Signaling by Leptin

Stable Identifier
Homo sapiens
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Leptin (LEP, OB, OBS), a circulating adipokine, and its receptor LEPR (DB, OBR) control food intake and energy balance and are implicated in obesity-related diseases (recently reviewed in Amitani et al. 2013, Dunmore and Brown 2013, Cottrell and Mercer 2012, La Cava 2012, Marroqui et al. 2012, Paz-Filho et al. 2012, Denver et al. 2011, Lee 2011, Marino et al. 2011, Morton and Schwartz 2011, Scherer and Buettner 2011, Shan and Yeo 2011, Wauman and Tavernier 2011, Dardeno et al. 2010, Bjorbaek 2009, Morris and Rui 2009, Myers et al. 2008), including cancer (Guo et al. 2012), inflammation (Newman and Gonzalez-Perez 2013, Iikuni et al. 2008), and angiogenesis (Gonzalez-Perez et al. 2013).
The identification of spontaneous mutations in the leptin gene (ob or LEP) and the leptin receptor gene (Ob-R, db or LEPR) genes in mice opened up a new field in obesity research. Leptin was discovered as the product of the gene affected by the ob (obesity) mutation, which causes obesity in mice. Likewise LEPR is the product of the gene affected by the db (diabetic) mutation. Leptin binding to LEPR induces canonical (JAK2/STATs; MAPK/ERK 1/2, PI-3K/AKT) and non-canonical signaling pathways (PKC, JNK, p38 MAPK and AMPK) in diverse cell types. The binding of leptin to the long isoform of LEPR (OB-Rl) initiates a phosphorylation cascade that results in transcriptional activation of target genes by STAT5 and STAT3 and activation of the PI3K pathway(not shown here), the MAPK/ERK pathway, and the mTOR/S6K pathway. Shorter LEPR isoforms with truncated intracellular domains are unable to activate the STAT pathway, but can transduce signals by way of activation of JAK2, IRS-1 or ERKs, including MAPKs.
LEPR is constitutively bound to the JAK2 kinase. Binding of LEP to LEPR causes a conformational change in LEPR that activates JAK2 autophosphorylation followed by phosphorylation of LEPR by JAK2. Phosphorylated LEPR binds STAT3, STAT5, and SHP2 which are then phosphorylated by JAK2. Phosphorylated JAK2 binds SH2B1 which then binds IRS1/2, resulting in phosphorylation of IRS1/2 by JAK2. Phosphorylated STAT3 and STAT5 dimerize and translocate to the nucleus where they activate transcription of target genes (Jovanovic et al. 2010). SHP2 activates the MAPK pathway. IRS1/2 activate the PI3K/AKT pathway which may be the activator of mTOR/S6K.
Several isoforms of LEPR have been identified (reviewed in Gorska et al. 2010). The long isoform (LEPRb, OBRb) is expressed in the hypothalamus and all types of immune cells. It is the only isoform known to fully activate signaling pathways in response to leptin. Shorter isoforms (LEPRa, LEPRc, LEPRd, and a soluble isoform LEPRe) are able to interact with JAK kinases and activate other pathways, however their roles in energy homeostasis are not fully characterized.
Literature References
PubMed ID Title Journal Year
17937601 Mechanisms of leptin action and leptin resistance

Cowley, MA, Münzberg, H, Myers, MG

Annu. Rev. Physiol. 2008
22289780 Oncogenic role and therapeutic target of leptin signaling in breast cancer and cancer stem cells

Gonzalez-Perez, RR, Liu, M, Guo, S, Wang, G, Torroella-Kouri, M

Biochim. Biophys. Acta 2012
21677426 Evolution of leptin structure and function

Bonett, RM, Denver, RJ, Boorse, GC

Neuroendocrinology 2011
22249808 Leptin receptors

Mercer, JG, Cottrell, EC

Handb Exp Pharmacol 2012
20198122 Leptin and Inflammation

Iikuni, N, Matarese, G, Lam, QL, Lu, L, La Cava, A

Curr Immunol Rev 2008
22458591 Proinflammatory activities of leptin in non-autoimmune conditions

La Cava, A

Inflamm Allergy Drug Targets 2012
23579596 The role of leptin in the control of insulin-glucose axis

Amitani, H, Asakawa, A, Inui, A, Amitani, M

Front Neurosci 2013
20553370 Identification of the global transcriptomic response of the hypothalamic arcuate nucleus to fasting and leptin

Tung, YC, Yeo, GS, O'Rahilly, S, Lam, BY, Jovanovic, Z

J. Neuroendocrinol. 2010
21527729 Leptin and the central nervous system control of glucose metabolism

Schwartz, MW, Morton, GJ

Physiol. Rev. 2011
23565489 Leptin therapy, insulin sensitivity, and glucose homeostasis

Mastronardi, C, Wong, ML, Licinio, J, Paz-Filho, G

Indian J Endocrinol Metab 2012
21331644 Central leptin and ghrelin signalling: comparing and contrasting their mechanisms of action in the brain

Yeo, GS, Shan, X

Rev Endocr Metab Disord 2011
20029269 Central leptin receptor action and resistance in obesity

Bjørbaek, C

J. Investig. Med. 2009
22211890 Obesity, leptin, and Alzheimer's disease

Lee, EB

Ann. N. Y. Acad. Sci. 2011
21713385 Yin and Yang of hypothalamic insulin and leptin signaling in regulating white adipose tissue metabolism

Buettner, C, Scherer, T

Rev Endocr Metab Disord 2011
23562747 Leptin-cytokine crosstalk in breast cancer

Newman, G, Gonzalez-Perez, RR

Mol. Cell. Endocrinol. 2013
21489811 Central insulin and leptin-mediated autonomic control of glucose homeostasis

Marino, JS, Xu, Y, Hill, JW

Trends Endocrinol. Metab. 2011
20600241 Leptin in human physiology and therapeutics

Chou, SH, Dardeno, TA, Moon, HS, Chamberland, JP, Fiorenza, CG, Mantzoros, CS

Front Neuroendocrinol 2010
21622208 Leptin receptor signaling: pathways to leptin resistance

Wauman, J, Tavernier, J

Front. Biosci. 2011
19724019 Recent advances in understanding leptin signaling and leptin resistance

Rui, L, Morris, DL

Am. J. Physiol. Endocrinol. Metab. 2009
22448029 Role of leptin in the pancreatic ?-cell: effects and signaling pathways

Caballero-Garrido, E, Quesada, I, Vieira, E, Nadal, A, Ripoll, C, Gonzalez, A, Ñeco, P, Marroquí, L

J. Mol. Endocrinol. 2012
21147620 Leptin receptors

Kucharska, A, Wasik, M, Ciepiela, O, Stelmaszczyk-Emmel, A, Gorska, E, Popko, K

Eur. J. Med. Res. 2010
22991412 The role of adipokines in beta-cell failure of type 2 diabetes

Brown, JE, Dunmore, SJ

J. Endocrinol. 2013
Cross References
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