Understanding leptin and leptin resistsance.

1. UNDERSTANDING Leptin and
leptin resistaNce
BY: B.V.S.SAI KIRAN
GVM13/-041

2. INTRODUCTION :
• MAN in the process of earning money and leading a luxurious life secured a
set of life style disorders .
• past two decades have witnessed an explosion of the incidence of
Obesity
Hypertension
Diabetes -2
Cardiovascular Disease
Cancers
Obesity tops the list of life style disorders .

3. • OBESITY being the prime case of all these life styles disorders is
of great concern .
• Estimates from the World Health Organization (WHO) indicate 600
million adults were obese by 2015.
• So Elucidating the mechanisms underlying obesity has become the
foremost thing for scientists.
• till that point of time every one knew that there would be some x
chemical/molecule/hormone that regulate the energy intake and
the energy expenditure through CNS
• Finally in 1994 scientists had identified this peripheral signalling
molecule to CNS as LEPTIN

4. Leptin biology :
• In 1994, Friedman’s laboratory cloned ob gene located on chromosome 7,
named this new hormone as ‘‘LEPTIN’’ from the Greek root ‘‘lepto’’,
meaning ‘‘thin’’.
• In 1995 db gene was identified which encodes the leptin receptor.
• It is primarily synthesized and secreted by WAT(white adipose tissue ).
• Other soureces are placenta, ovary, skeletal muscle, mammary epithelium,
bone marrow and lymphoid tissue.

5. Leptin receptors :
• Leptin receptor (LepR) belongs to long-chain helical cytokines superfamily.
• Via alternative splicing, Lepr, or db gene, produces six LepR isoforms (LepR a, b,
c, d, e and f)
• isoforms possess the same extracellular domain, but differ by their
transmembrane and cytoplasmic domains.
• LepR b is the only form that contains intracellular domain of approximately 300
amino acid residues. It is ubiquitously expressed in the body and mediates the
main effects of leptin on controlling energy homeostasis and body weight

6. Leptin receptor structure

7. Factors affecting the leptin levels
• Amount of body fat
• Subcutaneous fat vs visceral fat
• Sex of the individual
• Energy status of the individual
• Other factors (insulin, estrogen, glucocorticoids,glucose, fatty acid, etc)

8. Role of leptin in maintaining :body weight
• Body weight is normally maintained within a narrow range by a balance
between energy intake (food intake) and energy expenditure.
• When energy intake exceeds energy expenditure, excess energy is stored as
triglyceride in adipose tissue, resulting in overweight or obesity.
• Adipose tissue and the brain are two key components of this
neuroendocrine system that control energy balance by constantly
monitoring energy storage, availability, and consumption.

9. Leptin action on central nervous system
• Leptin reduces energy intake via central regulation of appetite and satiety, it
also promotes energy expenditure and mediates neuroendocrine function
and cognition .
• leptin receptor LepRb is highly expressed in the brain, particularly in the
arcuate (ARC), dorsomedial (DMH), ventromedial (VMH) and ventral
premamillary nuclei (PMV) of hypothalamus.
• These first-order neurons broadly connect to other neurons in the brain,
thus forming a sophisticated neural network .

11. • The ARC of the hypothalamus is a critical site of leptin action.
• LepR b expression was co-localized with two neuronal populations of ARC:
anorexigenic proopiomelanocortin (POMC) neurons and orexigenic agouti-
related peptide (AgRP)/neuropeptideY(NPY) neurons.
• Leptin signaling activation directly stimulates POMC neurons and thus releases
a-melanocyte-stimulating hormone (a-MSH).
• a-MSH is an anorexigenic neuropeptide that decreases food intake by binding
to and activating melanocortin-4 (MC4R).

