Adipose Tissue Metabolism

& Pathogenesis of Obesity

Dr. Samridha Panda
JR (Academic)
Contents
Where is it found?

Under skin 80%

Adipose
tissue Digestive
organs and 20%
kidneys
What are the components of Adipose tissue?

Adipose cells
Adipose
Preadipocytes
tissue
Vascular
Component
Macrophages

• It has a loose network of elastin and collagen fibres

What are their functions?
Major food
source

Mechanical
Insulator
Support

Cushioning Metabolism
effect Regulator
What are their types?

Adipose Tissue

White Adipose Brown

Tissue Adipose Tissue
Metabolism in adipose tissue

Metabolism in Adipose
Carbohydrate
Metabolism

tissue
Fat Metabolism
Carbohydrate Metabolism in Adipose
Tissue
• Three events

Insulin Glycolysis HMP Shunt

Glucose Entry Glycerol-3-

into adipose NADPH
tissue (GLUT4) phosphate

Glucose  TAG
Glucose-6- De novo synthesis
phosphate Synthesis of fatty acid
Carbohydrate Metabolism in Adipose
Tissue

Glucose Fatty acid Fat (TAG)

entry synthesis synthesis
Fat Metabolism in Adipose Tissue
Dietary TAG uptake

Fat Metabolism
(Chylomicron)

Endogenous TAG
Well Fed State
Uptake (VLDL)

Lipogenesis

Starvation Lipolysis
Fat Metabolism in Adipose Tissue

Fat Metabolism - Hormones

Dietary TAG uptake
(Lipoprotein Lipase)
Well Fed State
(Insulin)
Lipogenesis

Starvation (Glucagon, Lipolysis (Hormone

Epinephrine) sensitive Lipase)
Adipose tissue and Diabetes Mellitus

Lipolysis Free Fatty Acid

Diabetes
Mellitus Reduced
Decreased LPL
Chylomicron and
Activity
VLDL Catabolism
Endocrine function of Adipose Tissue

Leptin Adiponectin

Increases fatty
Decreases
acid uptake in
Appetite
muscle and liver

Increases
Increases
insulin
metabolic rate
sensitivity

Leptin Decreases with

resistance- decrease in
Obesity body weight
Obesity
• Obesity can be defined as an excess of body fat

Obesity

Excess Calorie
Storage

Body’s energy
Excess Calorie consuming
Intake activities
 Mechanisms of
management of excess
dietary calories :

Burning excess fuel Wasting fuel by diverting

Conversion of excess fuel
through additional it to heat production
to fat and storage in
exercise or physical through uncoupling and
adipose tissue
activity thermogenesis
 Prevalence
expected to
reach 89% in
males and 85%
in females Coronary heart
disease (CHD) :
97%.

Direct healthcare
costs associated Significant rise in
with obesity -
substantial Projections obesity-related
health conditions
increase
by 2030 Cancers : 61%.

Implementing interventions to Type 2

reduce the population's body mass diabetes: 21%.
index (BMI) levels by just 5% by
2030 can yield notable cost savings
 Obesity can be defined as
an excess of body fat.

BMI
surrogate
BMI is an marker for
indirect body fat
measure content
of obesity

individuals with a higher

proportion of muscle mass correlating height, weight
can have a higher BMI and amount of body fat in
an individual.
 Excess Body fat BMI

>25% (men) ; >35%

(women)

skin-fold thickness,
bioelectrical
Percent total body fat
Obesity can be defined impedance,
in terms of underwater weighing

inconvenient and
costly

Clinical practice

Waist circumference
Excess of abdominal
fat is most tightly
associated with the
metabolic risk factors
• Obesity is due to a combination
of increased fat cell
size (hypertrophy) or number
(hyperplasia) or both
 Poor Diet

