Adipose tissue in immunity

KARNATAKA VETERINARY, ANIMAL AND FISHERIES SCIENCES UNIV`ERSITY

VETERINARY COLLEGE, BENGALURUDEPT. OF VETERINARY BIOCHEMISTRY

ADIPOSE TISSUE IN IMMUNITY

Major advisor:Dr. V GIRISH KUMARCo-guide:Dr. V SEJIAN

Presented by,Dr. VIDYA M KMVHK 1519

Major credit seminar, Dept of Vety. Biochemistry, VCH, Hebbal, Bangalore

Plan of talk

Introduction

Structure of adipose tissue

Adipokines secreted by the adipose tissue

Immune cells in the adipose tissue

Interplay between adipose tissue and immunity

Conclusion


Introduction

• Complex, multidepot, anatomically dissectible discrete structure with a high metabolic activity.

• It comprises of two types of adipocytes, white and brown, each of which differ in their anatomy and physiology.

• Important functions:- Insulating layer- Mechanical protection- Energy storage


Mere fat storage sink????

Discovery of leptin


Produces many bioactive molecules, called adipokines, which regulate systemic metabolism and also possess immuno-regulatory properties.

Increased or altered production of these factors in obesity may lead to insulin resistance and metabolic syndrome.

Introduction contd..

Certain cytokines produced by AT include monocyte chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6), tumor necrosis factor (TNF-α), plasminogen activator inhibitor (PAI-1) and a few others.


• Loose fibrous connective tissue with cells that are specialized for storage of triglycerides.

• Complex; high metabolic activity.• Two types of adipocytes, white and brown.

a.White adipocyte store lipids.b.Brown adipocytes oxidize these lipids to produce heat (non-shivering thermogenesis) with the help of uncoupling protein (UCP1), a mitochondrial protein. This protein is found only in brown adipocytes .

(Cannon et al., 1982)

Structure and salient properties


Types of adipocytes

White adipocytes• Spherical• Unilocular• Diameter of 40μ to 160μm• Surrounded by distinct basal

membrane• Have elongated and thin

mitochondria with randomly oriented cristae.

Brown adipocytes• Polygonal• Multilocular• Diameter (15μ to 50μm).• Have large and numerous

mitochondria in the cytoplasm denser blood supply and nerve supply.

• Their numbers are more in young ones.

(Blanchette et al., 1995; Cinti, 2009)


• White and brown adipocytes are often found interspersed with one another and their relative amount is genetically determined and depends on age, sex, environmental temperature and nutritional status.

(Cinti, 2009)

• This is due to their plasticity to transdifferentiate reversibly into one another during biological energy demands.

• Eg. Exposure to cold;Exposure to warm;Pregnancy/lactation.

Transdifferentiation


• A study conducted by DiGirolamo et al (1998) proposed the “critical cell size” concept i.e., the maximum volume of adipocyte above which it cannot be hypertrophied and they undergo hyperplasia.

Adipose tissue is diffused in the body superficially and deeply as subcutaneous adipose tissue (SCAT) and visceral adipose tissue (VAT), respectively.

(Cinti, 2009)


Properties VAT SCAT

Inflammatory and immune cells More Less

Large adipocytes More Less

Glucocorticoid and androgen receptors More Less

Transdifferentiation capacity Low High

Metabolic activity Highly active Low

Lipolysis More sensitive Less

Insulin resistance More Less

Capaticity to generate FFA More Less

Capacity to uptake glucose More Less

Sensitivity to adrenergic stimulation More Less

(Wajchenberg, 2000; Ibrahim, 2009; Freedland, 2004)


• Adipokines• Immune cells• Connective tissue matrix• Nerve tissue• Stromal vascular cells• Together these components function as an integrated unit

which contribute to the inflammatory status of the body.

(Kershaw and Flier, 2004)

What attracts AT to be highly researchable issue ???!!!!


Adipokines

• Adipose tissue is capable of synthesizing a diverse group of peptides, proteins and cytokines.

• Adipokines are the bioactive peptides produced by the endocrine adipose organ which regulate systemic metabolism and also possess immunoregulatory properties.

