Subcutaneous white adipose tissue

Adipose tissue is divided into brown adipose tissue (BAT) and white adipose tissue (WAT). Brown adipose tissue - BAT is mainly characterized by multilocular lipid droplets and a large number of mitochondria, which confer the ability to produce heat through "non-shivering thermogenesis".

In contrast, white adipose tissue (WAT) consists of large adipocytes with a single lipid droplet and fewer mitochondria compared to BAT. This morphology gives WAT the capacity for energy storage and homeostasis in response to nutrient demand (van Marken Lichtenbelt W. 2012).

In humans, the WAT can be subdivided as follows:

• the visceral WAT (VAT) consists of the omental, mesenteric, retroperitoneal, gonadal and pericardial WAT
• the cutaneous/subcutaneous WAT (SAT). This is subdivided into a:
  • dermal WAT (dWAT) and the adjacent, deeper-lying subcutaneous WAT.
  • subcutaneous WAT.

Together with the dermis and epidermis, the subcutaneous WAT (SAT) forms the surface of the body and is essentially responsible for its contouring.

VAT and SAT have significantly different mechanical, biochemical and endocrine properties. Individuals with a high VAT mass are prone to endocrine disorders and metabolic disorders (Schlecht I et al. 2017; Shuster A et al. 2012). An increased VAT mass is directly related to a poor prognosis for metabolic diseases.

Diseases associated with obesity: Obesity is characterized by an excessive accumulation of body fat in the WAT. This is mainly due to an imbalance between energy intake and consumption. An increase in VAT and SAT masses leads to an increase in body mass index (BMI), which in turn is associated with the various comorbidities of obesity.

Obese people have a lower SAT mass. This contributes to a further deterioration of the insulin response and favors the development of T2 diabetes (Indulekha K et al.2011). This leads to the conclusion that both SAT and VAT influence insulin resistance, but with opposing roles. While an increase in SAT is associated with a better metabolic status, an increase in VAT is associated with a worsening of metabolic status.

The distribution of adipose tissue changes with both increasing adiposity and increasing age. An increase in SAT and the VAT/SAT ratio worsens the metabolic status of individuals as well as their life expectancy.

Changes in WAT with age: As with obesity, ageing is a major factor in metabolic deterioration and is associated with the development of metabolic syndrome. Ageing promotes the redistribution of WAT. There is a loss of SAT and a higher proportion of VAT (Schosserer M et al. 2018). This redistribution of WAT probably leads to a poorer metabolic status in older people compared to younger people.

Ageing affects the cell physiology of mesenchymal stem cells by altering cell proliferation capacity and plasticity and promoting cellular senescence characteristics. Aged fat cells exhibit a reduced proliferation rate and a decreased chondrogenic and osteogenic potential, which is associated with an increase in adipogenic differentiation and senescence behavior. They exhibit reduced functionality, which contributes to the metabolic impairment of adipose tissue. Adipokines are the main endocrine molecules secreted by adipose tissue and contribute to the structural and functional remodeling of WAT. These hormones are important for the chemoattraction of immune cells. They promote chronic and autocrine low-grade inflammation and are associated with several obesity-related pathologies.

The WAT consists of mature adipocytes and a stromal-vascular fraction (SVF), which includes preadipocytes, fibroblasts, endothelial cells, stem cells and immune cells. Each subpopulation in adipose tissue changes according to its metabolic status and the ageing process.

Mature adipocytes: One of the main cell types in WAT are mature adipocytes. They serve as energy stores and are able to secrete endocrine molecules that regulate metabolism. Hypertrophy of the adipocytes promotes hypoxia in the WAT. It induces latent WAT inflammation, which is associated with metabolic disorders (Shuster A et al. 2012).