Underlying Sedentary
Medical Lifestyle
Conditions Genetic factors

Risk
factor
Environmental
Sleep and
Deprivation Socioeconomic
Factors

Psychological
Factors
 ADIPOKINES
They include Produce Novel
Released by
Cell - signalling adipokines:
molecules
(cytokines)
Proinflammatory
Leptin and anti-
adipocytes inflammatory
cytokines
produced by the chemerin,
Adiponectin lipocalin-2,
adipose tissue In Obesity:
preadipocytes vaspin, and
Proinflamatory – Increased omentin-1,
Anti-inflammatory -Inhibited FSTL1, SPARC,
play functional Resistin SFRP5, CTRPs,
roles in energy FAM19A5,
homeostasis and adipose tissue- WISP1, PGRN,
metabolic status infiltrated nesfatin-
of the body, immune cells Role in development of insulin
resistance, type 2 diabetes 1,visfatin,
inflammation, Interleukin-6 apelin, RBP4,
obesity, etc. mellitus, and cardiovascular
disease associated with obesity. and PAI-1
other cell types
Tissue Necrosis within adipose
Factor tissue.
LEPTIN
• Leptin (Greek Leptos – thin)
• First identified as the product of
gene OB (obese)
• 167 amino acids
• Brain – receptors in hypothalamus
(arcuate nucleus)
• Principle role in energy
homeostasis
• curtailing appetite
• inducing satiety
• Leptin stimulates the sympathetic
nervous system, increasing blood
pressure, heart rate, and
thermogenesis by uncoupling
 Arcuate Nucleus : two
types of neuron

Orexigenic Anorexigenic

appetite stimulating appetite suppressing

releases α-
melanocyte
releases Neuropeptide Y
stimulating hormone
(melanocortin)
 Leptin Induced Signaling Cascade
• The leptin receptor -single
transmembrane segment
• Dimerization when leptin binds
• Both monomers are phosphorylated by a
Janus kinase (JAK).
• Docking sites for three proteins that are
signal transducers and activators of
transcription (STATs 3, 5, and 6; fat-STATS).
• The docked STATs - phosphorylation –
dimerization
• Induces transcription

increased synthesis of the

Leptin increased release of mitochondrial uncoupling protein increased catabolism and
acts through β3-adrenergic receptors stimulates transcription of UCP1
norepinephrine thermogenin (product of the UCP1 thermogenesis
gene) in adipocytes
Leptin regulation in response to starvation
Reduction in leptin level
triggered by nutritional
deficiency

Reverses the thermogenic

processes allowing fuel In liver and muscle,
conservation
Triggers decreased
production of TSH slowing
basal metabolism

Decreased LH, FSH Stimulates AMP-activated

preventing reproduction protein kinase (AMPK) -
favoring energy-producing
processes
Increased production of
glucocorticoid (mobilizing
the body's fuel-generating
resources).
Role of Insulin
Insulin
Secretion Signals
reflects both muscle, liver,
the size of and adipose
Acts in the
fat reserves tissues to
arcuate
(adiposity) increase the
nucleus to
and the conversion
regulate
current of glucose to
eating and
energy acetyl-CoA,
energy
balance providing
conservation
(blood the starting
glucose material for
level) fat synthesis
• Leptin increases insulin sensitivity
• via cross-talk between the protein
• tyrosine kinases activated by leptin
• and those activated by insulin
ADIPONECTIN
Sensitizes other organs to
the effects of insulin
Peptide hormone (224 Fatty acid uptake by
Amino acid) myocyte
Protects against
atherosclerosis
Functions Rate of β oxidation
Inhibits inflammatory
response
Blocks FA synthesis

Metabolic role

Blocks neoglucogenesis

Glucose uptake and

catabolism

Adiponectin triggers
phosphorylation and
activation of AMPK
AMPK Mediated adiponectin action
• Decreased reserves of
triacylglycerols in adipose
tissue triggers the release
• Inhibit energy-consuming
processes and stimulate
energy-producing processes
• Adiponectin acts through its
receptors in the brain to
stimulate feeding behaviour
and inhibit energy consuming
physical activity, and to
inhibit thermogenesis in
brown fat
• AMPK regulates specific
enzymes in key metabolic
processes phosphorylation
 adipose tissue
Discovered in mice in 2001 that induces insulin resistance
bone marrow
Belongs to a family of resistin-like molecules with different
expression patterns and effects
lung
RESISTIN
Found in
placental tissue
In obesity - Increase in resistin levels, particularly in individuals with
excess visceral adiposity
pancreatic islet cells
Contributes to insulin resistance - hallmark feature of metabolic
syndrome and type 2 diabetes
plasma
Implicated in the regulation of adipocyte differentiation and lipid
metabolism - potentially influencing the development of obesity

