Biomedical subjects

N E Rawson

Publications and source records attributed to N E Rawson.

7 recordsLinked to original sources

PubMed1998

Distribution and phenotype of neurons containing the ATP-sensitive K+ channel in rat brain.

Select groups of neurons within the brain alter their firing rate when ambient glucose levels change. These glucose-responsive neurons are integrated into systems which control energy balance in the body. They contain an ATP-sensitive K+ channel (KATP) which mediates this response. KATP channels are composed of an inwardly rectifying pore-forming unit (Kir6.1 or Kir6.2) and a sulfonylurea binding site. Here, we examined the anatomical distribution and phenotype of cells containing Kir6.2 mRNA within the rat brain by combinations of in situ hybridization and immunocytochemistry. Cells containing Kir6. 2 mRNA were widely distributed throughout the brain without apparent concentration in areas known to contain specific glucose-responsive neurons. Kir6.2 mRNA was present in neurons expressing neuron-specific enolase, tyrosine hydroxylase, neuropeptide Y (NPY) and the glutamic acid decarboxylase isoform, GAD65. No astrocytes expressing glial fibrillary acidic protein or oligodendrocytes expressing carbonic anhydrase II were found to co-express Kir6.2 mRNA. Virtually all of the NPY neurons in the hypothalamic arcuate n. and catecholamine neurons in the substantia nigra, pars compacta and locus coeruleus contained Kir6.2 mRNA. Epinephrine neurons in the C2 area also expressed high levels of Kir6.2, while noradrenergic neurons in A5 and A2 areas expressed lower levels. The widespread distribution of Kir6.2 mRNA suggests that the KATP channel may serve a neuroprotective role in neurons which are not directly involved in integrating signals related to the body's energy homeostasis.

Adenosine Triphosphate↗

PubMed1997

Selectivity and response characteristics of human olfactory neurons.

Transduction mechanisms were investigated in human olfactory neurons by determining characteristics of odorant-induced changes in intracellular calcium concentration ([Ca2+]i). Olfactory neurons were freshly isolated from nasal biopsies, allowed to attach to coverslips, and loaded with the calcium-sensitive indicator fura-2. Changes in [Ca2+]i were studied in response to exposure to individual odors, or odorant mixtures composed to distinguish between transduction pathways mediated by adenosine 3'5'-monophosphate (cAMP; mix A) or inositol 1,4,5-trisphosphate (InsP3; mix B). Overall, 52% of biopsies produced one or more odorant-responsive olfactory neurons, whereas 24% of all olfactory neurons tested responded to odorant exposure with a change in [Ca2+]i. As in olfactory neurons from other species, the data suggest that odorant exposure elicited calcium influx via second-messenger pathways involving cAMP or InsP3. Unlike olfactory neurons from other species that have been tested, some human olfactory neurons responded to odorants with decreases in [Ca2+]i. Also in contrast with olfactory neurons from other species, human olfactory neurons were better able to discriminate between odorant mixtures in that no neuron responded to more than one type of odor or mixture. These results suggest the presence of a previously unreported type of olfactory transduction mechanism, and raise the possibility that coding of odor qualities in humans may be accomplished to some degree differently than in other vertebrates, with the olfactory neuron itself making a greater contribution to the discrimination process.

Adolescent↗

PubMed1996

Fatty acid oxidation modulates the eating response to the fructose analogue 2,5-anhydro-D-mannitol.

The fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) stimulates feeding behavior in rats apparently through its effects on hepatic energy metabolism, where it reduces glucose utilization, traps phosphate, and decreases ATP. The extent to which the magnitude and duration of the eating response are dependent on the ability of the liver to switch to fat oxidation for energy production was investigated by manipulating substrate availability through dietary and pharmacological means. Rats adapted to a high-fat, low-carbohydrate diet preferentially use fat fuels for hepatic energy production and were insensitive to the effects of 2,5-AM on food intake. The lack of an eating response occurred despite similar changes in plasma fuels and liver glycogen compared with rats fed a low-fat, high-carbohydrate diet. In contrast, inhibiting fatty acid oxidation with methyl palmoxirate, which blocks transport of long-chain fatty acids to the mitochondria, potentiated the ability of 2,5-AM to stimulate feeding without altering its effects on plasma and liver fuels. These data demonstrate that the eating response to 2,5-AM is modulated by the availability of fat fuels and implicate a mechanism for initiation of feeding that is not dependent on inhibition of carbohydrate metabolism per se but rather integrates information about the use of both types of fuels.

Animals↗

PubMed1995

Functionally mature olfactory neurons from two anosmic patients with Kallmann syndrome.