• Eg. Leptin, adiponectin, visfatin, apelin, vaspin, omentin, resistin, hepacidin, etc.

(Trayhurn and Wood 2004)


• “The satiety hormone”• Zhang et al., 1994• Appetite.• Atherogenic. • Haematopoiesis and angiogenesis.• Puberty. • Obesity is associated with elevated leptin levels.• Leptin is a sensitive marker for predicting cardiovascular

risk and the metabolic syndrome.(Lago et al., 2007; Umemoto et al., 1997; Bouloumie et al., 1998)

Leptin


• It promotes survivability and maturation of DCs. • It increases the proliferative and phagocytic capacity of

macrophages and monocytes. It also promotes infiltration of macrophage into the wound site. (Goren et al., 2003)

• Stimulates chemotaxis. (Belouzard et al.,2006)

• Leptin promotes longevity of naive T cells and survivability of B cells.

• The production of TNF-α , IFN-γ and IL-2 are also enhanced.• Switching of cytokine production from T cell towards Th1

phenotype. (Faggioni et al., 2001)

Role of leptin in innate & adaptive immunity


Adiponectin

• Adiponectin is decreased in abdominal obesity.

(Shklyaev et al, 2003; Wolf et al., 2006; Ouchi et al., 1999)

Anti-atherogenic

Anti-diabetic

Anti-inflammatory


Resistin

• Induces insulin resistance.• Otherwise known as FIZZ3.

(Banerjee and Lazar, 2003)

(Reilly et al., 2005)

(Steppan et al., 2001)

Atherogenic

Pro-diabetic

Pro-inflammatory


Visfatin

• Produced by endotoxin stimulated neutrophils, wherein it helps to prevent the apoptosis.

• Induces chemotaxis.• Mimics the action of insulin by binding and activating the

insulin receptor thereby decreasing the insulin resistance.• Lowers plasma glucose concentrations.

(Fukuhara et al., 2005) (Jia et al., 2004)


Adipsin

• Also called as factor D, is involved in complement activation and metabolic control.

• Increased adipsin level reported with:- Adiposity,- Insulin resistance,- Dyslipidemia, and- Cardiovascular disease.

(Cianflone et al., 2003)


Amalgamation between metabolism and immunology in AT

• A close anatomical interaction with lymphoid organs.• Adipocytes are far more than lipid-storage cells.• Immune cells are co-localized with adipocytes in adipose

tissue.• Excess of adiposity.

(Pond, 2003; Fain et al., 2004; Saillan et al., 2003; Xu et al., 2003)

EVIDENCE?????


Why immune cells???

• Obesity provides bacterial and metabolic danger signals that mimic bacterial infection, and drives a shift in immune cell phenotypes and numbers, and inflammatory response.

• Housekeeping functions

How ????

- apoptotis- extracellular matrix remodeling- angiogenesis


Macrophages

Neutrophils

Mast cells

Eosinophils

Tregs

Th2 cells

CD4+ T cells

Pro-inflammatory cells

Anti-inflammatory cells

CD8+ T cells

Directly correlated to the extent of inflammatory response

Negatively correlated to the extent of inflammatory response

Adipose tissue resident immune cells

B cells


• Macrophages are the most abundantly found leukocytes in AT. Represent 5% of adipose cells in lean AT up to 25-30% in obese AT. (Nishimura et al., 2009)

• There are two phenotypic states, M1 (classically activated) and M2 (alternatively activated).– M2 phenotype maintain the state of insulin sensitivity through

secretion of anti-inflammatory cytokine IL-10.– The pro-inflammatory M1 macrophages produce IL-6 and TNF-α

which are directly involved in local and systemic inflammation, and insulin resistance.

(Odegaard et al. 2007; Wentworth et al. 2010)

Macrophages


• These M1 macrophages encircle the apoptosed necrotic adipocytes. This aggregate forms the typical ‘crown like structure’ (CLSs) appearance that phagocytose lipids from dying adipocytes and appear as foamy giant cells which is an indication of AT inflammation. (Cinti et al., 2005)

Macrophages contd..


