Metabolic abnormalities in obesity

Bari Siddiqui M AShyam Prasad B R

Energy Metabolism

• Obesity is caused by excessive intake of calories in relation to energy expenditure over a long period of time.

• The gastro intestinal tract has the capacity to absorb large amounts of nutrients.

• Large increases in body fat can result from even minor but chronic differences between energy intake and energy expenditure

Nutrient and Energy Model of Obesity

Obesity results from increased intake of energy or decreased expenditure of energy, as required by the first law of thermodynamics.

3

Energy Intake

Adipose tissue

Energy Expenditure

Total energy expenditure(TEE) 1. Resting energy expenditure(REE)- represents the

energy expended for normal cellular and organ function under post absorptive resting conditions- 70% of total TEE

2. Energy expended in physical activity – includes both volitional activity like exercise and non volitional activity like muscle contractions, maintaining posture- 20% of TEE

3. Thermic effect of food(TEF) – the energy expended in digestion, absorption and sympathetic nervous system activation after a meal

• Obese individuals have a greater rate of REE due to increased adipose tissue cell mass.

• During non weight bearing activities obese individuals spend the same amount of energy as lean individuals but during weight bearing activities obese individuals spend greater energy on physical activity.

• There is reduction in thermic effect of food due to insulin resistance and blunted sympathetic nervous system activity in obesity

• Diet induced weight loss reduces REE by 15 to 30%

Adipose tissue

• Energy depots that store triglycerides during feeding and release fatty acids during fasting

• Functions as endocrine organ and secretes - leptin - resistin - estrogens - tumor necrosis factor α

Adipocyte formation• Obesity is associated with increased number of adipocytes.• Adipocytes are formed from fibroblast precursor by extra

nuclear factors and signal transduction pathways for differentiation

Very early – Lipo protein lipase(LPL)Early - Methyl Isobutyl Xanthine(MIX) - Dexamethasone - Insulin - Enhancer Binding Protein(EBP)Intermediate – Peroxisome Proliferator Activated Receptor(PRAR)Late – EBP and adipocyte specific gene expression

Triglyceride storage• The major function of adipocytes is storage of

triglycerides • Triglycerides stored within adipose tissue

constitute the body’s major energy reserve• Triglycerides yield 9.3 kcal/g upon oxidation • Stored as oil inside the fat cell• Most of the triglycerides in adipocytes is

derived from chylomicrons and VLDL

Regulation of storage• Lipo protein lipase(LPL) – is a key regulator of

fat cell triglyceride uptake from circulating triglycerides.

• LPL is synthesized by adipocytes.• The interaction of LPL with chylomicrons and

VLDL release fatty acids from plasma triglycerides, which are then taken up by local adipocytes

LIPO PROTIEN LIPASE

Circulating chylomicrons and VLDL

Free fatty acids

ADIPOCYTES

Insulincortisol

TestosteroneGrowth hormoneCatecholaminesTumor necrosis factor

LIPOLYSIS Alterations in adipocyte lipolysis (triglyceride

breakdown) is observed in obesity and results in increased release of fatty acids into the circulation by

1. Hormone sensitive lipase (HSL)2. Adipose triglyceride lipase (ATGL)-ATGL is highly

expressed in white adipose tissue with less expression in skeletal muscle, accounts for 60-70% of triglyceride lipase activity in adipose and appears to be essential for the control of normal weight

HORMONE SENSITIVE LIPASE

Beta Oxidation Esterification

insulin catecholamines

adipocytes

free fatty acids

Lean person obese

Fatty acids derived from adipose tissue lipolysis and dietary intake are transported across the plasma membrane. The majority of fatty acids are directed towards β-oxidation in the mitochondria, where most fatty acids are completely oxidized. A smaller fraction of the fatty acids are esterified to form diglyceride and triglyceride and some fatty acids are converted into ceramide

Increased lipolysis from an enlarged adipose mass increases fatty acid delivery to peripheral tissues. Fatty acid uptake is greater and an increased fraction of the transported fatty acids are directed towards esterification, rather than oxidation. Accordingly, lipid metabolites accumulate in the tissue. A reduced mitochondrial capacity is associated with more incomplete oxidation of fatty acids.

Dysregulation of fatty acid metabolism in obesity

ENDOCRINE FUNCTION• The adipocyte produces and secretes a wide

variety of hormones and cytokines (termed ‘adipokines’) that influence many biological processes, including substrate metabolism.

• Adipose tissue uses adipokines as a communication tool to signal changes in its mass and energy status to other organs that control fuel usage, such as skeletal muscle and liver.

LEPTIN

Leptin is produced by adipose tissue to signal fat storage reserves in the body, and mediates long-term appetitive controls (i.e. to eat more when fat storages are low and less when fat storages are high).

