The leptin receptor promoter controls expression of a second distinct protein

Bailleul, Bernard; Akerblom, Ingrid; Strosberg, A. Donny

doi:10.1093/nar/25.14.2752

Cited by 58 publications

(54 citation statements)

References 22 publications

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“…In the human, the first two exons also encode a protein (leptin receptor gene-related protein; ref. 27), which has been identified in Xenopus (GenBank accession no. AW766133; the first four exons of the frog LR gene overlap with the N-terminal sequence of the leptin receptor generelated protein).…”

Section: Discussionmentioning

confidence: 99%

Leptin ( ob gene) of the South African clawed frog Xenopus laevis

Crespi

Denver

2006

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

148

133

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Leptin, the protein product of the obese (ob) gene, is a type-I cytokine hormone secreted by fat that is integral to food intake regulation and influences almost every physiological system in juvenile and adult mammals. Since the identification of leptin in the mouse in 1994, biologists have searched for orthologous genes in other species with limited success. In this article, we report the identification and functional characterization of leptin and leptin receptor (LR) in Xenopus. Despite low amino acid sequence similarity to mammalian leptins (Ϸ35%) the frog protein has a nearly identical predicted tertiary structure and can activate the frog and mouse LRs in vitro. We showed that recombinant frog leptin (rxLeptin) is a potent anorexigen in frogs, as it is in mammals, but this response does not develop until midprometamorphosis. However, during early prometamorphosis, exogenous rxLeptin induced growth and development of the hind limb, where LR mRNA is expressed. The rxLeptin also stimulated cell proliferation in cultured hind limbs from early prometamorphic tadpoles, as measured by [ 3 H]thymidine uptake. These findings are evidence that leptin can influence limb growth and differentiation during early development. Furthermore, the isolation and characterization of leptin and its receptor in a nonamniote provides an essential foundation for elucidating the structural and functional evolution of this important hormone.evolution ͉ metamorphosis ͉ obesity T he protein hormone leptin is a type-I cytokine secreted by adipocytes that acts on the CNS to regulate food intake and metabolism (1, 2). In addition to the regulation of body weight, leptin influences reproduction, growth, stress responses, and thyroid function (3, 4). Actions of leptin are both acute and chronic. For example, postprandial increases in plasma leptin inhibit food intake, whereas daily mean plasma leptin concentrations communicate long-term energy status to the brain (5). These actions are mediated by membrane leptin receptors (LRs), of which six isoforms have been identified in mammals (6). Leptin binding to the long form of the LR (LRb) activates the Janus kinase 2͞signal transducer and activator of transcription 3 (STAT-3) signaling pathway (7), which mediates leptin effects on food intake, glucose metabolism, and weight gain but does not affect fertility (8).The rising prevalence of human obesity and metabolic disorders (9) has focused research on the physiological role of leptin in energy balance and food intake in adult mammals. Recently, links between birth weight and adult-onset metabolic disorders (10) has turned attention to possible relationships among leptin, growth, and development during fetal stages. Circulating leptin is elevated in the human fetus during late gestation and correlates with fat mass and birth weight (11,12). In the fetal mouse, leptin and LR are expressed in liver, heart, hair follicles, and primordial bone before the formation of adipose tissue (13,14), and leptin is found in the circulation of fetal sheep (15)...

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Section: Discussionmentioning

confidence: 99%

Leptin ( ob gene) of the South African clawed frog Xenopus laevis

Crespi

Denver

2006

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

148

133

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“…OB-R and OB-RGRP are cotranscribed in humans from the same promoter (7). The observation that OB-RGRP regulates the cell surface expression of OB-R may explain why this coexpression has been conserved through evolution.…”

Section: Evolutionary Conservation Of the Coexpression Of Ob-r And Itmentioning

confidence: 97%

“…Several of these transcripts encode at least five OB-R isoforms, including the short OB-Ra isoform and the long signaling-competent OB-Rb isoform (1). An additional transcript is generated from the same locus encoding a protein called OB-RGRP [or leptin receptor overlapping transcript (LEPROT)], which does not share any sequence similarity with OB-R (7). In situ hybridization experiments show coexpression of the OB-R transcript and the associated OB-RGRP transcript in the mouse brain, including hypothalamic regions involved in body weight regulation (8).…”

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confidence: 99%

Silencing of OB-RGRP in mouse hypothalamic arcuate nucleus increases leptin receptor signaling and prevents diet-induced obesity

