Immunophysiology of obesity презентация

adipose tissue accumulation is a major risk factor for cardiometabolic disease, whereas subcutaneous fat seems to be neutral or protective. Other adipose tissue depots of note include the epicardium, the perivascular space, and bone marrow, but the functional significance of these tissues is largely unknown. Brown adipose tissue occurs in the supraclavicular and paraspinal regions. In contrast to white adipose tissue, brown adipose tissue is metabolically active, and it functions to utilize fuel to produce heat. In addition, ectopic lipid can accumulate in tissues, such as liver, in metabolically dysfunctional organisms.

of signaling pathways enabling the organism to adapt to a wide range of different metabolic challenges, such as starvation (голод), stress, infection, and short periods of gross energy excess. The functional pleiotropism of adipose tissue relies on its ability to synthesize and release a huge variety of hormones, cytokines, complement and growth factors, extracellular matrix proteins, and vasoactive factors, collectively termed adipokines. Obesity is associated with adipose tissue dysfunction leading to the onset of several pathologies including type 2 diabetes, dyslipidemia, nonalcoholic fatty liver, or hypertension, among others.
The mechanisms underlying the development of obesity and its associated comorbidities include the hypertrophy and/or hyperplasia of adipocytes, adipose tissue inflammation, impaired extracellular matrix remodeling, and fibrosis together with an altered secretion of adipokines. Recently, the potential role of brown and beige adipose tissue in the protection against obesity has been also recognized. In contrast to white adipocytes, which store energy in the form of fat, brown and beige fat cells display energy-dissipating capacity through the promotion of triacylglycerol clearance, glucose disposal, and generation of heat for thermogenesis. Identification of the morphological and molecular changes in white, beige, and brown adipose tissue during weight gain is of utmost relevance for the identification of pharmacological targets for the treatment of obesity and its associated metabolic diseases.

secreted by the adipocyte is growing rapidly. Several of these proteins/factors act as endocrine hormones, for example, leptin, IL-6, whereas others act locally, for example, TNF-a and the growth factors. The endocrine proteins/factors are proposed to influence distant tissues such as the liver, skeletal muscle or brain to modulate insulin action, that is, the 'endocrine hypothesis'. Paracrine/autocrine factors may also modulate insulin action if they promote or inhibit adipocyte proliferation and/or differentiation.

AC: articular chondrocytes, PMN: neutrophils, MMP: metalloprotease, COX-2: cyclooxygenase 2, ROS: reactive oxygen species, iNOS: inducible nitric oxide synthase, CC-CK: CC-chemokines, TG2: transglutaminase 2, and TERA: transitional endoplasmic reticulum ATPase.

macrophages, that is, M1 or classically activated (pro-inflammatory) macrophages and M2 or alternatively activated (anti-inflammatory) macrophages. Under lean condition, adipocytes secrete factors that promote M2 activation of macrophages, such as interleukin-4 (IL) and interleukin-13 (IL-13). M2 macrophages secrete anti-inflammatory mediators. On the other hand, adipocytes secrete pro-inflammatory FFAs, chemokines, and cytokines under obese condition. Activated M1 macrophages produce large amounts of pro-inflammatory cytokines, thereby accelerating inflammatory responses in adipose tissue through paracrine interaction between adipocytes and macrophages.

of the cells in adipose tissue, during obesity they constitute up to 50% of all adipose tissue cells.

In lean adipose tissue, T-helper type 2 (TH2) cells produce anti-inflammatory cytokines such as interleukin (IL)-4, 10, and 13 which promote alternatively activated M2 macrophage polarization. M2 polarization is also induced by regulatory T cells (Tregs) and eosinophils via IL-4. M2 macrophages secrete other anti-inflammatory signals such as IL-10 which maintain insulin sensitivity within lean adipose tissue. Conversely, TH1 type cytokines such as interferon (IFN)-γ stimulate M1 macrophage polarization in obese adipose tissue. Other immune cells are also increased in obese adipose tissue which contribute to insulin resistance including mast cells, B cells, and immunoglobulins (Igs). CD8(+) T cells promote Adipose tissue macrophages (ATM) accumulation and proinflammatory gene expression and are also increased as well. Contrary to the lean state, in which ATMs are distributed throughout the adipose tissue exposing limited inflammatory properties, ATMs in obese adipose tissue are located around dead adipocytes and form so-called crown-like structures (CLSs) while displaying profound proinflammatory features. Macrophage presence in CLSs within obese adipose tissue has been directly linked with insulin resistance.
M1 macrophages are proinflammatory, secreting cytokines such as TNF-α and IL-1β. Macrophages are bone-marrow-derived myeloid cells hence both M1 and M2 macrophages express the myeloid cell surface markers F4/80 and CD11b. However, only the M1 population expresses the marker CD11c.

during health and disease

• In addition to conventional functions such as clearing cellular debris and participating in tissue immune surveillance, lipid buffering is an important function of ATMs

• Obesity-induced inflammation, characterised by an elevated number of proinflammatory macrophages in adipose tissue, has been suggested to contribute to systemic insulin resistance

