Leptin’s Role in Lipodystrophic and Nonlipodystrophic Insulin-Resistant and Diabetic Individuals

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382 Moon et al Effects of Leptin on Glucose Metabolism Endocrine Reviews, June 2013, 34(3):377–412III. Leptin SignalingA. Leptin and JAK2/STAT3/STAT5 signalingIt has been shown that ObRb activates a cascade ofseveral signal transduction pathways, including Janus kinase2(JAK2)/signaltransducerandactivatoroftranscription3 (STAT3) (58) (Table 2 and Figure 1). The STATfamily comprises Src homology-2 (SH2) domain-containingtranscription factors situated in the cytoplasm in quiescentcells. STAT activation results in homo- or heterodimerization,nuclear translocation, and transcriptional activation.STAT3isatranscriptionfactorthatisencodedbytheSTAT3gene in humans (80). It mediates the expression of a varietyof genes in response to cell stimuli and thus plays a key rolein many cellular processes such as cell growth and apoptosis(80, 81). Constitutive STAT3 activation is associated withvarious human cancers and indicates poor prognosis, suggestingthat STAT3 has antiapoptotic and proliferative effects(82–84). In contrast, loss-of-function mutations in theSTAT3 gene result in hyper-IgE syndrome, associated withrecurrent infections as well as disordered bone and toothdevelopment (85, 86).The JAK2/STAT3 pathway is the first identified signalingmechanism associated with the leptin receptor andplays a pivotal role in energy homeostasis and neuroendocrinefunction (80, 81, 84) (Table 2 and Figure 1). Ithas been well established that leptin stimulates ObRbdimerization, which results in JAK2 activation, autophosphorylation,and phosphorylation of Tyr 985 , Tyr 1077 , andTyr 1138 , which act as docking sites for key downstreamsignaling molecules (59). Also, in response to leptin,STAT3 binds to phospho-Tyr 1138 , allowing JAK2 to phosphorylateand stimulate STAT3. Leptin binds to its ObRbreceptor and activates the JAK2/STAT3 pathway in theARC of the hypothalamus, inducing the transcription ofthe anorexigenic POMC and suppressing the orexigenicAgRP/NPY (65). Moreover, leptin administration inducesphosphorylation of JAK2/STAT3 in several cell lines includingkeratinocytes, endometrial cancer cells, murineadipocytes, and mouse adipose tissue (87). We have recentlydemonstrated for the first time that leptin activatesSTAT3 signaling in mouse GT1-7 hypothalamic, C2C12muscle, and AML12 liver cell lines (19). Also, we haveTable 2.Main Signaling Pathways, Main Sites of Action, and Main Effects of Activation by Leptin aSignalingPathway Primary Site of Action EffectsJAK2/STAT3 Hypothalamus, adipocytes, PBMCs, cancer cells, muscle cells, liver cells, etc Regulates appetite, energy balance, and body weightRegulates neuroendocrine functionRegulates cell proliferationRegulates cell growth and apoptosisRegulates bone and tooth developmentSTAT5 Hypothalamus, adipocytes, PBMCs, cancer cells, muscle cells, liver cells, etc Regulates energy balance and body weightRegulates oncogenesisMAPK Hypothalamus, adipocytes, PBMCs, cancer cells, muscle cells, liver cells, etc Regulates appetite and body weightRegulates fatty acid oxidationRegulates cell hypertrophyRegulates cell proliferation and differentiationAMPK Hypothalamus, adipocytes, PBMCs, cancer cells, muscle cells, liver cells, etc Regulates appetite, energy balance, and body weightRegulates gluconeogenesis and energy homeostasisRegulates fatty acid oxidationRegulates insulin resistanceRegulates cell proliferation and survivalRegulates oncogenesisPI3K/Akt/mTOR Hypothalamus, adipocytes, PBMCs, cancer cells, muscle cells, liver cells, etc Regulates appetite, fuel balance, and body weightRegulates insulin/leptin resistanceRegulates sympathetic outflowRegulates neuroendocrine functionRegulates adiposity and glucose homeostasisRegulates cell proliferationFoxO1 Hypothalamus, adipocytes, PBMCs, cancer cells, muscle cells, liver cells, etc Regulates appetite and body weightRegulates energy expenditureRegulates cell proliferation and differentiationRegulates insulin signalingSHP2/MAPK Hypothalamus, adipocytes, PBMCs, cancer cells, muscle cells, liver cells, etc Regulates appetite and body weightRegulates STAT3 signaling with SOCS3Regulates mitosis, proliferation, and differentiationRegulates cell apoptosis and survivalRegulates neuroendocrine functiona Adapted from Refs. 3 and 19–21.The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 10 June 2014. at 01:44 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/er.2012-1053 edrv.endojournals.org 383demonstrated that leptin activates STAT3 signaling in humanadipose tissue (hAT) in vivo and ex vivo and in humanprimary adipocytes in vitro (20, 21). Conversely, disruptingthe ability of the leptin receptor to activate the STAT3pathway in mice leads to severe obesity and several neuroendocrineabnormalities including decreased lineargrowth and infertility (88).Leptin may also activate phosphorylation of ObRb onTyr 1077 , which binds to STAT5 and stimulates STAT5phosphorylation (32) (Figure 1). STAT5 deletion in thebrain causes hyperphagia and