Role of Leptin in Obesity

Speaker:Rajat Chaudhary

Resource Faculty:Dr. Dilip ThakurAdditional ProfessorDept. of Basic & clinical physiology

Main Objective-Hypothalamic regulation of food intake and its disorders with reference to obesity

Discovery of leptin

1950 Dr. Jeffrey Friedman’s team on 1994

-from the Greek word “leptos”, meaning thin.

-Leptin is a 16-kilodalton adipocyte derived hormone that circulates in the serum in the free and bound form.

Sources of leptin - white adipose tissue

It can also be produced by: Brown adipose tissue Placenta Ovaries Skeletal muscle Stomach Mammary epithelial cells Bone marrow Pituitary gland and Liver

What does Leptin do?

Increases metabolic rate/energy expenditureDecreases food intake

How does it work?It works through two distinct types of

neurons in arcuate nucleus of Hypothalamus:

POMC/CART (Pro-opiomelanocortin/Cocaine and Amphetamine regulated

transcripts)neurons

NPY/AgRP (Neuropeptide Y/Agouti-related peptide)neurons

Leptin stimulates POMC/CART neurons to produce anorexigenic neuropeptide: Melanocyte Stimulating Hormone that results in:

1. Endocrine changes2. Increase sympathetic nerve activity

This stimulates energy expenditure.

Leptin inhibits NPY/AgRP neurons that produce feeding-inducing (orexigenic) neuropeptide: Neuropeptide Y that results in inhibition of food intake.

Neurotransmitters and Hormones that influence feeding and satiety centers

Anorexins• Leptin• α- MSH• CART (Cocaine and

Amphetamine-regulated Transcript)

• Insulin• Cholecystokinin• Peptide YY• CRH• CGRP(Calcitonin gene-related

peptide)• Glucagon• Oxytocin• Somatostatin

Orexins• Ghrelin• AGRP (Agouti Related

Proteins) • Neuropeptide Y• Orexin A• Orexin B• β-Endorphins• Galanin• MCH (Melanin-

Concentrating Hormone)

Centers for regulating food intake

Lateral NucleusFeeding Centre

Stimulation

Increased eating response

Destruction

Causes severe fatal anorexia

Ventromedial nucleusSatiety centerSatiety(sense of fullness)

Stimulation

Causes feeling of satiety and cessation of

eating

Destruction

Causes hyperphagia and may lead to Hypothalamic

obesity

Other hypothalamic centres that regulate food intake

Paraventricular nucleus(Satiety)- its lesion causes excessive eating behaviour

Dorsomedial nucleus(GI Stimulation)- its lesion causes depressed eating behaviour

Mammillary Body- partially control feeding reflexes such as licking the lips and swallowing

Feedback mechanism for control of food intake

Feeding stage :-Peptide YY (PYY), cholecystokinin (CCK), and insulin are gastrointestinal hormones that are released - suppress further feeding.

Excessive feeding: – Excess Fat –Increased leptin Production –Inhibition of food intake.

Fasting stage :-Ghrelin is released by the stomach, stimulates appetite.

Defects in leptin leading to obesity

Leptin resistance and obesityAlthough leptin is a circulating signal that reduces

appetite, in general, obese people have an unusually high circulating concentration of leptin. These people are said to be resistant to the effects of leptin. The high sustained concentrations of leptin from the enlarged adipose stores result in leptin desensitization.

Causes of resistance:1. Changes to leptin receptor signaling particularly in

arcuate nucleus2. Alterations during its formation3. Saturation of leptin transporters

Summary Leptin is peptide hormone secreted by adipose

tissue that causes increase in metabolic rate and inhibition of food intake through hypothalamic signaling.

Any lesion in hypothalamic centres may causes excessive eating behaviour resulting in obesity or fatal anorexia .

Obese people have high amount of leptin but are resistant to its action due to leptin desensitization.

ReferencesGuyton and Hall Textbook of Medical

PhysiologyGanong’s Review of Medical Physiologyhttp://

www.nature.com/nature/journal/v395/n6704/fig_tab/395763a0_F4.html