Therapeutic targeting of white adipose tissue metabolic dysfunction in obesity: mechanisms and opportunities

Figures

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  FIGURE 1. Immune spectrum in lean and obese adipose tissue. Lean adipose tissue is characterized by the presence of immune cells that promote an anti‐inflammatory environment. These immune cells, including Treg cells, eosinophils, TH2 cells, M2 macrophages, ILC2s, NKT cells, and γδT cells, play a crucial role in maintaining insulin sensitivity. Importantly, these immune cells establish residence in adipose tissue early in life. However, in obesity, the balance is disrupted as inflammatory immune cells are recruited. These include M1 macrophages, TH1 cells, CD8+ T cells, NK cells, ILC1s, and B cells. The displacement of anti‐inflammatory immune cells is facilitated by signals such as hypoxic and ER stress responses, as well as chemokines like MCP‐1/CCL2. This image is reproduced with permission from Man et al. 169 http://creativecommons.org/licenses/by/4.0/

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  FIGURE 2. Distinct modes of WAT expansion associate with metabolic health. Different expansion mechanisms of white adipose tissue upon overnutrition lead to distinct metabolic outcomes. Healthy expansion through adipocyte hyperplasia is associated with improved adipogenesis and angiogenesis, decreased inflammation, and improved insulin sensitivity. Pathological expansion through adipocyte hypertrophy is related to limited angiogenesis and promotes WAT hypoxia, fibrosis, and inflammation, ultimately leading to obesity‐associated metabolic complications.

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  FIGURE 3. Potential mechanisms of obesity‐induced insulin resistance. Chronic overnutrition induces dysfunctional white adipose tissues to release free fatty acids (FFAs), reactive oxygen species (ROS), and proinflammatory cytokines. Thus, surplus FFAs and other lipids accumulate in the cells of peripheral organs, such as muscle and liver; cause lipotoxicity; dysregulate organelles, including mitochondria and lysosomes; and inhibit the function of insulin through various signaling pathways targeting IRS kinases, including NF‐κB, P38 MAPK, JNK, and JAK–STAT, and so on, leading to insulin resistance in adipose tissues, muscles, and the liver. Dysfunctional organelles in turn increase the release of excess FFAs, proinflammatory cytokines, and ROS. Overall, obesity promotes chronic low‐grade systemic inflammation and the development of insulin resistance, eventually leading to immunometabolic dysfunction.

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  FIGURE 4. Potential signaling pathways and their roles in WAT during obesity. Under normal physiological conditions, the PI3K/AKT pathway activates GLUT4 and mTORC1 to increase glucose uptake and protein synthesis but inhibits lipolysis through FOXO1. The PI3K/AKT pathway is dysregulated in obesity, causing unhealthy AT expansion and inflammation, leading to insulin resistance. The MAPK signaling pathway is abnormally activated in obesity. Activation of MAPK signaling proteins, such as ERK1/2, JNK, and p38 MAPK, results in downstream regulation of TNFα, IL‐6, and PPARγ, leading to adipocyte hyperplasia, AT inflammation, and insulin resistance. The AMPK signaling pathway is inhibited in obesity. Thus, activation of AMPK may increase glucose uptake and decrease adipogenesis and lipogenesis, thereby improving insulin sensitivity and ameliorating obesity. ACC, acetyl‐CoA carboxylase; FAS, fatty acid synthesis; SREBP‐1c, sterol regulatory element‐binding protein 1c.

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  FIGURE 5. Potential antiobesity strategies. The figure outlines the potential antiobesity strategies discussed in the review, including pharmacological approaches, lifestyle interventions, and novel therapies and emerging targets.