A new brain glucosensor and its physiological significance

Oomura, Y.; Sasaki, Kohsuke; Suzuki, Kenji; Mutô, Toshinosuke; Li, Aijun; Ogita, Zen-ichi; Hanai, Kazuhiko; Tooyama, Ikuo; Kimura, Hiroshi; Yanaihara, Noboru

doi:10.1093/ajcn/55.1.278s

Cited by 69 publications

(54 citation statements)

References 17 publications

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“…For example, fasting reduces, and refeeding increases, endogenous hypothalamic FGF expression (mRNA and protein levels), and icv-administered FGF1 or -2 decreases food intake in rats (20,40). Feeding suppression by FGF1 is associated with upregulation of c-Fos activity in periventricular astrocytes (58) and increased protein kinase C activity in glucose-sensitive neurons of the lateral hypothalamus (41). icv-Administered anti-FGF1, anti-FGF2, or anti-FGFR1 polyclonal antibodies increase food intake (28,52).…”

Section: Discussionmentioning

confidence: 99%

Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys

Sun¹,

Malabunga²,

Tonra³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Leibel RL, Kussie P. Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys. Am J Physiol Endocrinol Metab 292: E964 -E976, 2007. First published November 28, 2006; doi:10.1152/ajpendo.00089.2006.-We generated three fully human monoclonal antibody antagonists against fibroblast growth factor receptor-1 (FGFR1) that potently block FGF signaling. We found that antibodies targeting the c-splice form of the receptor (FGFR1c) were anorexigenic when administered intraperitoneally three times weekly to mice, resulting in rapid, dose-dependent weight loss that plateaued (for doses Ͼ4 mg/kg) at 35-40% in 2 wk. Animals appeared healthy during treatment and regained their normal body weights and growth trajectories upon clearance of the antibodies from the bloodstream. Measurements of food consumption and energy expenditure indicated that the rapid weight loss was induced primarily by decreased energy intake and not by increased energy expenditure or cachexia and was accompanied by a greater reduction in fat than lean body mass. Hypophagia was not caused through malaise or illness, as indicated by absence of conditioned taste aversion, pica behavior, and decreased need-induced salt intake in rats. In support of a hypothalamic site of action, we found that, after intraperitoneal injections, anti-FGFR1c (IMC-A1), but not a control antibody, accumulated in the median eminence and adjacent mediobasal hypothalamus and that FGFR1c is enriched in the hypothalamus of mice. Furthermore, a single intracerebroventricular administration of 3 g of IMC-A1 via the 3rd ventricle to mice caused an ϳ36% reduction in food intake and an ϳ6% weight loss within the ensuing 24 h. Our data suggest that FGF signaling through FGFR1c may play a physiological role in hypothalamic feeding circuit and that blocking it leads to hypophagia and weight loss. energy homeostasis; hypothalamus; fibroblast growth factor receptor; food intake; obesity THE FGF-FGFR AXIS (fibroblast growth factor-fibroblast growth factor receptor) plays a central role in embryonic development, osteogenesis, tissue maintenance, and repair (24,42,46). FGF signaling is complex: at least 22 ligands are known that signal through four distinct cell surface receptors (FGFR1, -2, -3, and -4). Some FGF-knockouts (such as FGF4, -8, -9, -10, -18 and FGFR1) are embryonic lethal; others generate relatively mild phenotypes due to considerable redundancy in the signaling pathway(s) (10,24,42,46). Loss-of-function mutations in FGFR1 have been implicated in instances of hypogonadotropic hypogonadism (Kallmann syndrome), indicating a role for the receptor in human central nervous system (CNS)/hypothalamic development (45). FGF ligand-receptor binding induces receptor dimerization and autophosphorylation, leading to downstream activation of effector molecules such as mitogen-activating protein kinase (MAPK). In FGFR1, -2, and -3, alternative splicing of the exons encoding the third IgG-like domain produces either the b-or...

