The gene product of the ob locus is important in the regulation of body weight. The ob product was shown to be present as a 16-kilodalton protein in mouse and human plasma but was undetectable in plasma from C57BL/6J ob/ob mice. Plasma levels of this protein were increased in diabetic (db) mice, a mutant thought to be resistant to the effects of ob. Daily intraperitoneal injections of either mouse or human recombinant OB protein reduced the body weight of ob/ob mice by 30 percent after 2 weeks of treatment with no apparent toxicity but had no effect on db/db mice. The protein reduced food intake and increased energy expenditure in ob/ob mice. Injections of wild-type mice twice daily with the mouse protein resulted in a sustained 12 percent weight loss, decreased food intake, and a reduction of body fat from 12.2 to 0.7 percent. These data suggest that the OB protein serves an endocrine function to regulate body fat stores.
Leptin, the gene product of the obese gene, may play an important role in regulating body weight by signalling the size of the adipose tissue mass. Plasma leptin was found to be highly correlated with body mass index (BMI) in rodents and in 87 lean and obese humans. In humans, there was variability in plasma leptin at each BMI suggesting that there are differences in its secretion rate from fat. Weight loss due to food restriction was associated with a decrease in plasma leptin in samples from mice and obese humans.
Abstract-When apolipoprotein A-I mimetic peptides synthesized from either D-or L-amino acids were given orally to LDL receptor-null mice, only the peptide synthesized from D-amino acids was stable in the circulation and enhanced the ability of HDL to protect LDL against oxidation. The peptide synthesized from L-amino acids was rapidly degraded and excreted in the urine. When a peptide synthesized from D-amino acids (D-4F) was administered orally to LDL receptor-null mice on a Western diet, lesions decreased by 79%. When added to the drinking water of apoE-null mice, D-4F decreased lesions by approximately 75% at the lowest dose tested (0.05 mg/mL). The marked reduction in lesions occurred independent of changes in total plasma or HDL-cholesterol. Key Words: atherosclerosis Ⅲ HDL Ⅲ apo A-I Ⅲ LDL oxidation I nfusion 1 or transgenic expression 2 of apo A-I, the major apolipoprotein of HDL, protects against atherosclerosis in animals. Proposed mechanisms by which apo A-I protects include reverse cholesterol transport 3 and removal of low levels of oxidized lipids, "seeding molecules" required to oxidize LDL. 4 -6 Apo A-I and class A amphipathic helical peptide analogs of apo A-I remove these "seeding molecules" and prevent LDL oxidation. 4,5 Intraperitoneal administration of an apo A-I mimetic peptide enhanced the ability of HDL to protect LDL against oxidation and protected mice from diet-induced atherosclerosis without changing plasma cholesterol levels. 7 The major limitation for the use of apo A-I or apo A-I mimetic peptides as pharmacological agents has been the need for parenteral administration. Mammalian enzymes such as proteases recognize peptides and proteins synthesized from L-amino acids but rarely recognize those synthesized from D-amino acids. We report here that orally administered apo A-I mimetic peptides synthesized from D-amino acids dramatically inhibit atherosclerosis in mice independent of changes in total plasma or HDL-cholesterol. Methods MiceFemale LDL receptor-null or apoE-null mice on a C57BL/6J background were from Jackson Laboratory, Bar Harbor, Maine. LDL receptor-null mice were maintained on chow diet (Ralston Purina) until they were 4-weeks old when they were switched to a Western diet (Teklad, Madison, WI, diet No. 88137) for 6 weeks. ApoE-null mice were maintained on chow diet throughout the study. LDL receptor-null mice received the test peptide or a vehicle control by gastric gavage twice daily for the periods indicated. At 4-weeks old, the test peptide was added to the drinking water of some of the apoE-null mice and the apoE-null mice were continued on the chow diet. The lyophilized peptide was easily dissolved in a measured quantity of drinking water resulting in a clear solution and was measured and replaced with fresh solution every other day.Mice were bled under anesthesia from the retroorbital venous plexus with Animal Research Committee approval. Atherosclerotic lesions were measured as described. 8 LipoproteinsLDL and HDL were isolated as described. 4 Blood was obtained fr...
Chromatin dynamics that regulate Ifng gene expression are incompletely understood. By using cross-species comparative sequence analyses, we have identified conserved noncoding sequences (CNSs) upstream of the Ifng gene, one of which, located -22 kb from the transcriptional start site, contains clustered consensus binding sequences of transcription factors that function in T cell differentiation. CNS-22 was uniquely associated with histone modifications typical of accessible chromatin in both T helper 1 (Th1) and Th2 cells and demonstrated significant and selective T-bet (T-box transcription factor expressed in T cells, Tbx21)-dependent binding and enhancer activity in Th1 cells. Deletion of CNS-22 in the context of an Ifng reporter transgene ablated T cell receptor-dependent and -independent Ifng expression in Th1 effectors and similarly blocked expression by cytotoxic T lymphocytes and natural killer cells. Thus, a single distal element may be essential for Ifng gene expression by both innate and adaptive immune effector cell lineages.
We tested the hypothesis that innate immune signaling in utero could disrupt the structural development of the fetal lung, contributing to the pathogenesis of bronchopulmonary dysplasia. Injection of Escherichia coli lipopolysaccharide (LPS) into the amniotic fluid of E15 BALB/cJ mice increased the luminal volume density of fetal mouse lungs at embryonic day (E) 17 and E18. LPS also increased luminal volume and decreased distal lung branching in fetal mouse lung explants. This effect required NF-B activation and functional Toll-Like Receptor 4. Airway branching may require fibronectin-dependent epithelial-mesenchymal interactions, representing a potential target for innate immune signaling. Anti-fibronectin antibodies and LPS both blocked distal lung branching. By immunofluorescence, fibronectin localized to the clefts between newly formed airways but was restricted to peripheral mesenchymal cells in LPS-exposed explants. These data suggest that LPS may alter the expression pattern of mesenchymal fibronectin, potentially disrupting epithelial-mesenchymal interactions and inhibiting distal airway branching and alveolarization. This mechanism may link innate immune signaling with defects in structural development of the fetal lung. Developmental Dynamics 233:553-561, 2005.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.