Regulation of Catecholamine Synthesis by Leptin

Shibuya, Izumi; Utsunomiya, Kensuke; Toyohira, Yumiko; Ueno, S.; Tsutsui, Masato; Cheah, Tat Beng; Ueta, Yoichi; Izumi, Fujio; Yanagihara, Nobuyuki

doi:10.1111/j.1749-6632.2002.tb04517.x

Cited by 39 publications

(36 citation statements)

References 17 publications

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“…Indeed, leptin injection into ob/ob mice up-regulated circulating concentrations of norepinephrine, leading to elevations in intracellular cAMP (14,15). In keeping with these effects, leptin administration augmented M2 marker expression in WAT from leptin-sensitive ob/ob mice; these effects were blocked by pretreatment with β-adrenergic receptor antagonist propranolol ( Fig.…”

Section: Resultsmentioning

confidence: 53%

CREB pathway links PGE2 signaling with macrophage polarization

Luan

Yoon

Lay

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

244

182

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Obesity is thought to promote insulin resistance in part via activation of the innate immune system. Increases in proinflammatory cytokine production by M1 macrophages inhibit insulin signaling in white adipose tissue. In contrast, M2 macrophages have been found to enhance insulin sensitivity in part by reducing adipose tissue inflammation. The paracrine hormone prostaglandin E2 (PGE2) enhances M2 polarization in part through activation of the cAMP pathway, although the underlying mechanism is unclear. Here we show that PGE2 stimulates M2 polarization via the cyclic AMPresponsive element binding (CREB)-mediated induction of Krupplelike factor 4 (KLF4). Targeted disruption of CREB or the cAMP-regulated transcriptional coactivators 2 and 3 (CRTC2/3) in macrophages downregulated M2 marker gene expression and promoted insulin resistance in the context of high-fat diet feeding. As re-expression of KLF4 rescued M2 marker gene expression in CREB-depleted cells, our results demonstrate the importance of the CREB/CRTC pathway in maintaining insulin sensitivity in white adipose tissue via its effects on the innate immune system.U nder obese conditions, macrophage infiltration and activation in adipose tissue leads to a chronic inflammatory state with increased secretion of proinflammatory cytokines (1). The activation of IkB and Jun N-terminal kinases impairs insulin signaling in metabolic tissues and thereby contributes to insulin resistance (2-4). Classically activated M1 macrophages secrete proinflammatory cytokines, such as TNF-α and IL-12, which promote insulin resistance. Alternatively activated M2 macrophages are thought to protect adipocytes from the development of insulin resistance in response to IL-4 signaling (5, 6). Increases in STAT6 activity stimulate the expression of Krupplelike factor 4 (KLF4), which in turn promotes expression of the M2 program. Obesity causes an M2-to-M1 shift in adipose tissue that leads to insulin resistance (7).The eicosanoid prostaglandin E2 (PGE2) has been found to promote M2 macrophage polarization in part via induction of the cAMP pathway. Indeed, circulating catecholamines also exert potent anti-inflammatory effects on macrophage function via cAMP signaling (8). In this regard, a number of bacteria appear to evade the innate immune system by producing toxins that enhance cAMP production. cAMP stimulates the expression of cellular genes in part via the phosphorylation of CREB at Ser133 and via the dephosphorylation of the cAMP regulated transcriptional coactivators (CRTC) family of coactivators (9). Following its activation, the cyclic AMP-responsive element binding (CREB) pathway appears to block M1 macrophage function in part via the induction of the anti-inflammatory cytokine IL-10 (10, 11). Superimposed on these effects, cAMP also inhibits the expression of proinflammatory cytokines via the induction of class IIa histone deacetylases (HDACs) and subsequent deacetylation of NF-κB.Here we explore the potential roles of the class IIa HDAC and CREB/CRTC pathways in M2 macrophage...

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Section: Resultsmentioning

confidence: 53%

CREB pathway links PGE2 signaling with macrophage polarization

Luan

Yoon

Lay

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

244

182

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“…Interestingly, dehydroepiandrostenedione (DHEA) blocked NGF induced ERK activation and NGF dependent survival in PC12 cells (Ziegler et al 2008). Also the effects of leptin on catecholamine synthesis from medullary cells are mediated in part by ERKs (Utsunomiya et al 2001, Shibuya et al 2002. Clearly, in medullary cells sex steroids impact on the level of ERK activity as demonstrated by different studies (Brown et al 2001, Yanagihara et al 2005.…”

Section: Effectors Of Erk1/2 Activation In Adrenocortical Cellsmentioning

confidence: 98%

“…Also in rat adrenal zona glomerulosa cells ERK1/2 activation blocked cell proliferation and stimulated steroidogenesis (Otis et al 2005, Otis & Gallo-Payet 2007. A role of ERK1/2 for functional aspects of cortical ( Wu et al 2002, Chang et al 2008 or medullary cells (Cox & Parsons 1997, Takekoshi et al 2001, Shibuya et al 2002, Yanagihara et al 2005, Shinkai et al 2007) has also been provided by others. In addition to growth and function also migration is under control by ERK1/2 in adrenomedullary cells (Ho et al 2001(Ho et al , 2005.…”