Patients with Kallmann syndrome (KS) exhibit hypogonadotropic hypogonadism and anosmia [Kallmann et al., Am. J. Mental Def., 48 (1944) 203-236] secondary to failure of gonadotropin-releasing hormone (GnRH)-producing neurons to migrate from the olfactory placode to the brain, and to agenesis of the olfactory bulbs. It has been hypothesized that olfactory neurons (ON) from individuals with KS are immature partly on the basis of studies in animals showing that lack of synaptic connection of ON with the olfactory bulb results in expression of immature ON [Schwob et al., J. Neurosci., 12 (1979) 880-883]. To test this assumption, we obtained olfactory tissue samples from two males diagnosed with KS on the basis of medical history and MRI studies. Both patients were anosmic. The functioning of cells isolated from biopsies taken from the upper middle turbinate and septum was studied by measuring changes in intracellular Ca2+ concentration ([Cai]) using dual excitation fluorescence microscopy. Biopsies from both patients yielded cells that morphologically appeared to be ON. Seven of 16 cells that morphologically resembled ON responded with a change in [Cai] upon stimulation with an odorant mixture. These studies show that at least some ON in KS individuals are functionally mature and suggest that complete development of the olfactory bulbs is not required for differentiation of mature human ON.

Adolescent↗

PubMed1994

Hepatic phosphate trapping, decreased ATP, and increased feeding after 2,5-anhydro-D-mannitol.

The mechanism by which the fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) elicits feeding behavior was investigated by studying its metabolism and biochemical effects in liver. Thin-layer chromatography of liver extracts from rats given 2,5-AM containing 14C-labeled 2,5-AM showed that the analogue is phosphorylated in vivo with a time course that parallels the eating response. In vivo 31P nuclear magnetic resonance spectroscopy of rat liver during intravenous infusion of 2,5-AM and high-resolution nuclear magnetic resonance analyses of liver extracts showed that 2,5-AM is rapidly phosphorylated in liver, trapping hepatic phosphate and decreasing ATP, inorganic phosphate, and phosphate diesters. These changes occurred in a time frame in which the feeding response is elicited in conscious animals given the same dose of 2,5-AM by the same route. During an interval in which 2,5-AM increased eating, it also increased urinary uric acid excretion, implicating enhanced adenosine degradation in the reduction in hepatic ATP. These results provide the first direct evidence that changes in a high-energy phosphate-carrying compound in liver may provide a signal to initiate eating behavior.

Adenosine Triphosphate↗

PubMed1994

Phosphate loading prevents the decrease in ATP and increase in food intake produced by 2,5-anhydro-D-mannitol.

The fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) triggers feeding in rats apparently by its action in the liver. In vivo phosphorylation of this analogue decreases hepatic inorganic phosphate and ATP by trapping of phosphate in the mono- and diphosphorylated forms of 2,5-AM. To determine whether hepatic phosphate depletion and decreased ATP are involved in the eating response to 2,5-AM, rats were treated with excess sodium phosphate before injection of 2,5-AM. Phosphate loading prevented both the increase in food intake and the decrease in liver ATP, without affecting the changes seen in plasma fuels produced by 2,5-AM treatment. Phosphate loading did not influence water intake or eating elicited by insulin or 2-deoxy-D-glucose, indicating that the effect on 2,5-AM-induced eating was behaviorally specific and not due to malaise. These data suggest that 2,5-AM elicits eating by trapping phosphate and reducing ATP in liver.

Adenosine Triphosphate↗

PubMed1994

L-ethionine, an amino acid analogue, stimulates eating in rats.

The fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) triggers feeding in rats through its actions in liver, which include a decrease in ATP due to trapping of phosphate. To determine whether decreasing liver ATP by a different means would also trigger feeding, we gave rats L-ethionine (ETH), an amino acid analogue that reduces ATP in liver by trapping adenosine as S-adenosyl-L-ethionine. ETH-treatment increased food intake from 4 to 8 h after administration, without affecting 24-h intake. Two hours after treatment, liver ATP was 25% lower in rats given ETH than in vehicle-treated controls. Circulating fuels and liver lactate and pyruvate were not affected by ETH treatment, whereas liver glycogen was 15% lower in ETH-treated rats. These results are the first to show that an amino acid analogue elicits feeding in rats fed protein-sufficient diets. Because a decrease in liver ATP is the only common effect of ETH and 2,5-AM observed thus far, a signal related to liver ATP status may be involved in the mechanism for initiation of feeding in rats.

Amino Acids↗