• Their origin, as well as a combination of peripheral changes and adipose tissue-derived stressors, probably contribute to ATM dysfunction and inflammatory traits during obesity

• Identification of transcriptional differences between ATMs from lean vs obese adipose tissue at several key points during the development of obesity and insulin resistance
may reveal upstream triggers, regulatory factors and intracellular pathways that shape ATM function

• Targeting metabolic capacity rather than the inflammatory phenotype of ATMs may hold potential to restore ATM function and adipose tissue homeostasis in obese individuals

of white and brown fat mass and their metabolic activity via sensory innervation and metabolic and hormonal signals traveling through the general circulation. Two main brain areas are involved in this detection the hypothalamus (Hypo) and the brain stem (NTS for Nucleus of the Tractus Solitarius). In turn the brain modulates adipose tissues activity via the autonomic nervous system mainly the sympathetic one.

Apart its well-known effect on lipolysis, sympathetic nervous system plays a role in regulating the anabolic pathways . Thus it has been shown that stimulation of sympathetic nerves has no main effect on glucose uptake, utilization and lipogenesis in WAT. Whereas, as already mentioned, there are evidences that PNS innervation increases insulin sensitivity in WAT.

Brown adipose tissue activity is mainly under the control of the sympathetic system via the binding of norepinephrine on beta adrenoceptor that induces lipolysis. This leads to an enhanced thermogenesis. Norepinephrine induces also an increase lipolysis by stimulating its gene transcription.

more recently, the progression of obesity has also been attributed to a shift in immune function from an M2 to M1 type responses.
Work by both Spiegelman and Lumengetal demonstrate critical interactions between adipose tissue metabolism and the immune system, and the active role of adipose tissue macrophage (ATM) polarization in the progression of obesity. Lean individuals in a non-inflammatory state maintain a relatively low percentage (~10–15%) of resident ATMs. Healthy adipose tissue consists of uniformly distributed alternatively activated M2 macrophages. The M2 polarized state in healthy adipose tissue is maintained by eosinophils, which secrete IL-4. Polarized M2 ATMs secrete interleukin-10 (IL-10), which regulates glucose homeostasis within adipose tissue and systemic tissues including muscle. In turn adipose resident invariant natural killer Tcells (iNKT) induces the M2 phenotype through secretion of IL-10. Healthy adipocytes, in turn, secrete anti-inflammatory adipokines such as adiponectin, a hormone that acts synergistically with IL-4 to exert anti-inflammatory effects.

a common origin of these two cell types. Studies have shown not only cross-talk between ATMs and adipocytes, but a great deal of plasticity between these two lineages compartments. Furthermore, while still controversial several studies have suggested that some adipocytes and adipose progenitors may be hematopoietic stem cell-derived. In addition, Coussin et al.(2013) have shown that hematopoietic stem cells that can reconstitute lethally irradiated recipient mice exist within adipose tissue, and more recent studies have supported the concept that adipose tissue is an extramedullary source of hematopoietic stem/progenitor cells. Yet other studies have demonstrated the phagocytic capacity of pre-adipocytes and adipocytes suggesting they can adopt macrophage-like functions.

In the late 2000s, Lumeng et al. identified adipose tissue inflammation as an important early event in the development of obesity related complications.

maintain oxygen supply and critical nutrients to promote adipose tissue homeostasis. However, under pathological conditions, the existing adipocytes enlarge, angiogenesis is limited, and tissue hypoxia ensues, resulting in the recruitment of inflammatory cells.

regulate the development and the thermogenic function of brown and beige adipocytes. Conversely, brown beige adipocytes might also promote nerve remodelling by producing neurotrophic factors, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neuregulin 4 (NRG4). 

b | Brown and/or beige adipocytes and vasculature. Adipocytes secrete vascular endothelial growth factor (VEGF) to stimulate angiogenesis. The enhanced vasculature provides increased nutrition and oxygen to sustain thermogenesis in brown and beige adipocytes, thereby promoting energy expenditure and insulin sensitivity. 

c | Immune cell regulation of beige adipocytes. Interleukin-33 (IL-33) (of unknown cellular source) activates group 2 innate lymphoid cells (ILC2s), which secrete IL-13 and IL-5. IL-5 activates eosinophils, which produce IL-4. IL-4, in turn, induces the differentiation of M2 macrophages, which provide a crucial source of catecholamines for beige fat activation. IL-4 (from eosinophils or ILC2s) also acts directly on platelet-derived growth factor receptor-α (PDGFRA)+ precursors to increase their proliferation and differentiation into beige adipocytes. Furthermore, ILC2s secrete Met-encephalin peptides to promote beige adipocyte differentiation. Meteorin-like protein (METRNL) secreted by muscle and WAT activates eosinophils and type II cytokine signalling to drive beige adipocyte development.

conditions, including:
Coronary heart disease
High blood pressure
Stroke
Type 2 diabetes
Cancer
Sleep apnea (внезапная остановка дыхания во сне)
Gallstones (желчный камень)
Osteoarthritis