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Immunology 3, Main points: Obesity results in enlarged adipocytes -…
Immunology 3
Role of inflammation in obesity
During the development of obesity, adipose tissue shows increased macrophages infiltration, with greater pro-inflammatory M1 activation as opposed to the M2 phenotype in lean subjects.
Obesity also results in adipokine profile shifting towards elevated pro-inflammatory adipokines such as leptin and reduced levels of anti-inflammatory adipokines such as adiponectin. There will also be increased production of cytokines TNF-alpha, CNP, IL-6.
Consequently, these AT macrophages secrete high levels of pro-inflammatory cytokines, resulting in obesity-associated chronic low-grade inflammation.
Intracellularly, several pathways have been hypothesized to induce the pro-inflammatory activation of macrophages in AT including the Toll-like receptor (TLR4).
TNF-alpha and IL-6 are known to promote lipolysis and the secretion of FFA.
Visceral fat is an important site for IL-6 secretion
and provide a potential link between visceral fat and systemic inflammation in individuals with abdominal obesity.
In adults, the amount of brown adipose tissue is inversely correlated to BMI, especially in older people.
On the other hand, white adipose tissue is found to regulate physiologic and pathologic processes, including immunity and inflammation.
Adipose tissue produces and releases a variety of pro-inflammatory and anti-inflammatory factors, including the adipokines leptin, adiponectin, and resistin, as well as cytokines and chemokines, such as TNF-α, IL-6, and MCP-1.
Enlargement of adipocytes
(obesity) is associated with an increase in physical stress and ROS production, and increased secretion of FFA and inflammatory cytokines.
Adipocyte hypertrophy can lead to cell rupture
Explain which chemokines/cytokines are central in the development of atherosclerosis
Vasocrine Signalling
Excess intake of calories results in increased deposition of perivascular adipose tissue around vessels. The overproduction of adipokines, and signalling from perivascular fat deposits to the arteries could then lead to inflammation and atherosclerosis
The most potent inhibitor of (insulin and) endothelial nitrogen oxide dependent vasodilation among cytokines is
TNF-alpha
It is suggested that a high concentration of cytokines leads to a blunted activation of endothelial Nitrogen Oxide synthesis and increased release of ethlin-1, restyling in the constriction of the arteriole (blood vessels).
Epicardial Adipose Tissue:
Epicardial fat reflects cardiac and visceral adiposity and is related to intima-media thickness, an increase in vascular stiffness and inflammation
Enlargement of adipocytes
(obesity) is associated with an increase in physical stress and ROS production, and increased secretion of FFA and inflammatory cytokines.
MCP-1 (cytokine) is secreted from the macrophage and are also expressed before inflammatory macrophage markers. They will attract more macrophages. These circulating mononuclear cells are in pro-inflammatory state and are key players in endothelial dysfunction (which is a risk factor for atherosclerosis).
Possible involvement of adipokines in insulin resistance
Large adipocytes are more frequently found in subjects with impaired glucose tolerance and type II diabetes.
Insulin receptor substrate-1 (IRS-1) is a key molecule in the insulin signalling pathway, and failure to activate IRS-1 leads to system insulin resistance
Inhibitory phosphorylation of IRS-1 can be induced through inflammatory agents such as TNF-alpha and IL-6, but also through activation of receptors such as toll-like receptors or intracellular molecules such as lipids or ROS.
Consequence of decreased insulin production as a result of lipid accumulation in the pancreas combined with diminished activation of the insulin receptor in adipocytes results in impairment of insulin stimulated glucose transport, a reduced anti-lipolytic effect and an increase in the amount of FFA released.
These effects will lead to the development of insulin resistance, type II diabetes and CVD.
What are chemokine and cytokines?
Cytokines are not structurally linked together by an amino acid sequence motif or three-dimensional structure but rather through their biological activity
Chemokines are linked structurally together by differences in their amino acid sequence motif
Cytokines are an exceptionally large and diverse group of pro- or anti-inflammatory factors that are grouped into families based upon their structural homology or that of their receptors. Chemokines are a group of secreted proteins within the cytokine family whose generic function is to induce cell migration
Main points:
Obesity results in enlarged adipocytes --> associated with increase secretion of FFA, inflammatory cytokines (TNF-alpha, IL-6, CNP) --> IL-6 is associated with visceral obesity
Development of obesity result in adipose tissue having greater macrophage infiltration with greater pro-inflammatory M1 activation than M2 phenotype in lean subjects --> macrophage will secrete pro-inflamamotry cytokines --> To maintain AT homeostasis in this lipid-rich microenvironment, macrophages increase their adiposity by activating lysosomal lipid metabolism