Leptin is an adipocyte-derived hormone with potent weight reducing effects. Genetically obese rodents with mutations of leptin or the leptin receptor are defective in leptin signaling and develop morbid obesity and diabetes. Interestingly, the levels of both leptin mRNA and protein are increased by up to 20-fold in these animals, suggesting the existence of a feedback mechanism controlling the amount of leptin in circulation. In this report, we attempted to determine whether the up-regulation of circulating leptin in Zucker Diabetic Fatty rats, which are nonresponsive to leptin due to a receptor point mutation, is entirely due to increased expression of leptin. We demonstrate that the high level of circulating leptin in these rats is attributable to at least two factors: increased leptin expression by the adipose tissue and delayed clearance of leptin from circulation due to binding to its soluble receptor. The latter conclusion was supported by three lines of evidence: 1) The soluble leptin receptor is up-regulated by about 20-fold in Zucker Diabetic Fatty rats; 2) Adenovirus-mediated overexpression of the soluble leptin receptor results in a similar -fold increase of circulating leptin; 3) In ob/ob mice, which have no endogenous leptin, exogenously administered leptin reaches a higher level when the soluble leptin receptor is overexpressed. The weightreducing effect of leptin is enhanced in C57Bl/6 ob/ob mice with overexpression of the soluble leptin receptor. Soluble leptin receptor may be a significant factor determining the amount of total leptin in circulation.Leptin is an adipocyte-derived hormone of 167 amino acids (1). It has potent weight-reducing effects in vivo (2-4). In ob/ob mice, the gene encoding leptin is mutated, resulting in morbid obesity and associated abnormalities, including hyperphagia, hypothermia, diabetes, and infertility.The leptin receptor, OB-R, 1 is a member of the cytokine receptor family (5). It is encoded by the diabetes (db) gene, mutation of which also results in morbid obesity and other abnormalities similar to that in ob/ob mice. OB-R is alternatively spliced into at least five transcripts from a single gene. These transcripts encode proteins that are called the long (OBRb), short (OB-Ra, -c, and -d), and soluble (OB-Re) forms of the leptin receptor. With the exception of the soluble leptin receptor, receptor isoforms differ from each other by the alternative use of a unique terminal coding exon (6). OB-Rb is essential in mediating leptin's weight-reducing and other biological effects (6, 7).OB-R is expressed in both the nervous system and peripheral tissues. The relative levels of expression of different receptor isoforms vary among different tissues, providing a possible mechanism of regulating leptin's biological activity at various leptin target sites (8). OB-Rb is enriched in the hypothalamus, the site of leptin's action on food intake and body weight. Leptin activation of OB-Rb within this brain region results in the inhibition of neuropeptide Y/agouti-related protein ...
Leptin is the protein product encoded by the obese (ob) gene. It is a circulating hormone produced primarily by the adipose tissue. ob/ob mice with mutations of the gene encoding leptin become morbidly obese, infertile, hyperphagic, hypothermic, and diabetic. Since the cloning of leptin in 1994, our knowledge in body weight regulation and the role played by leptin has increased substantially. We now know that leptin signals through its receptor, OB-R, which is a member of the cytokine receptor superfamily. Leptin serves as an adiposity signal to inform the brain the adipose tissue mass in a negative feedback loop regulating food intake and energy expenditure. Leptin also plays important roles in angiogenesis, immune function, fertility, and bone formation. Humans with mutations in the gene encoding leptin are also morbidly obese and respond to leptin treatment, demonstrating that enhancing or inhibiting leptin's activities in vivo may have potential therapeutic benefits.
Leptin is an adipocyte-derived hormone with potent effects on food intake and body weight. Genetically obese rodents with mutations of leptin or leptin receptor develop morbid obesity and diabetes. The receptor for leptin, OB-R, is alternatively spliced to at least five transcripts, encoding receptors designated OB-Ra, -b, -c, -d, and -e. OB-Re does not encode a transmembrane domain and is secreted. In humans, transcripts corresponding to OB-Re have not been discovered. However, soluble leptin receptor does circulate in human plasma and represents the major leptin-binding activity. In this report, we attempted to determine whether the soluble leptin receptor may also be derived from membranespanning receptor isoforms by ectodomain shedding. Using stable cell lines expressing both OB-Ra, the most abundant leptin receptor isoform, and OB-Rb, the signaling form of the leptin receptor, we demonstrate that soluble leptin receptor protein can indeed be generated by proteolytic cleavage of these two receptor isoforms in vitro. Experiments using adenoviruses expressing dually tagged OB-Ra or Ob-Rb also demonstrate that soluble leptin receptor may be derived from ectodomain shedding of both receptor isoforms in vivo. Because our earlier and other studies have shown that the soluble receptors modulate the levels as well as activity of leptin, our findings suggest that regulated shedding of the ectodomain of membrane-spanning leptin receptors may represent a novel mechanism of modulating leptin's biological activity.Leptin is an adipocyte-derived hormone of 167 amino acids (1). It has potent weight-reducing effects in vivo (2-4). In ob/ob mice, the gene encoding leptin is mutated, resulting in morbid obesity and associated abnormalities, including hyperphagia, hypothermia, diabetes, and infertility.The leptin receptor, OB-R, is a member of the cytokine receptor family (5). It is encoded by the diabetes (db) gene, mutation of which also results in phenotypes similar to that exhibited by ob/ob mice. OB-R is alternatively spliced into at least five transcripts from a single gene. These transcripts encode proteins that are called the long (OB-Rb), short (OB-Ra, -c, and -d), and soluble (OB-Re) forms of the leptin receptor. With the exception of the soluble leptin receptor, other receptor isoforms differ from each other by the alternative use of a unique terminal coding exon (6). OB-Rb is essential in mediating leptin's weight-reducing effects via the hypothalamus (6, 7).OB-R is expressed in both the nervous system and in peripheral tissues. The relative expression levels of different receptor isoforms vary among tissues, possibly to allow leptin's biological activity to be more precisely regulated at various leptin target sites (8). OB-Rb is enriched in the hypothalamus, the site of leptin's action on food intake and body weight. Leptin activation of OB-Rb within this brain region results in the inhibition of neuropeptide Y/agouti-related protein neurons and activation of pro-opiomelanocortin neurons (9). Leptinactivated pro-o...