• Comprises of 1.5% of stromal vascular fraction of AT.• Perpetuates the inflammation. (Soehnlein et al.,

2009)

• In obese individuals, elevated plasma myeloperoxidase level is reported which is a neutrophil marker; indicative of inflammation. (Andrade et al., 2012)

• Besides, the activity of neutrophil specific elastase is also increased in obesity corresponding to the infiltration of neutrophils. It promotes insulin resistance through increased expression of pro-inflammatory genes.

(Talukdar et al., 2012)

Neutrophils


• They produce cytokines IL-12 and IL-15 which are involved in – Inducing the differentiation of naive T cells into Th1 cells– Proliferation of CD8+ T cells – Activation NK cells.

(Hashimoto et al., 2011)

• Their circulating numbers are increased in obesity and also have a role in aggregation of macrophages around the adipocytes. (Dominguez and Ardavin, 2011)

Dendritic cells


• More numerous in lean VAT, and are major producers of IL-4 & IL-13, which help to promote M2 macrophage polarization to maintain a ‘lean phenotype’ through “browning”. (Wu et al. 2011)

• Obese individuals have increased mast cells within VAT compared to lean individuals.

• Express proinflammatory cytokines including TNFα, IL-1β, and IL-6.

Eosinophils

Mast cells


• CD 8+ T cells are cytotoxic T lymphocytes.• Important mediators of adaptive immunity against certain

viral, protozoan, and bacterial pathogens.• CD8+ T cells increase the recruitment of macrophages to

adipose tissues.• Also promote monocyte differentiation into M1

macrophages. (Rausch et al.,

2008)

CD 8+ T cells


• Recognize polypeptides presented by class II MHC molecules on the surface of APCs such as macrophages and dendritic cells.

• Activated or effector CD4+ T cells then release cytokines that recruit other immune cells to the area, resulting in inflammation.

• Subdivided into three functionally distinct effector cells:– Th1 (IFN-γ)– Th2 (IL-4/ IL-13)– Th17 cells (IL-17) (Oestreich et

al., 2012)

CD4+ T cells


• Insulin-sensitizing effect of CD4+ T cells depend on Th2 cells.

• The ratio of Th1 to Th2 cells is increased significantly during obesity. – The Th1 cells are increased in obesity while Th2 cells are reduced.

• Th1 cells secrete IFNγ, helps the polarization of M2 macrophages and thus it acts as a pro-inflammatory immune cell.

(Winer et al., 2011)

CD 4+ T cells contd..


• Tregs are found in more numbers in lean AT and they are reduced in obesity. Critical for the for maintenance of an anti-inflammatory environment at steady state in lean adipose tissue.

• Sustains the macrophages in M2 state through secretion of IL-10.

• Tregs are highly enriched in AT of lean individuals. Their number declines in obese individuals.

(Feuerer et al. 2009; Cipolletta et al. 2012)

Treg cells


TNF-α

• Mainly there are two mechanisms by which TNFα exerts its metabolic effects. – Inhibit expression of genes involved in uptake and storage of

glucose, adipogenesis and lipogenesis in AT – While in liver it suppresses expression of genes involved

fatty acid oxidation and increases expression of genes involved in synthesis of cholesterol and fatty acids.

(Ruan et al., 2002)

– Inhibits insulin signaling either by reducing the levels of insulin signaling components or by inducing the inhibitory phosphorylation of insulin receptor substrates (IRSs).

(Rui et al., 2001)


• It influences apoptosis of adipocytes. (Coppack, 2001)• TNFα is an important mediator in synthesis of IL-6, acute-

phase protein and haptoglobin. (Peeraully

et al., 2004)

• TNF-α is increased in obesity.• Pro-inflammatory• Pro-diabetic• Pro-atherogenic

(Fain et al., 2004)

TNFα contd..


IL-6• 30% of circulating IL-6 originates from adipose tissue and

is increased is obesity.• Pro-atherogenic: increase vascular inflammation.• Pro-diabetic: decrease insulin signalling.• Major regulator of hepatic CRP production.