Iinvolved in inflammation and immune responses - promoting the

release of pro-inflammatory cytokines.
The Impact of Diet on Gene Expression
Related to Body Mass Maintenance
• Proteins in a family of ligand-activated transcription factors
-peroxisome proliferator-activated receptors (PPARs)
• Dietary lipid - altering the expression of genes involved in
fat and carbohydrate metabolism
• First recognized for their roles in peroxisome synthesis
• Ligands : fatty acids or fatty acid derivatives, synthetic
agonists
• PPARγ, PPARδ, and PPARα
• They act in the nucleus by forming heterodimers with
retinoid X receptor - binding to regulatory regions of DNA
near the genes under their control - changing the rate of
transcription of those genes.
 • expressed primarily in liver and adipose tissue
• Activation of genes

PPARγ
• differentiation of fibroblasts into adipocytes
• encode proteins required for lipid synthesis and storage in
adipocytes
• PPARγ is activated by the thiazolidinedione drugs which are used
to treat type 2 diabetes

• expressed in liver, kidney, heart, skeletal muscle, and brown

adipose tissue

PPARα
• Ligands - eicosanoids, free fatty acids
• Fibrates, such as fenofibrate and ciprofibrate (treat coronary
heart disease by raising HDL and lowering blood triacylglycerols)
• Turns on the genes necessary for the uptake and β oxidation of
fatty acids and formation of ketone bodies during fasting

• key regulators of fat oxidation

• Senses changes in dietary lipid

PPARδ
• PPARδ acts in liver and muscle
• Transcription of at least nine genes encoding proteins for β
oxidation and for energy dissipation through uncoupling of
mitochondria
• Causes fat depletion, weight loss, and thermogenesis
“Lipid Burden” • Adipocytes normally synthesize and store TG (insulin sensitive and produce leptin)

Hypothesis: • Obese individuals - the adipocytes overfilled, and less sensitive to insulin

• Gene expression for the development of new adipocytes (genes for the transcription
factors SREBP1 and PPARγ) is downregulated in the adipocytes of obese individuals
but is upregulated in other tissues, including skeletal muscle and liver

• Ectopic lipid droplets

• excess stored fatty acids and TAGs are toxic to liver and muscle –susceptible individual

• Insulin resistance - changes in the activities of signaling enzymes and transcription

factors

• Adiponectin synthesis in adipocytes and adiponectin level in the blood decrease with
obesity, and increase with weight loss

• Chronic inflammation of adipose tissue is a common feature of obesity

• Genes associated with inflammation and macrophage activity are upregulated
• macrophage invasion of adipose tissue

• Lipid-laden adipocytes – lipoapoptosis triggered by abnormal concentrations of lipids

Obesity Related • Primarily characterized by increased levels of plasma free
Dyslipidemia fatty acids and TG, decreased levels of HDL, and abnormal
LDL composition
• Uncontrolled Lipolysis - Synthesis of VLDL
• Increased levels of free fatty acids can decrease mRNA
expression or activity of LPL in adipose tissue and skeletal
muscle
• Inhibit lipolysis of chylomicrons, promotes
hypertriglyceridemia
• Hypertriglyceridemia further triggers a cholesteryl ester
transfer protein-mediated exchange of triglycerides for
cholesterol esters between triglyceride-rich lipoproteins
(VLDL, IDL) and lipoproteins, which are relatively richer in
cholesterol esters (LDL, HDL), which leads to a decreased
HDL- cholesterol concentration and a reduction in
triglyceride content in LDL
• The increased TG in LDL is hydrolyzed by hepatic lipase (HL),
leading to the formation of small, dense LDL particles
(higher risk of cardiovascular diseases)
 Metabolic Syndrome
• Distinctive combination of reversible major risk factors for
cardiovascular disease and type 2 diabetes
• Gerald Jerry Reaven - first to draw attention to this clustering of
metabolic abnormalities, particularly in overweight individuals.
-‘syndrome X’
• ‘Metabolic syndrome’ has gained international acceptance and
International Classification of Diseases coding
• Diagnostic criteria - number of organizations including the
WHO,EGIR, NCEP, IDF, AHA and the American Association of
Clinical Endocrinologists.
• The most widely accepted criteria for the metabolic syndrome
are those adopted by the NCEP and IDF -reflect
cardiometabolic risks
MHO & MUO
• Metabolically Healthy Obesity (MHO) and Metabolically Unhealthy
Obesity (MUO) are two distinct subtypes of obesity that differ in their
metabolic profile and associated health risks
Summary
Thank you!