Angiopoietin-like protein 4 (Angptl4) is a recently identified circulating protein expressed primarily in adipose tissue and liver. Also known as peroxisome proliferator-activated receptor (PPAR)-␥ angiopoietin-related, fasting induced adipose factor, and hepatic fibrinogen/angiopoietin-related protein, recombinant Angptl4 causes increase of plasma very low density lipoprotein levels by inhibition of lipoprotein lipase activity. Similar to angiopoietins and other angiopoietinlike proteins, Angptl4 contains an amino-terminal coiled-coil domain and a carboxyl-terminal fibrinogenlike domain. We report here that Angptl4 is evolutionarily conserved among several mammalian species and that full-length Angptl4 protein is an oligomer containing intermolecular disulfide bonds. Oligomerized Angptl4 undergoes proteolytic processing to release its carboxyl fibrinogen-like domain, which circulates as a monomer. Angptl4's N-terminal coiled-coil domain mediates its oligomerization, which by itself is sufficient to form higher order oligomeric structure. Adenovirus-mediated overexpression of Angptl4 in 293 cells shows that conversion of full-length, oligomerized Angptl4 is mediated by a cell-associated protease activity induced by serum. These findings demonstrate a novel property of angiopoietin-like proteins and suggest that oligomerization and proteolytic processing of Angptl4 may regulate its biological activities in vivo.
STAT3 is a ubiquitous transcription factor that is indispensable during early embryogenesis. To study the functions of STAT3 postnatally, we generated conditional STAT3-deficient mice. To that end, STAT3 lox/lox mice were crossed with mice expressing Cre under the control of rat insulin II gene promoter (RIP-Cre mice). Immunohistochemical and Western blot analyses showed that STAT3 is deleted from  cells in the islets of Langerhans. Genomic DNA PCR revealed that STAT3 deletion also occurred in the hypothalamus. lox/lox mice also failed to decrease adiposity or to correct other abnormalities in these mice. These data thus suggest that loss of STAT3 in the hypothalamus caused by RIP-Cre action likely interferes with normal body weight homeostasis and glucose metabolism. Signal transducers and activators of transcription (STAT)proteins are a family of latent cytoplasmic transcription factors that are produced in many cell types and that are activated by tyrosine phosphorylation and dimerization in response to a wide variety of extracellular ligands, such as cytokines and growth factors (12,36). One member of this family, STAT3, is expressed ubiquitously and is transiently activated by a large number of ligands, including epidermal growth factor, plateletderived growth factor, interleukin 6 (IL-6), ciliary neurotrophic factor (CNTF), oncostatin M, leukemia inhibitory factor, leptin, growth hormone, and prolactin, as well as a number of oncogenic receptor and nonreceptor (Src-like) tyrosine kinases (12). While gene disruption approaches have been used extensively to define the functions of members of the STAT family of transcription factors (18), the knockout of STAT3 results in early embryonic lethality (42). At the cellular level, STAT3 is required in order to maintain the pluripotency of embryonic stem cells, as demonstrated by the reduced ability of cells to undergo undifferentiated clonal growth when the level of STAT3 is reduced (33).The early embryonic lethality of STAT3 knockout mice prevents any type of physiological study (42). To overcome this limitation, many laboratories have employed tissue-specific conditional gene targeting to study STAT3 function in adult mice (2,3,24,39). These efforts have led to the elucidation of the roles played by STAT3 in various aspects of cytokine and growth factor signaling in different tissues and cell types. For instance, in T cells, STAT3 functions to transduce the antiapoptotic function of IL-6 independently from that of Bcl-2 (41); in macrophages and neutrophils, STAT3 is required to suppress the overshooting of inflammatory stimulus-induced proinflammatory response (40); in keratinocytes, loss of STAT3 results in compromised wound healing (19,34,35); in the mammary gland, loss of STAT3 causes delayed mammary gland involution after weaning (9); in the liver, STAT3 is required to mediate the ability of both IL-6-and lipopolysaccharide-induced acute-phase gene expressions (4); in sensory neurons, loss of STAT3 is associated with their enhanced death, which is normally p...
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