Quantitative Expression Analysis of Genes Regulated by Both Obesity and Leptin Reveals a Regulatory Loop between Leptin and Pituitary-derived ACTH

Renz, Mark; Tomlinson, Elizabeth; Hultgren, Bruce; Levin, Nancy; Gu, Qimin; Shimkets, Richard A.; Lewin, David A.; Stewart, Timothy A.

doi:10.1074/jbc.275.14.10429

Cited by 29 publications

(15 citation statements)

References 57 publications

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“…At the level of the pituitary, another study demonstrated that prolonged systemic administration of leptin increased ACTH concentrations in both adrenalectomized female rats and intact animals [30] . In contrast to these studies, chronic administration of leptin reduced POMC expression in the anterior pituitary of obese mice [35] . In rats, contrasting effects of leptin administration on steroid hormone secretion have been documented, with some studies showing a marked stimulation, and others describing a lowering effect of leptin on plasma corticosterone levels, depending on the route and duration of administration [30] .…”

Section: Leptin and The Hpa Axismentioning

confidence: 43%

Adipokines and Cardiovascular Risk in Cushing’s Syndrome

et al. 2011

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Cushing’s syndrome (CS) is associated with increased cardiovascular morbidity and mortality. Recent evidence also suggests that increased cardiovascular risk may persist even after long-term remission of CS. Increased central obesity, a typical feature of CS, is associated with altered production of adipokines, which contributes to the pathogenesis of several metabolic and cardiovascular complications observed in this condition. In vitro and in vivo studies have shown a relationship between cortisol and adipokines in several experimental settings. In patients with either active or ‘cured’ CS, an increase in leptin and resistin levels as well as the release of pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, may be associated with increased cardiovascular risk. For other adipokines, including adiponectin, results are inconclusive. Studies are needed to further elucidate the interactions between clinical and subclinical increases in cortisol production and altered adipokine release in CS.

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Section: Leptin and The Hpa Axismentioning

confidence: 43%

Adipokines and Cardiovascular Risk in Cushing’s Syndrome

et al. 2011

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“…The generation of mature ␣MSH from POMC requires a complex pathway of posttranslational modifications involving numerous enzymes such as PC1 and PC2. Interestingly, Renz et al (29) have suggested that leptin may regulate PC2 expression in the pituitary, raising the possibility that this regulation may also occur in POMC neurons. We therefore cannot rule out that the increase in total ␣MSH in response to leptin is a result of both a stimulatory effect on pomc gene expression (13,16,25) and enhanced posttranslational processing of the POMC precursor.…”

Section: Discussionmentioning

confidence: 99%

N-acetylation of hypothalamic α-melanocyte-stimulating hormone and regulation by leptin

Guo

Münzberg

Stuart

et al. 2004

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

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The central melanocortin system is critical in the regulation of appetite and body weight, and leptin exerts its anorexigenic actions partly by increasing hypothalamic proopiomelanocortin (POMC) expression. The POMC-derived peptide ␣-melanocytestimulating hormone (␣MSH) is a melanocortin 4 receptor agonist, and its potency in reducing energy intake is strongly increased by N-acetylation. The reason for the higher biological activity of N-acetylated ␣MSH (Act-␣MSH) compared with that of N-desacetylated ␣MSH (Des-␣MSH) is unclear, and regulation of acetylation by leptin has not been investigated. We show here that total hypothalamic ␣MSH levels are decreased in leptin-deficient ob͞ob mice and increased in leptin-treated ob͞ob and C57BL͞6J mice. The increase in total ␣MSH occurred as soon as 3 h after leptin injection and was entirely due to an increase in Act-␣MSH. Consistent with this observation, leptin rapidly induced the enzymatic activity of a N-acetyltransferase in the hypothalamus of mice. In 293T cells expressing the melanocortin 4 receptor, Act-␣MSH is far more potent than Des-␣MSH in stimulating cAMP accumulation, an effect caused by a dramatically increased stability of Act-␣MSH. Moreover, Des-␣MSH is rapidly degraded in the hypothalamus after intracerebroventricular injection in rats and was less potent in inhibiting energy intake. The results suggest that leptin activates a N-acetyltransferase in POMC neurons, leading to increased hypothalamic levels of Act-␣MSH. Due to its increased stability, this posttranslational modification of ␣MSH may play a critical role in leptin action via the central melanocortin pathway.T he adipocyte-derived hormone leptin is expressed in fat tissue and acts on the central nervous system to inform key regulatory centers about energy stores (1-3). Leptin receptors (ObRs) are highly expressed within the hypothalamus, including in proopiomelanocortin (POMC) neurons located in the arcuate nucleus (4, 5). POMC-derived neuropeptides, primarily ␣-melanocyte-stimulating hormone (␣MSH), activate the melanocortin 4 receptor (MC4R) and function downstream of leptin signaling to regulate energy balance, although other pathways are also important (6-10). Supporting the role of the melanocortin pathway in leptin action are data showing that central injection of synthetic melanocortin receptor antagonists inhibits the effect of leptin to reduce food intake (10). Furthermore, mutations in the pomc and mc4r genes result in severe obesity in mice (6, 11) and humans (7,12).Studies investigating the regulation of POMC neurons by leptin have focused mainly on gene expression analyses. It is known that fasting, which is a state of low serum leptin levels, results in reduced amounts of POMC mRNA levels. This reduction is also seen in the hypothalamus of the leptin-deficient ob͞ob mice (13-16). In addition, hypothalamic POMC mRNA is stimulated by the administration of recombinant leptin to rodents (16). However, few studies have examined regulation of hypothalamic POMC-derived peptides, such as ...