Leptin acts on receptors in the hypothalamus of the brain where it inhibits appetite by

1. counteracting the effects of neuropeptide Y (a potent feeding stimulant secreted by cells in the gut and in the hypothalamus)

2. Counteracting the effects of Anandamide (another potent feeding stimulant that binds to the same receptors as THC, the active ingredient of marijuana); and

3. promoting the synthesis of α-MSH, an appetite suppressant. This inhibition is long-term, in contrast to the rapid inhibition of eating by cholecystokinin (CCK) and the slower suppression of hunger between meals mediated by PYY3-36.

Ghrelin

Ghrelin is produced by the stomach modulating short-term appetitive control (i.e. to eat when the stomach is empty and to stop when the stomach is stretched)

• Ghrelin is secreted mainly by the stomach, • Has paracrine or endocrine effects on GI motility• Circulate in the blood and act on CNS growth

hormone secretagogue receptors (GHS-Rs) inside and outside the blood–brain barrier.

• Known target areas in the CNS include the hypothalamus, the ventral tegmentum and nucleus accumbens, the hippocampus and GHS-R populations in the brainstem area.

• The actions of ghrelin in the CNS contribute to the control of food intake and co-regulate tissue-specific cellular pathways in the periphery, thereby governing glucose, lipid and energy metabolism.

Central pathway While Leptin and Ghrelin are

produced peripherally, they control appetite through their actions on the central nervous system. In particular, they act on the hypothalamus, a region of the brain central to the regulation of food intake and energy expenditure.

There are several circuits within the hypothalamus that contribute to its role in integrating appetite.

• The melanocortin pathway being the most well understood.

• The circuit begins with an area of the hypothalamus, the arcuate nucleus, that has outputs to the lateral hypothalamus (LH) and ventromedial hypothalamus (VMH), the brain's feeding and satiety centers, respectively.

• The Arcuate nucleus contains two distinct groups of neurons.

The first group co-expresses Neuropeptide Y (NPY) and Agouti-related peptide (AgRP) and has stimulatory inputs to the LH and inhibitory inputs to the VMH

The second group coexpresses pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript(CART) and has stimulatory inputs to the VMH and inhibitory inputs to the LH

• Consequently, NPY/AgRP neurons stimulate feeding and inhibit satiety, while POMC/CART neurons stimulate satiety and inhibit feeding

• Both groups of arcuate nucleus neurons are regulated in part by leptin. Leptin inhibits the NPY/AgRP group while stimulating the POMC/CART group

Arcuate Nucleus

Paraventricular Nucleus

Lateral Hypothalamus

PeripheralAdipositySignals

Appetite

NPY/AgRP

NPY/AgRP

-a MSH CART

+

OrexinMCH

CRHOxytocin

-a MSH CART

FEEDING CENTER

SATIETY CENTER

LECTIN

SUMMARY

28

BrainBrain

NPYAGRPgalanin

Orexin-Adynorphin

StimulateStimulateα-MSHCRH/UCNGLP-I

CARTNE5-HT

InibitInibit

Central SignalsCentral Signals

Glucose

CCK, GLP-1,Apo-A-IVVagal afferents

Insulin

Ghrelin

Leptin

Cortisol

Peripheral signalsPeripheral signals Peripheral organsPeripheral organs

+

+

Gastrointestinaltract

Adiposetissue

FoodIntake

Adrenal glands

External factorsEmotionsFood characteristicsLifestyle behaviorsEnvironmental cues

BrainBrain

NPYAGRPgalanin

Orexin-Adynorphin

StimulateStimulateα-MSHCRH/UCNGLP-I

CARTNE5-HT

InibitInibit

Central SignalsCentral Signals

Glucose

CCK, GLP-1,Apo-A-IVVagal afferents

Insulin

Ghrelin

Leptin

Cortisol

Peripheral signalsPeripheral signals Peripheral organsPeripheral organs

+

+

+

+

Gastrointestinaltract

Adiposetissue

FoodIntake

Adrenal glands

External factorsEmotionsFood characteristicsLifestyle behaviorsEnvironmental cues

External factorsEmotionsFood characteristicsLifestyle behaviorsEnvironmental cues

Morton G.J., et.al., Nature 443:289-295, 2006

Hedonic CNS Pathways

Morton G.J., et.al., Nature 443:289-295, 2006

Homeostatic CNS Pathways

Genetics

• Leptin gene mutations• Leptin receptor mutations• Prohormone convertase1 gene mutation• Pro-opiomelanocortin gene mutation• Melanocortin 4 receptor gene mutation• SIM1 gene mutation

Medical Complications of Obesity

Pulmonary diseaseabnormal functionobstructive sleep apneahypoventilation syndrome

32

Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis

Gall bladder disease

Gynecologic abnormalitiesabnormal mensesinfertilityPCOS

Osteoarthritis

Gout

Phlebitisvenous stasis

Cancerbreast, uterus, cervixcolon, esophagus, pancreaskidney, prostate

Severe pancreatitis

CHD Diabetes Dyslipidemia Hypertension

Cataracts

Stroke