Section: Intracellular Control Of Adrenal Growthmentioning

confidence: 99%

“…The permanent perception of diverse factors affecting adrenal growth and function argues in favor of one common intracellular target, which coordinates and integrates the different stimuli and which further represents a potent effector of central cellular responses like proliferation, survival, apoptosis, or differentiation. As a potential candidate for an intracellular target in adrenal cells extracellular signal regulated kinases 1/2 (ERK1/2) have been demonstrated to affect cell proliferation , Andreis et al 2000, Lepique et al 2000, Lotfi et al 2000, Whitworth et al 2002, Ferreira et al 2007, apoptosis (Mazzocchi et al 2004, Edwin & Patel 2008 cell survival (Ziegler et al 2006), cell migration (Ho et al 2001(Ho et al , 2005, or synthesis and secretion of cortical ( Wu et al 2002, Otis et al 2005, Kempná et al 2007, Chang et al 2008 or medullary hormones (Cox & Parsons 1997, Shibuya et al 2002. Thus, in fact, ERK1/2 have the potential and format to represent such common targets with multiple biological effects in the adrenal gland as proposed before (Chabre et al 1995).…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of adrenal gland growth: signal integration by extracellular signal regulated kinases1/2

Hoeflich¹,

Bielohuby²

2008

Journal of Molecular Endocrinology

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The adrenal gland influences a multitude of processes during stress response, but also potently affects the immune system, glucose metabolism, electrolyte or water homeostasis, and cardiovascular functions. According to the present understanding, the adrenal cortex is tightly controlled by the hypothalamic-pituitary-adrenal axis. This axis involves hypothalamic CRH and pituitary ACTH which determine processes of adrenocortical growth and function. However, control of the adrenal gland comprises a plethora of additional endogenous or exogenous factors. Among those are diverse hormones, psychosocial parameters, physiological stress, secondary plant products, or even environmental pollutants. In the present review, we summarize the current view of endocrine growth control in the adrenal gland. We then discuss intracellular mechanisms of adrenal growth control and focus on extracellular signal regulated kinases 1/2 ( ERK1/2), which have been demonstrated to be controlled by not only ACTH or angiotensin II, but also by a large number of additional effectors. On the basis of these multiple exogenous or endogenous factors which impact on the adrenal gland through ERK1/2 activity, we speculate on a mechanism by which ERK1/2 act as a central integrative growth regulatory elements in the adrenal gland.

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“…28 Leptin reduces apoptosis in endothelial cells, promoting the development of vascular proliferative disease. 29 Leptin also phosphorylates and activates tyrosine hydroxylase, and subsequently stimulates catecholamine synthesis through MAP kinase in the adrenal medulla, 30 indicating the possible involvement of peripheral leptin in the development of hypertension, in addition to the activation of sympathetic activities. Leptin stimulates in vitro lung cancer (SQ-5) cell proliferation by the activation of the MAP kinase cascade.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of appetite by nasal leptin administration in rats

et al. 2005

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OBJECTIVE: Leptin inhibits appetite and reduces body weight. However, subcutaneous leptin administration is not very effective on weight reduction. The present studies were undertaken to test the hypotheses that nasally administered leptin effectively accesses to the brain and inhibits appetite. METHODS: Recombinant leptin (0.5 mg/rat) was administered into the bilateral nasal spaces of rats (i.n.). Changes in serum immunoreactive leptin (IRL) and cerebrospinal fluid (CSF)-IRL concentrations after i.n. leptin administration were compared after intraperitoneal (i.p.) administration. The influence of 0.1 or 0.5% lysophosphatidylcholine (LPC) as an optimizer of leptin absorption was examined. The anorexic effects of i.n. leptin were compared with i.p. leptin in ad libitum fed rats. RESULTS: The i.n. leptin increased CSF-IRL concentrations, although serum IRL concentrations of rats administered leptin i.n. were lower than those administered i.p. The addition of 0.1 and 0.5% LPC dose-dependently increased serum IRL concentrations, but did not modify CSF-IRL concentrations in i.n. leptin-treated rats. The i.n. leptin inhibited dark-time food consumption at 0-1 h and 3-6 h in ad libitum fed rats. In contrast, i.p. leptin reduced food consumption only for an hour. Phosphorylated signal transducer and activator of transcription (STAT) 3 immunoreactive cells increased in the arcuate nucleus (ARC) of the hypothalamus at 3 h only following i.n. leptin. CONCLUSION: The present study demonstrated that i.n. leptin caused longer inhibition of appetite and phosphorylation of STAT3 in ARC. It is concluded that the trans-nasal route may be useful for the selective access of leptin to the brain in obese people.

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Regulation of Catecholamine Synthesis by Leptin

Cited by 39 publications

References 17 publications

CREB pathway links PGE2 signaling with macrophage polarization

CREB pathway links PGE2 signaling with macrophage polarization

Mechanisms of adrenal gland growth: signal integration by extracellular signal regulated kinases1/2

Inhibition of appetite by nasal leptin administration in rats

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