Leptin Signaling in Obesity
Obesity is a multi-factorial trait primarily caused by an imbalance between energy intake and expenditure, leading to fat deposition in the body. This condition is exacerbated by an underlying genetic susceptibility to weight gain. Leptin is one of the 'satiety factors' that signals the status of energy stores to the hypothalamus. It is a peptide hormone produced mainly by adipocytes. Its production is regulated by indicators of positive energy status such as insulin and glucocorticoids...
Pathway Summary
Obesity is a multi-factorial trait primarily caused by an imbalance between energy intake and expenditure, leading to fat deposition in the body. This condition is exacerbated by an underlying genetic susceptibility to weight gain. Leptin is one of the 'satiety factors' that signals the status of energy stores to the hypothalamus. It is a peptide hormone produced mainly by adipocytes. Its production is regulated by indicators of positive energy status such as insulin and glucocorticoids. Adequate levels of leptin not only turn off the pathways for hyperphagia and obesity but also permit energy expenditure towards biological processes such as reproduction and growth.Leptin signals via the long form of its receptor LEPRb, which is found on POMC (pro-opiomelanocortin)/CART (cocaine and amphetamine-regulated transcript) and NPY (neuropeptide Y)/AGRP (agouti-related peptide) neurons in the hypothalamus. The former neurons produce the anorexigenic peptides POMC and CART, while the latter produce the orexigenic peptides NPY and AGRP. Under conditions of positive energy status, Leptin released by adipocytes binds to LEPRb on neurons in the hypothalamus, triggering multiple signal transduction pathways. For example, on being activated by ligand binding, LEPRb activates the JAK2-STAT3 pathway which eventually leads to increased expression of SOCS3 and POMC in POMC neurons while increasing SOCS3 and decreasing NPY expression in NPY neurons. SOCS3 inhibits leptin signaling by inhibiting JAK2 phosphorylation. Leptin also signals via the PI3K/AKT pathway leading to phosphorylation and nuclear exclusion of FOXO1, thereby indirectly inhibiting expression of NPY and AGRP while facilitating the expression of POMC. Leptin also inhibits ghrelin-induced activation of NPY neurons via the PI3K/PDE3 pathway. Thus, leptin in response to satiety mediates the induction of the anorexigenic peptide POMC while suppressing orexigenic peptides, NPY and AGRP. POMC is processed to α-MSH which then activates downstream energy expenditure pathways. Inhibition of NPY and AGRP leads to inhibition of hyperphagia and obesity.
Leptin Signaling in Obesity Genes list
Explore Genes related to Leptin Signaling in Obesity
ADCY1adenylate cyclase 1 ADCY10adenylate cyclase 10 ADCY2adenylate cyclase 2 ADCY3adenylate cyclase 3 ADCY4adenylate cyclase 4 ADCY5adenylate cyclase 5 ADCY6adenylate cyclase 6 ADCY7adenylate cyclase 7 ADCY8adenylate cyclase 8 ADCY9adenylate cyclase 9 AGRPagouti related neuropeptide AKT1AKT serine/threonine kinase 1 AKT2AKT serine/threonine kinase 2 AKT3AKT serine/threonine kinase 3 CAMPcathelicidin antimicrobial peptide FOXO1forkhead box O1 GHRLghrelin and obestatin prepropeptide GHSRgrowth hormone secretagogue receptor GRB2growth factor receptor bound protein 2 GUCY1A1guanylate cyclase 1 soluble subunit alpha 1 GUCY1B1guanylate cyclase 1 soluble subunit beta 1 JAK2Janus kinase 2 LEPleptin LEPRleptin receptor MAP2K1mitogen-activated protein kinase kinase 1 MAP2K2mitogen-activated protein kinase kinase 2 MAPK1mitogen-activated protein kinase 1 MAPK14mitogen-activated protein kinase 14 MAPK3mitogen-activated protein kinase 3 NOTUMnotum, palmitoleoyl-protein carboxylesterase NPYneuropeptide Y PDE3Aphosphodiesterase 3A PDE3Bphosphodiesterase 3B PDIA3protein disulfide isomerase family A member 3 PIK3C2Aphosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha PIK3C2Bphosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 beta PIK3C2Gphosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 gamma PIK3C3phosphatidylinositol 3-kinase catalytic subunit type 3 PIK3CAphosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha PIK3CBphosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta PIK3CDphosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta PIK3CGphosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma PIK3R1phosphoinositide-3-kinase regulatory subunit 1 PIK3R2phosphoinositide-3-kinase regulatory subunit 2 PIK3R3phosphoinositide-3-kinase regulatory subunit 3 PIK3R4phosphoinositide-3-kinase regulatory subunit 4 PIK3R5phosphoinositide-3-kinase regulatory subunit 5 PIK3R6phosphoinositide-3-kinase regulatory subunit 6 PLCB1phospholipase C beta 1 PLCB2phospholipase C beta 2 PLCB3phospholipase C beta 3 PLCB4phospholipase C beta 4 PLCD1phospholipase C delta 1 PLCD3phospholipase C delta 3 PLCD4phospholipase C delta 4 PLCE1phospholipase C epsilon 1 PLCG1phospholipase C gamma 1 PLCG2phospholipase C gamma 2 PLCH1phospholipase C eta 1 PLCH2phospholipase C eta 2 PLCL1phospholipase C like 1 (inactive) PLCL2phospholipase C like 2 PLCZ1phospholipase C zeta 1 POMCproopiomelanocortin PRKACAprotein kinase cAMP-activated catalytic subunit alpha PRKACBprotein kinase cAMP-activated catalytic subunit beta PRKACGprotein kinase cAMP-activated catalytic subunit gamma PRKAG1protein kinase AMP-activated non-catalytic subunit gamma 1 PRKAG2protein kinase AMP-activated non-catalytic subunit gamma 2 PRKAR1Aprotein kinase cAMP-dependent type I regulatory subunit alpha PRKAR1Bprotein kinase cAMP-dependent type I regulatory subunit beta PRKAR2Aprotein kinase cAMP-dependent type II regulatory subunit alpha PRKAR2Bprotein kinase cAMP-dependent type II regulatory subunit beta PTPN11protein tyrosine phosphatase non-receptor type 11 SOCS3suppressor of cytokine signaling 3 STAT3signal transducer and activator of transcription 3