12. • On the other side, leptin also inhibits orexigenic neuropeptides AgRP and
NPY, which antagonize the a-MSH/MC4R signaling and thus reduce appetite.
• Leptin deficiency is also correlated with hypogonadism ,pubertal failure .
• recent studies indicate leptin could markedly promote cognition and
memory

13. Leptin function on peripheral tissue
• In the skeletal muscle, leptin enhances fatty acid oxidation and
glucose uptake.
• In the pancreas, leptin inhibits insulin and glucagon secretion.
• In the liver, leptin reduces lipid accumulation.
• leptin interacts with bone marrow stromal cells and osteoblasts to
increase overall bone mass.

14. Effects of leptin in the central nervous system and
peripheral tissues

15. Leptin signalling mechanism: diverse action
The binding of leptin to LepRb activates a series of signaling pathways
• janus kinase 2 (JAK2)
• signal transducer and activator of transcription 3 (STAT3)
• src homology-2-containing protein tyrosine phosphatase 2 (SHP2)
• growth factor receptor-bound protein 2 (Grb2)
• mitogen-activated protein kinase (MAPK)
• insulin receptor substrates (IRS)
• phosphatidylinositol 3 kinase (PI3K)
• mammalian target of rapamycin (mTOR)
• forkhead box O1 (FoxO1)
• 50 adenosine monophosphate-activated protein kinase (AMPK)

17. Leptin and STAT3-dependent pathways
• Leptin binds to the extracellular domain of LepRb, causing a conformational
change that results in autophosphorylation of associated JAK2 tyrosine kinase,
which then phosphorylates LepRb in the indicated residues (Tyr985, Tyr1077
and Tyr1138).
• Phosphorylated Tyr1138 recruits and phosphorylates the transcription factor
STAT3.
• Phosphorylated STAT3 then homodimerizes and translocates to the nucleus,
where it induces transcription of an anorexigenic neuropeptide POMC and
suppresses that of orexigenic neuropeptides AgRP and NPY
• On the other side, phosphorylated Tyr1077 binds to and phosphorylates
STAT5,which is a minor pathway .

19. Regulation of stat 3 pathway
• JAK2/STAT3 pathways are controlled positively by SH2B adaptor protein 1 (SH2B1).
• SH2B1 is an adaptor protein that binds to Tyr813 and enhances JAK2 activation, thus
promoting leptin signalling.
• Negatively controlled by suppressor of cytokine signaling 3 (SOCS3), protein tyrosine
phosphatase 1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP).
• SOCS3 is a target gene of JAK2/STAT3 signaling pathway. It attenuates leptin receptor
signaling by binding Tyr985 on LepRb and inhibiting JAK2, thus providing a pivotal
negative feedback mechanism and preventing the overactivation of leptin signaling
pathways.
• PTP1B mediates the dephosphorylation of JAK2 and TCPTP dephosphorylates STAT3,
limiting the extent of leptin action .

21. Interactions of leptin and insulin signaling in hypothalamus- STAT3
INDEPENDENT
• leptin and insulin signaling have similar intracellular pathways in hypothalamic
neurons.
• FoxO1 stimulates expression of NPY and AgRP, inhibits POMC, and blocks
STAT3 action in AgRP and POMC neurons.
• Leptin activates PI3K and Akt through IRS phosphorylation.
• The PI3K pathway stimulates POMC expressing neurons through ATP-sensitive
potassium channels and voltage-gated calcium channels .
• ForkheadboxO1 (FoxO1), a transcription factor inactivated by Akt, appears to
be an important downstream mediator of PI3K signalling.

23. • Inactivation of FoxO1 via leptin or insulin signaling allows STAT3 to bind to
pomc and agrp promoters.
• Another pathway recruited by leptin is the mammalian target of rapamycin
(mTOR), a downstream target of PI3K/Akt.
• Leptin stimulates phosphorylation of p70 S6 kinase (S6K) via mTOR in the
hypothalamus,which has anorexigenic effect .
• Leptin also induces phosphodiesterase 3B (PDE3B) activity, which results in a
decrease in cyclic adenosine monophosphate (cAMP) levels via the PI3K
pathway in the hypothalamus.