The number of adipocytes in an individual's AT remains largely constant throughout life (Spalding KL et al. 2008). Obesity also does not lead to a numerical increase in adipocytes but to an increase in adipocyte hypertrophy. This activates the ERK and p38 MAPK signaling pathways, which leads to an increase in CCL2 expression in adipocytes. This contributes to macrophage recruitment and adipocyte apoptosis. The resulting release of triglycerides in turn activates the TLR4 receptors in macrophages, which activates the IKK/NF-κB signaling pathway and thus TNF-alpha secretion. Both triglycerides and TNF-alpha are crucial for the development of insulin resistance, as they inhibit the IRS-1 signaling cascade and influence glucose uptake into the AT. Thus, an increase in WAT promotes the infiltration of proinflammatory immune cells, increased secretion of cytokines. The prognosis of related metabolic diseases is worsened.

Preadipocytes: Preadipocytes are the precursor cells of adipocytes. They play an essential role in adipogenesis. This is also related to the metabolic status and age of the test subjects. The adipogenic capacity of subcutaneous preadipocytes is higher than that of preadipocytes from visceral or omental adipose tissue. The number of differentiated preadipocytes is significantly higher in lean women than in obese women. Women with a higher degree of obesity (BMI > 35 kg/m2) are more susceptible to apoptosis stimuli than lean women with a lower degree of obesity (BMI < 35 kg/m2).

Immune cells:

• Macrophages: Macrophages were the first immune population described in AT (ATMs). ATMs can be roughly divided into M1 with a proinflammatory phenotype and M2 with an immunosuppressive phenotype. Both subpopulations are present in the adipose tissue (AT) in different proportions, whereby the total number of macrophages per gram of WAT is comparable in subjects with similar BMI in SAT and VAT (Lesna IK et al. 2017).
  The M1 phenotype is predominantly found in obese WAT and in high proportions in subjects with metabolic complications. Hypertrophy of WAT increases chemokine expression (CCL2) in adipocytes, the secretion of adipokines. This leads to the recruitment of M1 macrophages (Tourniaire F et al. 2013). With an increase in weight and thus also in adipocyte size, there is an increase in M1 macrophages (M1 type) (Weisberg SP et al. 2003). WAT-infiltrated ATMs are responsible for the expression of TNF-alpha, MCP-1, IFN-gamma, iNOS and interleukin-6 in the WAT. Importantly, the number of macrophages in the WAT is higher in obese subjects than in lean subjects. AT-M1 macrophages show a higher infiltration and a stronger correlation with BMI than VAT-M1 macrophages.
• Aging is characterized (analogous to obesity) by an increase in the number of macrophages of the M1 phenotype and a decrease in macrophages of the M2 phenotype in WAT. A comparison of the number of ATMs in premenopausal and postmenopausal women showed that the M1 phenotype occurred more frequently in older test subjects in the VAT than in the SAT (Kralova Lesna I et al.2016). Animal experiments show that the M1/M2 ratio increases with age, suggesting the promotion of a proinflammatory phenotype. Studies investigating the influence of weight loss on the number of ATMs showed a decrease in the M1 phenotype after weight reduction. An increase in BMI is associated with higher macrophage infiltration in the AT and subsequently with a deterioration in insulin sensitivity.
• T cells: ^CD4+Tcells are divided into regulatory T cells (Tregs) and T helper cells (Th helper cells: Th1, Th2 and Th17 cells). Both obesity and aging promote the infiltration of T cells in the WAT, favoring a pro-inflammatory state (favoring the development of metabolic diseases). The infiltration of adipose tissue with Th2 cells is associated with an anti-inflammatory response. It is accompanied by WAT hypertrophy and is associated with metabolic complications.
• ^CD4+ T-regulatory cells (Treg): Tregs have an immunomodulatory role as they are responsible for the control of adipose tissue inflammation and the development of IR. Animal experiments have shown the presence of a higher proportion of Tregs in SAT and VAT in lean mice (compared to obese mice). Obesity leads to a reduction of Tregs in adipose tissue and to a change in the signature of the remaining Treg population. In contrast, aging promotes an increase in Treg infiltration in the AT. These findings suggest that Tregs prevent adipose tissue inflammation in obesity. However, the number of Treg cells is increased in aging models, so further evidence is needed to determine their role in the aging process.
• ^CD8+ T cells: This T cell subtype is characterized by the secretion of IFN-gamma. Its population increases with obesity and with ageing in VAT and SAT (Travers RL et al. 2015). CD8+ ^gene expression also correlates with BMI in SAT. Depletion of CD8+ ^T cells improves glucose tolerance, insulin sensitivity and inflammation of adipose tissue. Increased infiltration of CD8+ T ^cells leads to macrophage recruitment and M1 polarization, which in turn increases adipose tissue inflammation.
• B cells: An increase in B cells infiltrating the WAT has been observed in obesity and aging. In animal experiments, B1 accumulation correlates with age in VAT, but not in SAT, suggesting that these cells may contribute to age-related metabolic diseases. Drug-impaired B cell function leads to an improvement in age-related isulin resistance.
• Inflammaging is a chronic inflammation that occurs in the elderly (Muller L et al. 2019) and parallels insulin resistance in the elderly.
• B2 cells: Mice have an increased number of B2 cells in the VAT in both obesity and old age.
• Dendritic cells: The number of dendritic cells (DCs), i.e. conventional DCs (cDCs as antigen-presenting cells) and plasmacytoid DCs are increased in adipose tissue of obese subjects (Merad M et al. 2013). Obese mice show increased accumulation of DCs in WAT with higher gene expression levels for IL-2, IL-1α, IFN-gamma and IL-1beta, but not for IL-6 and TNF-alpha. It is likely that pDCs act as a source of IFN secretion and M1 polarization and consequently promote inflammation and insulin resistance in obesity (Ghosh AR et al. 2016). These findings suggest that DC infiltration and the resulting IFN-1 secretion contribute to a proinflammatory phenotype. The role of DCs in senescence remains to be clarified.