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Section: Discussionmentioning

confidence: 99%

Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys

Sun¹,

Malabunga²,

Tonra³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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“…Glucose level elevation in cerebro-spinal fluid, following food intake, induces bFGF synthesis and its release by ependymal cells, which are glial cells related to astrocytes [47]. In the case of hyperglycemia the glucose level could be high enough to elicit a similar induction of bFGF but also in other glial cells such as astrocytes.…”

Section: Aldose Reductase Growth Factors Glucose and Growth Controlmentioning

confidence: 99%

Long‐term induction of an aldose reductase protein by basic fibroblast growth factor in rat astrocytes in vitro

Laeng¹,

Bouillon²,

Taupenot

et al. 1995

Electrophoresis

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Basic fibroblast growth factor (bFGF) is known to elicit various developmental-like effects on astrocytes in vitro, but these effects were studied mainly over short-term periods. In this work we asked the question whether bFGF could induce long-term effects on rat astrocytes in culture. This factor was found to induce only a transient mitogenic effect lasting less than 48 h, even when the treatment was carried on for 4 days. By contrast, it induced long-term effects on the rate of synthesis of several proteins as seen by two-dimensional polyacrylamide gel electrophoresis after labeling the cells with [35S]methionine. The most upregulated protein was extracted from preparative gels of soluble extracts of cultured bFGF-treated astrocytes and of normal brain. It was characterized by internal amino acid microsequencing. Two tryptic digest peptides had N-terminal sequences similar to rat lens aldose reductase. This protein was also expressed in oligodendroglial and neuronal cells in culture, but it was not upregulated by bFGF. Aldose reductase is thought to be involved in a minor pathway of glucose metabolism and in diabetic complications. Its long-term regulation by bFGF will possibly help in the understanding of its actual physiological role.

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“…Bidirectional inward and outward transport occurs at all interfaces depicted; however, this review emphasizes transport of substances into the brain. (21,24,30,38,68) Ependyma LV, 3V, 4V Leaky c Single Allows the CSF Bsink action^on the brain due to high permeability (11,56,57,59,61,62) CVOs 3V, 4V Tight Single Integrates hormonal and neural activity to effect fluid homeostasis (2,38,75,76,111) PiaYglia SAS d Leaky Multiple Protects brain by filtering and buffering actions on SAS CSF (3,148,149) Arachnoid SAS Tight Multiple Secretes neurotrophic peptides and reabsorbs CSF in the villi (1Y3, 34,40,127,129) a Virtually all epithelia in the CSF system can metabolize drugs. b LV, 3V, and 4V refer to the lateral, third, and fourth ventricles, respectively.…”

Section: Choroidal Blood Flow and Interstitial Fluid Dynamicsmentioning

confidence: 99%

Enhanced Prospects for Drug Delivery and Brain Targeting by the Choroid Plexus–CSF Route

et al. 2005

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The choroid plexus (CP), i.e., the blood-cerebrospinal fluid barrier (BCSFB) interface, is an epithelial boundary exploitable for drug delivery to brain. Agents transported from blood to lateral ventricles are convected by CSF volume transmission (bulk flow) to many periventricular targets. These include the caudate, hippocampus, specialized circumventricular organs, hypothalamus, and the downstream pia-glia and arachnoid membranes. The CSF circulatory system normally provides micronutrients, neurotrophins, hormones, neuropeptides, and growth factors extensively to neuronal networks. Therefore, drugs directed to CSF can modulate a variety of endocrine, immunologic, and behavioral phenomema; and can help to restore brain interstitial and cellular homeostasis disrupted by disease and trauma. This review integrates information from animal models that demonstrates marked physiologic effects of substances introduced into the ventricular system. It also recapitulates how pharmacologic agents administered into the CSF system prevent disease or enhance the brain's ability to recover from chemical and physical insults. In regard to drug distribution in the CNS, the BCSFB interaction with the blood-brain barrier is discussed. With a view toward translational CSF pharmacotherapy, there are several promising innovations in progress: bone marrow cell infusions, CP encapsulation and transplants, neural stem cell augmentation, phage display of peptide ligands for CP epithelium, CSF gene transfer, regulation of leukocyte and cytokine trafficking at the BCSFB, and the purification of neurotoxic CSF in degenerative states. The progressively increasing pharmacological significance of the CP-CSF nexus is analyzed in light of treating AIDS, multiple sclerosis, stroke, hydrocephalus, and Alzheimer's disease.

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A new brain glucosensor and its physiological significance

Cited by 69 publications

References 17 publications

Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys

Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys

Long‐term induction of an aldose reductase protein by basic fibroblast growth factor in rat astrocytes in vitro

Enhanced Prospects for Drug Delivery and Brain Targeting by the Choroid Plexus–CSF Route

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