-5 or -6; GLUT4, glucose transporter type 4; AP2, adipocyte fatty acid-binding protein 2.