Obesity affects more than one billion people worldwide and often leads to cardiometabolic chronic comorbidities. It induces senescence-related alterations in adipose tissue, and senescence is closely linked to obesity. Fully elucidating the pathways through which vitamin D exerts anti-inflammatory effects may improve our understanding of local adipose tissue inflammation and the pathogenesis of metabolic disorders.
1. Introduction
Adipose tissue (AT), traditionally considered an inert organ primarily responsible for energy storage and release, has emerged as a subject of increasing research interest in recent decades. Studies have revealed that white adipose tissue (WAT) has far more intricate functions than previously realized, exhibiting numerous connections and being responsible for multiple processes within the body. As one of the largest endocrine organs, WAT actively synthesizes hormones such as adiponectin, adipsin, apelin, leptin, resistin, and visfatin. These hormones are involved in regulating inflammation, insulin secretion, insulin sensitivity, and food intake, and they respond to both environmental and internal cues by releasing proinflammatory cytokines
[1].
In addition to adipose cells, the stromal vascular fraction (SVF), which is regarded as the local “immune system”, plays a crucial role in AT. It surrounds crown-like structures and perivascular spaces and comprises mesenchymal, endothelial, and immune cells such as macrophages, eosinophils, and Th
2 CD4+ T cells
[1]. These cells interact with sympathetic nerve endings and produce neurotrophic factors, impacting local sympathetic activity
[2]. Diverse macrophage subpopulations in AT can determine whether the environment is pro- or anti-inflammatory, with M1 macrophages releasing proinflammatory cytokines (TNFα, IL-1β, IL-12, and IL-23) and M2 macrophages producing anti-inflammatory cytokines (IL-10)
[3][4]. White-adipose-tissue-resident multipotent stromal cells (WAT-MSCs) have been shown to support both group-2 innate lymphoid cell (ILC2) activity and the proliferation of adipose tissue eosinophils (ATEs); the latter play a crucial role in maintaining the M2 polarization of macrophages
[5][6].
In humans and rodent models, obesity is characterized by an imbalance in the growth and size of adipocytes, with AT exhibiting hypertrophy in comparison to the surrounding vascular tissue
[7]. This imbalance results in regional hypoxia, apoptosis, chemokine release, and inflammatory cell recruitment. This process initiates local inflammation, later leading to systemic subclinical inflammation
[7]. The metabolic disruptions contribute to the ongoing cycle of AT dysfunction and inflammation, resulting in the development of a diversity of systemic problems in patients with obesity.
Ageing leads to a rise in the percentage of body fat and a shift in the distribution of AT from the subcutaneous layers to visceral layers (visceral AT, VAT). AT senescence increases the accumulation of senescent cells and alters the preadipocyte cell phenotype, resulting in elevated secretion of proinflammatory cytokines, which consequently contribute to the inflammageing of VAT.
Although inflammation is common in both obesity and senescence, there are key differences between obesity-related AT inflammation and inflammageing with respect to their causes and mechanism and the types of cells and inflammatory cytokines involved. Obesity is associated with early and pronounced AT senescence, and AT senescence increases the risk for obesity, suggesting that obesity and senescence, while not identical, interact and contribute to the development of subclinical inflammation associated with insulin resistance and metabolic syndrome.
Individuals with both obesity and vitamin D insufficiency exhibit elevated levels of proinflammatory cytokines, such as IL-6 and TNFα (tumor necrosis factor α). An umbrella meta-analysis showed beneficial results for vitamin D supplementation on obesity-associated inflammation
[8]. Moreover, treatment with vitamin D suppresses the generation of inflammatory markers induced by the NF-κB (nuclear factor kappa B subunit 1) pathway in human adipocytes and preadipocytes. Furthermore, the molecular mechanism by which vitamin D supplementation impacts NF-κB signaling in hypertrophic and inflamed AT is not fully understood
[9]. Of particular significance is the phenomenon of adipose cell senescence, and its link to obesity has recently attracted significant research attention. The NF-κB pathway is just one of the common pathways through which vitamin D may modulate both local inflammation and inflammageing. Identifying the common target cells and pathways of vitamin D in adipose cells and the SVF may be of interest for better understanding the mechanisms of obesity and AT senescence. This avenue of investigation has the potential to yield valuable insights and targets for improving metabolic health.
2. Vitamin D and Inflammation in Obesity
2.1. Adipocyte Dynamics in Obesity: Connections with Cellular Senescence
During the ageing process, damage from various agents accumulates in cells, which triggers senescence, leading to the loss of the cells’ ability to divide and exhibit specific characteristics
[10]. Cellular senescence occurs due to various factors: DNA damage, telomere shortening, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, mitotic stress, oxidative stress, and oncogene activation
[11][12][13]. DNA damage, especially DNA double-strand breaks, activates a response pathway, culminating in the activation of the p53/p21 axis, thereby inducing cell cycle arrest
[13]. This is characterized by irreversible cell cycle arrest in the G1 or G2 phase, orchestrated by tumor suppressor proteins and kinases such as p53, p16, and p21
[1][14][15]. Although senescent cells do not proliferate, they remain metabolically active, displaying alterations in gene expression and chromatin structure
[1].
AT is particularly susceptible to ageing, as it is among the most-affected tissues by age-related deterioration
[16] and is one of the organs where cellular senescence begins earliest
[17]. Life expectancy declines with obesity, and fat mass increases with age in both mice and humans. Caloric restriction increases lifespan, which is attributed to a reduction in the volume of VAT depots
[18]. Obesity is associated with age-related changes and an elevated number of senescent cells in AT
[19].
Cellular senescence, while advantageous for tissue repair and tumor suppression, can be detrimental when chronic, such as in obesity. One of the primary regulators of lipid homeostasis, SREBP1c (sterol regulatory element-binding protein 1), known to modulate cholesterol and fatty acid metabolism, appears to play a crucial role in protecting against adipocyte senescence. Obesity-induced DNA damage triggers adipocyte senescence. The protective role of SREBP1c involves the maintenance of genome stability, increasing PARP1 (poly (ADP-ribose) polymerase 1)’s DNA repair capability. Adipocytes deficient in SREBP1c show increased inflammation, implying that adipocyte senescence might be an early event preceding inflammatory responses in WAT in the context of obesity
[20][21].
Senescence and obesity both result in increased cellular dysfunction and inflammation. However, senescence is characterized by an increase in the number of nondividing, inflammatory cells, while obesity is characterized by expansion and proliferation of adipocytes, which are accompanied by metabolic disruptions (Figure 1).
This entry is adapted from the peer-reviewed paper 10.3390/metabo14010004