Couturier

Sarkis

Séron

et al. 2007

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

106

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Obesity is a major public health problem and is often associated with type 2 diabetes mellitus, cardiovascular disease, and metabolic syndrome. Leptin is the crucial adipostatic hormone that controls food intake and body weight through the activation of specific leptin receptors (OB-R) in the hypothalamic arcuate nucleus (ARC). However, in most obese patients, high circulating levels of leptin fail to bring about weight loss. The prevention of this ''leptin resistance'' is a major goal for obesity research. We report here a successful prevention of diet-induced obesity (DIO) by silencing a negative regulator of OB-R function, the OB-R gene-related protein (OB-RGRP), whose transcript is genetically linked to the OB-R transcript. We provide in vitro evidence that OB-RGRP controls OB-R function by negatively regulating its cell surface expression. In the DIO mouse model, obesity was prevented by silencing OB-RGRP through stereotactic injection of a lentiviral vector encoding a shRNA directed against OB-RGRP in the ARC. This work demonstrates that OB-RGRP is a potential target for obesity treatment. Indeed, regulators of the receptor could be more appropriate targets than the receptor itself. This finding could serve as the basis for an approach to identifying potential new therapeutic targets for a variety of diseases, including obesity.leptin receptor overlapping transcript ͉ leptin resistance ͉ gene therapy ͉ receptor trafficking ͉ metabolic syndrome L eptin and its receptor (OB-R) were initially identified and characterized because of their involvement in the regulation of energy balance, metabolism, and neuroendocrine responses to food intake (1). Subsequently, leptin has also been shown to be important in wound healing (2), angiogenesis (3), and bone mass and immune system regulation (4, 5). OB-R belongs to the class I cytokine receptor family, which typically uses the JAK/STAT signaling pathway (6). The human OB-R gene on chromosome 1 generates multiple transcripts. Several of these transcripts encode at least five OB-R isoforms, including the short OB-Ra isoform and the long signaling-competent OB-Rb isoform (1). An additional transcript is generated from the same locus encoding a protein called OB-RGRP [or leptin receptor overlapping transcript (LEPROT)], which does not share any sequence similarity with OB-R (7). In situ hybridization experiments show coexpression of the OB-R transcript and the associated OB-RGRP transcript in the mouse brain, including hypothalamic regions involved in body weight regulation (8). Evolutionarily conserved coexpression of two ORFs is often observed in prokaryotes and viruses; however, there are few known cases in eukaryotes (9). Mammals have a single OB-RGRP homologue called LEPROTL1 (leptin receptor overlapping transcript-like 1), that has 70% amino acid sequence similarity with OB-RGRP and whose gene maps on chromosome 8 in humans (10). In yeast, Vps55p, a functional homologue of OB-RGRP, plays a role in protein transport from the Golgi to the vacuole and in the late endoc...

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“…Both SMP1 (small membrane protein 1) and c21orf4 encode predicted homologues of Vps68p, whereas OB-RGRP and LEPROTL1 are homologous to Vps55p (Bailleul et al, 1997). OBRGRP has previously been shown to complement the CPY-trafficking defects of a vps55 mutant when expressed in yeast, indicating functional conservation (Belgareh-Touze et al, 2002).…”

Section: The Vps55/68 Complex Is Required For Two Transport Steps Outmentioning

confidence: 99%

Global Analysis of Yeast Endosomal Transport Identifies the Vps55/68 Sorting Complex

Schluter

Lam

Brumm

et al. 2008

MBoC

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Endosomal transport is critical for cellular processes ranging from receptor down-regulation and retroviral budding to the immune response. A full understanding of endosome sorting requires a comprehensive picture of the multiprotein complexes that orchestrate vesicle formation and fusion. Here, we use unsupervised, large-scale phenotypic analysis and a novel computational approach for the global identification of endosomal transport factors. This technique effectively identifies components of known and novel protein assemblies. We report the characterization of a previously undescribed endosome sorting complex that contains two well-conserved proteins with four predicted membrane-spanning domains. Vps55p and Vps68p form a complex that acts with or downstream of ESCRT function to regulate endosomal trafficking. Loss of Vps68p disrupts recycling to the TGN as well as onward trafficking to the vacuole without preventing the formation of lumenal vesicles within the MVB. Our results suggest the Vps55/68 complex mediates a novel, conserved step in the endosomal maturation process. INTRODUCTIONEndosomal protein sorting is a highly conserved cellular process that is required for receptor down-regulation, viral replication, and development (Katzmann et al., 2002;Morita and Sundquist, 2004). Much progress has been made in recent years in identifying distinct multiprotein complexes that regulate the fusion of primary endocytic vesicles, the maturation of an early endosome into a multivesicular body (MVB), and the recycling of proteins and lipids to other organelles (Gruenberg and Stenmark, 2004;Bonifacino and Rojas, 2006). The ESCRT-I, -II, and -III complexes (endosomal-sorting complex required for transport), which act in sequence to regulate the formation of internal vesicles at the MVB, play a central role in endosome biogenesis (Katzmann et al., 2002;Hurley and Emr, 2006). Other transport complexes regulate the targeting and fusion of endosomes or endosome-derived vesicles with other organelles (Bowers and Stevens, 2005;Bonifacino and Rojas, 2006).Many components of the endosomal-sorting machinery were first identified in yeast genetic screens for mutants that are defective in protein transport to the yeast vacuole, which requires functional endosomal sorting and recycling (Bowers and Stevens, 2005). Most of these components have a conserved role in endosome biogenesis in higher cells. Mammalian homologues have been identified for most if not all yeast ESCRT subunits (von Schwedler et al., 2003;Hurley and Emr, 2006), and at least some of the machinery that regulates recycling from the MVB is also well conserved. For example, the five-subunit retromer complex that mediates endosome-to-trans-Golgi network (TGN) transport in yeast is associated with tubular regions of the endosome in mammalian cells and mediates retrograde transport (Arighi et al., 2004;Seaman, 2004). In the past 20 years, classical genetic screens have identified more than 50 vacuole protein-sorting (VPS) genes (Bowers and Stevens, 2005). Surprisingly, ...

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The leptin receptor promoter controls expression of a second distinct protein

Cited by 58 publications

References 22 publications

Leptin ( ob gene) of the South African clawed frog Xenopus laevis

Leptin ( ob gene) of the South African clawed frog Xenopus laevis

Silencing of OB-RGRP in mouse hypothalamic arcuate nucleus increases leptin receptor signaling and prevents diet-induced obesity

Global Analysis of Yeast Endosomal Transport Identifies the Vps55/68 Sorting Complex

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