No abstract

The pathogenesis of cachexia in patients with uremia is unknown. We tested the hypothesis that uremia-associated cachexia is caused by leptin signaling through the hypothalamic melanocortin receptor 4 (MC4-R). We performed either subtotal nephrectomy (N) or sham operations in WT, leptin receptor-deficient (db/db), and MC4-R knockout (MC4-RKO) mice. The animals were on 17% protein diets, and none of the uremic animals were acidotic. WT-N mice produced a classic syndrome of cachexia characterized by decreased food intake, increased metabolic rate, and loss of lean body mass. Corrected leptin levels were elevated. db/db mice and MC4-RKO mice resisted the cachexic effects of uremia on weight gain, body composition, and metabolic rate. Likewise, treatment of WT mice with intracranial agouti-related peptide reversed the cachexic effects of uremia on appetite, weight gain, body composition, and metabolic rate. Gene expression of ubiquitin C and proteasome subunits C2, C3, and C9 was not changed in the uremic animals, suggesting that other pathways are involved in this model of nonacidotic uremic cachexia. The results of this study suggest that elevated circulating levels of cytokines such as leptin may be an important cause of uremia-associated cachexia via signaling through the central melanocortin system.

The identification of a second case of severe growth failure associated with STAT5b mutation implicates a unique and critical role for STAT5b in GH stimulation of IGF-I gene expression and statural growth.

ALS is critical for maintaining normal serum concentrations of IGF-I and IGFBP-3, most likely by prolonging the half-lives of both proteins. ALS deficiency can be associated with moderate growth failure, but in this patient, the onset and progression of puberty appear to be normal. Altogether the results support a modest role for the ternary complex in the regulation of stature.

Abstract. Leishmania are parasitic protozoa with two major stages in their life cycle: flagellated promastigotes that live in the gut of the insect vector and nonflagellated amastigotes that live inside the lysosomes of the vertebrate host macrophages. The Pro-1 glucose transporter of L. enriettii exists as two isoforms, iso-1 and iso-2, which are both expressed primarily in the promastigote stage of the life cycle. These two isoforms constitute modular structures: they differ exclusively and extensively in their NH~-terminal hydrophilic domains, but the remainder of each isoform sequence is identical to that of the other. We have localized these glucose transporters within promastigotes by two approaches. In the first method, we have raised a polyclonal antibody against the COOH-terminal hydrophilic domain shared by both iso-1 and iso-2, and we have used this antibody to detect the transporters by confocal immunofluorescence microscopy and immunoelectron microscopy. The staining observed with this antibody occurs primarily on the plasma membrane and the membrane of the flagellar pocket, but there is also light staining on the flagellum. We have also localized each isoform separately by introducing an epitope tag into each protein sequence, These experiments demonstrate that iso-1, the minor isoform, resides primarily on the flagellar membrane, while iso-2, the major isoform, is located on the plasma membrane and the flagellar pocket. Hence, each isoform is differentially sorted, and the structural information for targeting each transporter isoform to its correct membrane address resides within the NH2-terminal hydrophilic domain.F IACILITATED glucose transporters are integral membrane proteins (31), present in a diverse spectrum of organisms from bacteria to humans, that shuttle glucose across the plasma membrane and allow uptake and subsequent metabolism of this vital nutrient. Many organisms possess multiple glucose transporter isoforms with distinct biochemical properties (35), and some of these isoforms are localized to different subcellular compartments. Thus, mammalian GLUT1 is targeted primarily to the plasma membrane in fat and muscle cells, whereas GLUT4 is directed primarily to intracellular vesicles (32) that fuse with the plasma membrane after insulin stimulation of the target cell. A problem of considerable interest has been to determine how such isoforms are differentially targeted to their respective subcellular locations. Previous studies on the parasitic protozoan Leishmania enriettii have revealed that this microorganism expresses two closely related isoforms (34) of a major glucose transporter designated Pro-1. Both isoforms of the Pro-1 transporter are expressed in the promastigote or insect stage of the parasite life cycle, but their mRNAs accumulate to only a residual level in the amastigote form of the parasite that lives within the macrophage lysosomes of the vertebrate host (4). These two isoforms (iso-1 and iso-2) possess distinct NH2-terminal hydrophilic domains, predicted to be orien...