Changes in immune cells infiltrating the WAT in obesity and aging:

Immune cells are responsible for maintaining homeostasis in adipose tissue by secreting anti-inflammatory cytokines via M2, Tregs, Th2, Bregs and B1 cells (lymphocytes), which contributes to the maintenance of insulin sensitivity. In obese or aged WAT, there is an increase in proinflammatory immune cells such as M1, Th1, CD8+ T, 4BL and B2 cells. This shift leads to adipose tissue dysfunction and insulin resistance. Diets that lead to weight loss contribute to an improvement in metabolic status (Rossmeislová L et al. 2013).

Inflammaging: Aging, like obesity, is characterized by chronic, low-grade systemic inflammation in multiple tissues due to immune system dysregulation - "inflammaging" (Franceschi C et al. 2014). As adipose tissue ages, inflammaging contributes to the development and progression of metabolic diseases in older people and impairs their life expectancy.

Adipose tissue remodeling in old age: Obesity-associated metabolic complications are also observed in old age and are associated with a shortened lifespan. In this context, metabolic interventions that lead to weight loss also increase life expectancy (Masoro EJ 2006; Picard F et al. 2005). Rapamycin-treated obese mice, IRS1-null and S6K1-null mice showed limited adipogenesis and increased lifespan. This suggests that fat accumulation contributes to the reduction of life expectancy in old age.

Role of extracellular matrix in adipose tissue and fibrosis: In late stages of obesity, there is an accumulation of extracellular matrix (ECM) proteins and subsequent fibrosis of adipose tissue, which is associated with the proinflammatory phenotype observed in obesity. Studies in obese humans and mouse models have shown that collagen expression in the WAT is increased in obese subjects and correlates with insulin resistance, inflammatory markers, the size of fibrotic areas and the number of infiltrated macrophages (Reggio S et al. 2016). In addition, COL6 (collagen-6) knockout mice showed less AT fibrosis and inflammation and improved glucose metabolism.

Apoptosis and adipose tissue: Adipocyte apoptosis and fibrosis are crucial events that promote AT macrophage infiltration and subsequently the development of obesity-associated metabolic diseases. The AT of obese mice showed greater hypertrophy and inflammation, events typically associated with a proapoptotic phenotype. Evidence suggests that adipocyte apoptosis may be the origin of macrophage infiltration in the AT and thus trigger obesity-associated diseases. These findings suggest that apoptosis and fibrosis of the AT is higher in older people, which in turn promotes metabolic diseases.

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