(Fernandez and Ricart, 2003)

• IL-10 is a classical anti-inflammatory cytokine expressed by Tregs, macrophages (M2) and other cells. This cytokine promotes insulin sensitivity.

IL-10


C reactive protein (CRP)• Pro-atherogenic• Pro-diabetic (Yudkin et al., 2000)

• Pro-atherogenic (Gabay & Kushner, 1999)

• It recruits monocytes to sites of inflammation.• Increased in obesity and insulin resistance.• Inhibitory effect on growth & differentiation of adipocyte.

(Wellen and Hotamisligil, 2003)

Plasminogen activator inhibitor-1 (PAI-1)

Monocyte chemoattractant protein-1


Inflammation of adipose tissue

Anti-inflammatory adipokines and

cytokines

Anti-inflammatory immune cells

Pro-inflammatory immune cells

Pro-inflammatory adipokines and

cytokines

Adaptive immune

cells

Innate immune

cells

Adaptive immune

cells

Innate immune

cells

B cells

NK cells

Th1 CD4+ T cells

Cytotoxic CD8+ T cells

Mast cells

Dendritic cells

Neutrophils

M1 macrophages

M2 macrophages

Eosinophils iNK cells

Th2 CD4+ T cells

Tregs

Leptin Visfatin Apelin

TNFα IL-6 IL-1β MCP-1 CRP

Adiponectin

IL-13 IL-4

AdipsinPAI-1


• Lipids are the essential signaling moieties in metabolic regulation. Besides, they are also required for enhancing the inflammatory gene expression in AT. (Shi et al., 2006)

• There are many mechanisms through which lipids carry out the inflammatory functions.– The NFκB pathway– Jun N-terminal kinases (JNKs)– Endoplasmic reticular (ER) stress– Inflammasomes– Peroxisome Proliferator-Activated Receptors (PPAR) – Cell death (Strowig et

al., 2012)

Molecular mediators of AT inflammation


• During– Positive energy balance– Negative energy balance

Fate of adipose tissue

Obesity Calorie insufficiency


Obesity

• The hallmark of metabolic syndrome, is a heterogenous disorder characterized by chronic, low-grade inflammation with increased infiltration of immune cells to the AT leading to insulin resistance. (Creely et al., 2006)

• Obese individuals have a body mass index (BMI) of more than 30. (Dixit, 2008)


Obese adipose tissue is characterized by

Adipocyte hypertrophy

“ADIPOSE TISSUE REMODELING”

Progression of chronic inflammation

Extracellular matrix overproduction

Increased prod. of proinflammatory adipocytokines

Increased angiogenesis

Immune cell infiltration



• Calorie restriction (CR), or caloric restriction, or energy restriction.

• Caused due to negative energy balance in the body.

(Speakman and Mitchell, 2011)

Fate of AT in Calorie restriction

CR leads to alterations in body composition, particularly fat loss, reductions in adipokines, lowered circulating glucose, insulin and insulin-like growth factor (IGF)-1, leading to subsequent improvements in insulin sensitivity.


Positive effects• Decreased body fat• Blood pressure• Improved lipid profile• Low serum T3 conc.• Decreased resting heart rate

Negative effects• Anemia• Lower extremity edema• Muscle wasting• Weakness• Neurological deficits• Dizziness• Irritability• Lethargy• Depression.

Calorie restriction contd..


• AT was found to be associated in controlling many biological functions apart from the usual energy metabolism in mammals– Adipokines and cytokines

• AT also was found to be the source of resident immune cells – both adaptive and innate immunity

• There is a strong interrelationship between adipose tissue and immunity

Conclusion


Acknowledgements:

• Dr. V Girish Kumar, Prof and Head, Dept. of Veterinary Biochemistry, Bangalore.

• Dr. V Sejian, Senior scientist; Dr. Krishnan, Dr. Bagath, NIANP, Adugodi, Bangalore.

• Dr. Satyanarayan, Prof and Head, Dept. of Veterinary Pathology.

• Dr. Karthikesh, Associate Professor, Dept. of Veterinary Biochemistry, Bidar.


?Thank you

Date post:	05-Apr-2017
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Adipose tissue in immunity

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