25. • Inhibition of PDE3B activity reverses leptin’s effects on food intake and body
weight,suggestingthatPDE3Bplaysanimportantrolein mediating leptin
signaling in the hypothalamus .
• Activation of ERK1/2 appears to be mediated by either SHP2 from Tyr985 of
LepRb or directly from JAK2 which improve the effect of leptin on energy
homeostasis .
• Leptin exerts an inhibitory effect on AMPK in the hypothalamus, thereby
stimulating ACC and subsequently suppressing food intake.

26. Leptin resistance:
• Actually, leptin replacement treatment could improve or normalize the
neuroendocrine and metabolic abnormalities in leptin deficiency conditions
such as lipodystrophy, hypothalamic amenorrhea and congenital leptin
deficiency (CLD).
• Obese individuals have elevated adipose leptin expression and plasma leptin
levels,and these highleptin levels FAIL to reduce excess adiposity.
• Exogenous leptin administration exerts poor effect on weight reduction in the
majority of human obesity .
• This phenomenon of coexistence of high leptin levels and obesity is referred to
as leptin resistance.

27. Mechanisms underlying leptin resistance
The mechanism underlying leptin resistance are multifactorial and
complicated .
• attenuation in leptin signalling
• Impairment in leptin transportation
• endoplasmic reticulum (ER) stress
• deficiency in autophagy and inflammation

28. Mechanisms ofleptin resistance

29. Impairment in leptin transportation to the brain
• To act centrally, circulating leptin must first enter the brain through the blood–
brain barrier.
• LepRa, LepRe and megalin have been proposed to be involved in this process
of leptin transport .
• During obesity, the cerebrospinal-fluid/serum leptin ratio is decreased,
indicating impairment in leptin transport.
• As serum leptin levels increase during obesity, the leptin transporter is
increasingly saturated and blocks the access of leptin into the CNS.
• more studies are needed to clarify the reason for impaired brain leptin
transport and the relationship between this and leptin resistance.

30. Attenuation in leptin signaling
• Impairment in each component of the leptin signaling pathways could lead
to leptin resistance.
• As explained previously, leptin signaling is negatively regulated by SOCS3,
PTP1B, TCPTP . The expression levels of hypothalamic SOCS3, PTP1B and
TCPTP are elevated in obesity and thus might contribute to attenuation of
leptin signaling and leptin resistance .

31. ER stress:
• ER stress in hypothalamic neurons can impair leptin signalling.
• Increased ER stress activates, unfolded protein response (UPR) in the
hypothalamus of which contribute to leptin resistance.
• Impaired POMC processing might by the reason for leptin resistance

32. Deficiency in autophagy
• Recent studies indicate autophagy is associated with leptin resistance.
• Inhibition of autophagy in the hypothalamus by knocking down autophagy-
related protein 7 (Atg7) exhibits obesity and leptin resistance.
• POMC neuron-specific Atg7-knockout mice display leptin resistance
probably due to the inability of leptin to activate and phosphorylate STAT3.

33. Inflammation
• Obesity is associated with low-grade chronic inflammation.
• Activation of the toll-like receptors (TLRs) or hypothalamic IKKb/NF-kB
pathway is reported to induce hypothalamic inflammation and leptin
resistance.

34. Conclusions and future directions:
• So by now Leptin has been firmly established as the essential hormone for
the maintenance of energy homeostasis and body weight, and leptin
resistance has been widely recognized as the key risk factor for obesity.
• Multiple factors, including inflammation and ER stress, have been identified as
factors for leptin resistance.
• However, the anatomic connection and synaptic transmission of the brain
neural circuitry that control energy homeostasis and body weight, how
different branches of the LEPRb pathways act specifically and/or coordinately
to regulate different aspects , molecular events that lead to leptin resistance
remains to be unclear and need further research in the future .