Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders

Abstract

The adipose tissue is a central metabolic organ in the regulation of whole-body energy homeostasis. The white adipose tissue functions as a key energy reservoir for other organs, whereas the brown adipose tissue accumulates lipids for cold-induced adaptive thermogenesis. Adipose tissues secrete various hormones, cytokines, and metabolites (termed as adipokines) that control systemic energy balance by regulating appetitive signals from the central nerve system as well as metabolic activity in peripheral tissues. In response to changes in the nutritional status, the adipose tissue undergoes dynamic remodeling, including quantitative and qualitative alterations in adipose tissue-resident cells. A growing body of evidence indicates that adipose tissue remodeling in obesity is closely associated with adipose tissue function. Changes in the number and size of the adipocytes affect the microenvironment of expanded fat tissues, accompanied by alterations in adipokine secretion, adipocyte death, local hypoxia, and fatty acid fluxes. Concurrently, stromal vascular cells in the adipose tissue, including immune cells, are involved in numerous adaptive processes, such as dead adipocyte clearance, adipogenesis, and angiogenesis, all of which are dysregulated in obese adipose tissue remodeling. Chronic overnutrition triggers uncontrolled inflammatory responses, leading to systemic low-grade inflammation and metabolic disorders, such as insulin resistance. This review will discuss current mechanistic understandings of adipose tissue remodeling processes in adaptive energy homeostasis and pathological remodeling of adipose tissue in connection with immune response.

Keywords: adipose tissue; adipose tissue macrophage; hypertrophic adipocyte; iNKT cell; inflammatory response; metabolic disorder; obesity.

Figure 1

Adipose tissue functions in energy homeostasis and thermal regulation. (A) In humans, BAT localized around the shoulders and ribs contributes to heat generation. Brown adipocytes exhibit abundant mitochondria and UCP-1 expression related to thermogenesis. It has recently been speculated that BAT efficiency for fat-burning could be harnessed to reduce obesity. Visceral WAT (VAT) and subcutaneous WAT (SAT) possesses considerable capacities for energy storage. VAT surrounds intra-abdominal organs, whereas SAT spreads throughout the body beneath the skin. These fat tissues secrete various adipokines to regulate energy homeostasis. VAT is more strongly associated with obesity-induced metabolic disorders than SAT. (B) In adult mice, BAT is well developed and easily observed compared with that in adult humans. Among WAT depots within the abdominal cavity, the paired gonadal depots located around the ovaries in females and the testes in males are studied as a model of VAT. However, these depots do not exist in humans. The paired inguinal depots in the anterior to the upper part of the hind limbs are representative SATs in mice.

Figure 2

Characteristics of hypertrophic and hyperplasic adipocytes. In obesity, adipose tissue expansion occurs by two different mechanisms. Hypertrophic adipose expansion through increased adipocyte size is associated with such harmful phenomena as increased basal fatty acids release, pro-inflammatory cytokine release, immune cell recruitment, hypoxia, fibrosis, decreased adiponectin, and impaired insulin sensitivity. On the other hand, hyperplasic adipose expansion though increased adipocyte number is linked to beneficial phenomena, such as increased adiponectin, decreased basal fatty acids release, pro-inflammatory cytokine release, immune cell recruitment, hypoxia, fibrosis, and improved insulin sensitivity.

Figure 3

Actin cytoskeleton and insulin-stimulated GLUT4 translocation control in adipocytes. In adipocytes, cytosolic and cortical actin organization is involved in GLUT4 storing vesicle (GSV) transport by insulin stimulation. When adipocytes are hypertrophied, enlarged unilocular lipid droplets and expanded cell volume may impede cortical actin dynamics, resulting in improper/deficient translocation of GSVs. This indicates the importance of the adipocyte cytoskeleton in the regulation of adipocyte glucose metabolism in response to insulin.

Figure 4

Balance of immune responses in the regulation of adipose tissue function. Lean adipose tissue harbors various anti-inflammatory immune cells, such as eosinophils, M2 macrophages, Th2 cells, iNKT cells, and Treg cells. These immune cells help in maintaining insulin sensitivity and store extra energy in the form of TGs. In obese adipose tissue, the numbers of pro-inflammatory immune cells, including neutrophils, M1 macrophages, mast cells, Th1 cells, and CD8 T cells, are greatly elevated. Simultaneously reduced number of anti-inflammatory immune cells accelerates pro-inflammatory response and adipose tissue dysfunction.

Figure 5

Invariant natural killer T (iNKT) cell-mediated regulation of anti-inflammatory response in the adipose tissue. Adipocytes secrete various inflammation-inducing factors including FFAs upon excess energy intake, such as HFD. In addition, antigen presentation by CD1d on adipocytes could activate iNKT cells, which rapidly secrete great quantities of cytokines, such as IL-4, IL-2, and IL-10. IL-4 produced by iNKT cells induces macrophage polarization into M2 type and arginase expression. IL-2 secretion by iNKT cells promotes Treg cell function in the adipose tissue. Activation of anti-inflammatory responses mediated by iNKT cells could play a crucial role in the suppression of excessive pro-inflammatory response in the adipose tissue upon HFD.