Leptin receptor knockout-induced depression-like behaviors and attenuated antidepressant effects of exercise are associated with STAT3/SOCS3 signaling

Leptin in depression: a potential therapeutic target

“…CSDS mice displayed central leptin resistance; administration of a melanocortin agonist worsens stress-induced behavioral deficits, while mice lacking the melanocortin 4-receptor display attenuated symptoms β3-adrenergic receptors 65 Lep (ob/ob) mice LepTg mice DIO mice FST, SPT Excess leptin reversed depression-like behaviors; leptin failed to induce an antidepressant action or alter c-Fos expression in the hippocampus of DIO mice, but significantly increased hippocampal BDNF concentrations in CD mice TrkB/BDNF signaling pathway in hippocampus 67 LeprDAT-Cre mice (LepRb was selectively deleted in dopamine neurons.) SPT, FST, TST LeprDAT-Cre mice displayed an anxiogenic-like phenotype, while depression-like behaviors were not affected; microinjection of the D1 antagonist SCH23390 into the CeA attenuated the anxiogenic phenotype DA signalings in midbrain 70 CUS rats OFT, SPT, FST Leptin administration reversed the CUS-induced reduction of hippocampal neurogenesis and depression-like behaviors; leptin increased β-catenin and reversed the inhibitory effects of dexamethasone on β-catenin GSK-3β/β-catenin signaling-dependent neurogenesis 66 LepRb cKO mice (LepRb was ablated in glutamatergic neurons of forebrain) FST, TST, RT, SPT, LHT, Hot-plate test, EPM, OFT, LDT Lepr cKO mice displayed depression-like behavioral deficits loss of Lepr in forebrain glutamatergic neurons facilitated NMDA-induced hippocampal LTD NMDA-mediated LTD 73 LepRb (db/db) mice SPT, FST, TST, LA LepRb (db/db) displayed resistance to treatment with either fluoxetine or desipramine; fluoxetine failed to stimulate phosphorylation of Akt(Thr308) and GSK-3β(Ser9) in the hippocampus and PFC of db/db mice Akt/GSK signaling 68 LepRb (db/db) mice SPT, FST, TST, OFT LepRb (db/db) mice displayed depression-like behaviors; STAT3 activity and phosphorylation at Tyr 705 were decreased by LepRb KO, which did not involve iIKKb/NFjB signaling STAT3/SOCS3 signaling 69 CSDS chronic social defeat stress, CUS chronic unpredictable stress, LA locomotor activity, TST tail suspension test, FST forced swim test, SPT saccharin preference test, LHT learned helplessness test, EPM elevated plus-maze, OFT open-field test, LDT light dark test, RT rotarod test, LepTg mice (transgenic skinny mice overexpressing leptin in the liver), ...…”

“…Studies in mice with genetic deletions of the leptin gene and the LepRb gene further confirmed the critical role of leptin in depression. LepRb (db/db) mice 68 , 69 and Lep (ob/ob) mice 67 display depression-like behavioral deficits (see Table 2 ). Leptin was reported to stimulate the glycogen synthase kinase (GSK)-3β/β-catenin signaling pathway and reverse the inhibitory effects of a glucocorticoid receptor agonist on β-catenin, indicating that GSK-3β/β-catenin signaling pathway-dependent neurogenesis is implicated in leptin’s antidepressant effect 66 .…”

Problematic eating behaviours, changes in appetite, and weight gain in Major Depressive Disorder: The role of leptin

“…In animal studies, chronic stress decreases plasma leptin levels (Lu et al, 2006) and insufficient circulating leptin is associated with MDD-like behaviours (e.g. Ge et al, 2013;Liu et al, 2017). Administration of leptin to rats after laboratory stressors reversed MDD-like behaviour; suggesting that leptin may also have antidepressant like efficacy (Kim et al, 2006;Hirano, Miyata & Kamei, 2007).…”

Mood‐related central and peripheral clocks

“…A number of rodent studies have revealed an antidepressant effect of leptin, with the hippocampus being a primary site of action (Garza, Guo, Zhang, & Lu, ; Lu, Kim, Frazer, & Zhang, ; Yamada et al., ). Furthermore, global and site‐specific (i.e., hippocampus and cortex) knockout of the leptin receptor induces depressive‐like behavior (Guo, Huang, Garza, Chua, & Lu, ; Guo et al., ; Liu et al., ; Sharma, Elased, Garrett, & Lucot, ). In humans, high levels of leptin are associated with atypical depression, with the association being more robust for increased adiposity, appetite, and weight (Milaneschi, Lamers, Bot, Drent, & Penninx, ).…”