patients as potential ligands of TLR4 (Epitope

patients and therefore, negatively correlates with insulin
sensitivity. It has often been proposed to mediate a crosstalk between
adipocytes and macrophages. Metabolic endotoxemia is detected by TLR2 inducing
pancreatic islet inflammation. As a result, high-fat diet, ceramides and other
stress proteins (DAMPs) behave as potential ligands of TLR4 (Epitope Sharing)
both in adipocytes and macrophages leading to an elevated secretion of
in?ammatory cytokines like TNF? and IFN?, macrophage in?ltration and a
change in macrophage polarization towards an M1 in?ammatory phenotype (ATM).

INNATE
IMMUNITY
Nucleotide oligomerization domain (NOD) 1 and 2 are intracellular proteins that
recognize cell wall peptidoglycan moieties from gram-negative and gram-positive
bacteria, respectively. Peptidoglycan-induced activation of NOD1 in adipocytes or
hepatocytes and NOD2 in muscle cells trigger insulin resistance through the
production of in?ammatory mediators and the activation of MAP kinases signaling
leading to desensitization of IRS1 function. Four different inflammasomes
namely NLRP1, NLRP3, NLRC4 and AIM2 which are activated by pathogen and danger associated
signals leading to the processing of IL-1? and IL-18 by caspase-1. The
expression of NLRP3 and caspase-1 is also increased in adipose tissue of obese
mice and overweight subjects with type 2 diabetes. Findings suggest that the NLRP3
inflammasome is activated by fatty acids and ceramides expressed in a lipotoxic
environment in obesity. Other molecules such as ATP, glucose, oxidized LDL,
uric acid and crystals of cholesterol that are elevated in obesity contribute
to the activation of inflammasome and production of ROS.

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ADIPOSITY AND HORMONES
Visceral adipocytes that surround organs are very active and responsive
cells. Not only do they generate hormones such as leptin that regulate metabolism,
but also secrete a variety of proinflammatory mediators, including TNF? and
IL-6. Leptin, a polypeptide hormone that is produced by adipocytes in
proportion to triglyceride content, links changes in body fat stores to
adaptive responses in the central control of energy balance. When fat mass decreases,
the level of plasma leptin falls so that appetite is stimulated until the fat
mass is recovered. However, in obese individuals where the concentration of
free fatty acids is extremely high, higher leptin levels prevail. As a result,
the threshold for “feelings of satiety” increases than normal. High glucose
levels further impair leptin’s ability to cross the blood-brain barrier
promoting obesity.

Excess adiposity induces a switch from Th2
immunoregulatory cell types to CD4 Th1 IFN? synthesising immunoinflammatory
cells. Researches in this field have proven that adipose tissues behave like
endocrine organs that secrete hormones or cytokines termed as adipokines.
Adipokines play crucial roles in the regulation of appetite and satiety
control, energy expenditure, insulin sensitivity and insulin secretion,
endothelial function and blood pressure. A number of adipokines that have been identified
include IL-6, resistin, retinol-binding protein 4 (RBP-4), omentin, chemerin,
progranulin and monocyte chemoattractant protein-1 (MCP-1). Adiponectin is a
30-kDa secretory hormone produced predominantly by adipocytes, the expression
and secretion of which is elevated during adipocyte differentiation. In the
liver, adiponectin stimulates glucose and FA oxidation through activation of
the AMPK pathway and reduces lipogenesis by minimizing SREBP-1c expression.
However during obesity, adiponectin levels show a drastic depletion indicating
a role for hypoadiponectinaemia in relation to insulin resistance.

Further, obesity-associated systemic inflammation is
characterized by increased circulating concentrations of proinflammatory
cytokines and chemokines, and activation of several kinases that regulate
inflammation, including c-Jun NH2 terminal kinase, I?B-kinase ?/ nuclear factor
?B and mammalian target of rapamycin/S6 kinase that interfere with insulin
action in adipocytes and hepatocytes.

SOCS PROTEINS
The
Suppressor of Cytokine Signalling (SOCS) is a signal transducer and activator
of transcription induced Stat inhibitor. They are induced by several
inflammatory cytokines and are involved in a negative feedback loop leading to
the termination of cytokines action. Several cellular studies have demonstrated
that SOCS negatively regulate the signalling pathway of hormones including
leptin and insulin. SOCS1, SOCS6, and SOCS7 are also involved in the
desensitization of insulin signalling. SOCS3 inhibits insulin signalling by a
direct binding phosphorylation of IRS2. SOCS1 and SOCS6 also inhibit the
tyrosine kinase activity of the insulin receptor. In obesity, inflammation
leads to an up-regulation of SOCS proteins in hypothalamus, liver, muscles, and
adipose tissue.

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