obesity to a lesser extentthan STAT3 deletion, suggesting that the ObRb/JAK2/STAT5 pathway may also play a role in the regulationof body weight and energy balance by leptin (70) (Table2). It is important to study in depth the effects of leptinon human hypothalamic or other CNS cells; leptinincreasedSTAT3/STAT5 signaling in several tissuesand cells may have important clinical implications includingoncogenesis.B. Leptin and AMPK signalingAMPK is an evolutionarily conserved serine/threonineprotein kinase central to the regulation of cellgrowth, proliferation, differentiation, motility, and survival(71) (Table 2 and Figure 1). AMPK is considereda cellular energy sensor that is stimulated by an increasein the intracellular AMP to ATP ratio (71). In its classicalrole as an intracellular metabolic stress-sensingkinase, AMPK switches on fatty acid oxidation and glucoseuptake while switching off hepatic gluconeogenesis.It also exerts a broader role in metabolism by controllingappetite (89, 90). AMPK is also involved incellular energy homeostasis through AMPK phosphorylationand inhibition of ACC, thus stimulating fattyacid oxidation (91–93).Leptin’s actions in peripheral tissues are partly due to itseffects on AMPK, which contribute to leptin’s effects onfatty acid oxidation and glucose uptake (94). In mouseskeletal muscle, leptin activates AMPK, which leads tophosphorylation and inhibition of ACC and subsequentstimulation of fatty acid oxidation. There appear to be 2mechanisms through which leptin activates AMPK inmuscle (95, 96). One pathway involves the hypothalamusincluding the -adrenergic pathway, resulting in a prolongedeffect, and as shown in our previous ex vivo and invitro experiments (84), the second mechanism encompassesleptin’s direct effect on skeletal muscle. The abilityof leptin to stimulate fatty acid oxidation in skeletal muscle,which plays a pivotal role in the pathophysiology ofinsulin resistance (97, 98), may prevent lipotoxicity andsubsequent insulin resistance and may underlie leptin’sability to improve insulin resistance and metabolic syndromein hypoleptinemic humans (99, 100), thus supportingthe potential use of leptin in treating lipodystrophyand, possibly, obesity and type 2 diabetes.In contrast to its actions in muscle, leptin has beenshown to exert an inhibitory effect on AMPK in the hypothalamusthat results in stimulation of the hypothalamicACC and subsequent reduction of food intake andweight gain (86). Leptin’s hypothalamic effects on AMPKare in part mediated by the MC4R pathway, which promotesanorexia (86). Moreover, the Ca 2 /calmodulindependentprotein kinase (CaMKK2) is an upstream activatorof AMPK in the hypothalamus, whereas CAMKK2inhibition reduces appetite and body weight (88). Theseobservations indicate that the hypothalamic CaMKK2/AMPK/ACC pathway may also mediate leptin’s anorexigenicaction. Further in vivo studies in humans are neededto elucidate whether leptin administration may alter invivo signaling by altering a third intermediate factor thatpossibly could not be studied in vitro.C. Leptin and PI3K/Akt/mTOR signalingPhosphatidylinositol-3 kinase (PI3K) has been linkedto an extraordinarily diverse group of cellular functions,including cell growth, proliferation, differentiation, motility,survival, and intracellular trafficking (101–103)(Table 2 and Figure 1). These functions are related to theability of class I PI3Ks, which are responsible for the productionof phosphatidylinositol 3-phosphate, phosphatidylinositol(3,4)-bisphosphate, and phosphatidylinositol(3,4,5)-trisphosphate, to modulate protein kinase B, suggestingthat PI3K/Akt/mammalian target of rapamycin(mTOR) signaling pathway play an important role in diabetesmellitus (103, 104). Leptin activates ribosomal S6kinase, an important physiological substrate of mTORkinase in the hypothalamus (92). The PI3K/Akt/mTORsignaling pathway is required for an extremely diversearray of cellular activities including proliferation and survival(105–107).Leptin increases cell proliferation in mouse GT1-7 hypothalamic,C2C12 muscle, and AML12 liver cell linesthrough mTOR and Akt signaling pathways (19). Moreover,in vitro and in vivo studies have suggested that leptinstimulates cell proliferation through PI3K signaling inmyocytes (19, 108) and hepatocytes (109). Leptin mayalso stimulate this pathway in human cancer cells (110,111) and in human adipose (21), liver (112), and muscletissues (19, 113). Similar to the JAK2/STAT3 pathway, thePI3K pathway is also important in central leptin action.This pathway activates POMC-expressing neurons by activatingATP-sensitive potassium channels and voltagegatedcalcium channels (114). Also, similar to insulin, theappetite-suppressing effects of leptin are attenuated by in-The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 10 June 2014. at 01:44 For personal use only. No other uses without permission. . All rights reserved.
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Leptin’s Role in Lipodystrophic and Nonlipodystrophic Insulin-Resistant and Diabetic Individuals

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