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“…This method requires no a priori gene sequence and provides Ͼ95% coverage of the expressed genome with a sensitivity of detection greater than 1:100,000 (45). GeneCalling has recently been used to identify genes linked to cardiac hypertrophy, obesity, and endothelial cell differentiation in vitro and it has been extensively confirmed by Northern blot analysis, semiquantitative RT-PCR, and real-time PCR (25,39,45).…”

Section: Adhesion To Fibronectin Through the ␣5␤1 Integrin Is Sufficimentioning

confidence: 99%

α5β1 Integrin Activates an NF-κB-Dependent Program of Gene Expression Important for Angiogenesis and Inflammation

Klein

Fougerolles

Blaikie

et al. 2002

Molecular and Cellular Biology

117

104

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GeneCalling, a genome-wide method of mRNA profiling, reveals that endothelial cells adhering to fibronectin through the ␣5␤1 integrin, but not to laminin through the ␣2␤1 integrin, undergo a complex program of gene expression. Several of the genes identified are regulated by the NF-B transcription factor, and many are implicated in the regulation of inflammation and angiogenesis. Adhesion of endothelial cells to fibronectin activates NF-B through a signaling pathway requiring Ras, phosphatidylinositol 3-kinase, and Rho family proteins, whereas adhesion to laminin has a limited effect. Retroviral transfer of the superrepressor of NF-B, IB-2A, blocks basic fibroblast growth factor-induced angiogenesis in vivo. These results suggest that engagement of the ␣5␤1 integrin promotes an NF-B-dependent program of gene expression that coordinately regulates angiogenesis and inflammation.Angiogenesis, the formation of new blood vessels from preexisting ones, requires endothelial cells to migrate, proliferate, and ultimately assemble into tubes that regulate selective transport of white blood cells and solutes from their lumen to the interstitium and vice versa (20,40). Several observations suggest that angiogenesis and inflammation proceed in a coordinate fashion and sustain one another during wound healing and tissue repair as well as in a variety of chronic inflammatory diseases and in cancer (23). Although it is increasingly clear that endothelial cells mediate angiogenesis and also have broad immune functions (37), the signaling pathways and gene expression mechanisms that allow a coordinate regulation of angiogenesis and inflammation by endothelial cells are incompletely understood.Angiogenesis requires the interaction of endothelial cells with both angiogenic growth factors and extracellular matrix components (13,22,56). The process can be subdivided into two phases. During the invasive and proliferative phase, endothelial cells undergo multiple interactions with a fibronectinrich interstitial matrix, whereas during the maturation phase they assemble a laminin-rich basement membrane and form a capillary (41). Gene knockout studies have indicated that the ␣5␤1 integrin and its ligand fibronectin are required for vasculogenesis in the mouse (15, 57), and peptide and antibody blocking experiments have also implicated this receptor-ligand pair in postnatal angiogenesis (27). The relatively promiscuous ␣v integrins are largely dispensable for vascular development in the embryo (2) but are thought to participate in postnatal angiogenesis in response to growth factors, such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), or tumors (6). In particular, ␣v␤3 promotes the survival and maturation of newly formed blood vessels through inhibition of p53 (7, 50). Finally, antibodies to the collagen-and laminin-binding integrins ␣1␤1 and ␣2␤1 inhibit VEGF-induced angiogenesis, suggesting that these integrins may also play a role in vascular development (44).Integrins have multiple adhesive and ...

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Quantitative Expression Analysis of Genes Regulated by Both Obesity and Leptin Reveals a Regulatory Loop between Leptin and Pituitary-derived ACTH

Cited by 29 publications

References 57 publications

Adipokines and Cardiovascular Risk in Cushing’s Syndrome

Adipokines and Cardiovascular Risk in Cushing’s Syndrome

N-acetylation of hypothalamic α-melanocyte-stimulating hormone and regulation by leptin

α5β1 Integrin Activates an NF-κB-Dependent Program of Gene Expression Important for Angiogenesis and Inflammation

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