The impact of air pollution on terrestrial managed and natural vegetation.

Although awareness that air pollution can damage vegetation dates back at least to the 1600s, the processes and mechanisms of damage were not rigorously studied until the late twentieth century. In the UK following the Industrial Revolution, urban air quality became very poor, with highly phytotoxic SO2 and NO2 concentrations, and remained that way until the mid-twentieth century. Since then both air quality, and our understanding of pollutants and their impacts, have greatly improved. Air pollutants remain a threat to natural and managed ecosystems. Air pollution imparts impacts through four major threats to vegetation are discussed through in a series of case studies. Gas-phase effects by the primary emissions of SO2 and NO2 are discussed in the context of impacts on lichens in urban areas. The effects of wet and dry deposited acidity from sulfur and nitrogen compounds are considered with a particular focus on forest decline. Ecosystem eutrophication by nitrogen deposition focuses on heathland decline in the Netherlands, and ground-level ozone at phytotoxic concentrations is discussed by considering impacts on semi-natural vegetation. We find that, although air is getting cleaner, there is much room for additional improvement, especially for the effects of eutrophication on managed and natural ecosystems. This article is part of a discussion meeting issue 'Air quality, past present and future'.

Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease.

A number of distinct beta-amyloid (Abeta) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural Abeta-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic Abeta and amyloidogenic non-Abeta species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21-89 years. Antibody reactivity was most prominent against oligomeric assemblies of Abeta and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of Abeta1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant Abeta, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from Abeta toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with Abeta the monkeys developed high titers not only against Abeta peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of Abeta antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD.

A review of domestic land use change attributable to U.S. biofuel policy.

Estimates of land use change (LUC) attributable to the U.S. Renewable Fuel Standard (RFS) are critical for evaluation of the program's impacts on air and water quality, biodiversity, and soil quality. To improve our understanding of the range of published estimates, we reviewed 29 studies published since 2008 attributing domestic LUC to the RFS, updating previous comparisons and adding a growing number of empirical approaches to estimating biofuel-induced LUC. To identify principal reasons underlying differences in reported effects, we documented key attributes of studies' methods including spatial extent, time period, baseline scenario, policy influence, and LUC definitions. Across computable general equilibrium (CGE) and partial equilibrium (PE) economic simulation model studies we found a range of 0.01-2.45 million acres of net cropland expansion per billion-gallon increase in biofuels. Empirical approaches reporting national-scale estimates fall within this range, reporting 0.38-0.66 million acres per billion-gallon increase. Empirical studies had a much smaller range of estimates and were closer to PE approaches than CGE. Studies generally did not represent all the potential drivers of biofuel production, and instead reported projections reflecting a combination of RFS impacts and other influences. Additional refinements to the modeling and empirical approaches reviewed in this study can further improve our understanding of the land use change driven by biofuels and the RFS Program.

Modeled Vegetation Community Trajectories: Effects from Climate Change, Atmospheric Nitrogen Deposition, and Soil Acidification Recovery.

Forest understory plant communities in the United States harbor most of the vegetation diversity of forests and are often sensitive to changes in climate and atmospheric deposition of nitrogen (N). As temperature increases from human-caused climate change and soils recover from long term atmospheric deposition of N and sulfur (S), it is unclear how these important ecosystem components will respond. We used the newly developed US-PROPS model - based on species response functions for over 1,500 species - to evaluate the potential impacts of atmospheric N deposition and climate change on species occurrence probability for a case study in the forested ecosystems of the Great Smoky Mountains National Park (GRSM), an iconic park in the southeastern United States. We evaluated six future scenarios from various combinations of two potential recoveries of soil pH (no change, +0.5 pH units) and three climate futures (no change, +1.5, +3.0 deg C). Species critical loads (CLs) of N deposition and projected responses for each scenario were determined. Critical loads were estimated to be low (< 2 kg N/ha/yr) to protect all species under current and expected future conditions across broad regions of GRSM and these CLs were exceeded at large spatial extents among scenarios. Northern hardwood, yellow pine, and chestnut oak forests were among the most N-sensitive vegetation map classes found within GRSM. Potential future air temperature conditions generally led to decreases in the maximum occurrence probability for species. Therefore, CLs were considered "unattainable" in these situations because the specified level of protection used for CL determination (i.e., maximum occurrence probability under ambient conditions) was not attainable. Although some species showed decreases in maximum occurrence probability with simulated increases in soil pH, most species were favored by increased pH. The importance of our study is rooted in the methodology described here for establishing regional CLs and for evaluating future conditions, which is transferable to other national parks in the U.S. and in Europe where the original PROPS model was developed.

Threshold effects of air pollution and climate change on understory plant communities at forested sites in the eastern United States.

Forest understory plant communities in the eastern United States are often diverse and are potentially sensitive to changes in climate and atmospheric inputs of nitrogen caused by air pollution. In recent years, empirical and processed-based mathematical models have been developed to investigate such changes in plant communities. In the study reported here, a robust set of understory vegetation response functions (expressed as version 2 of the Probability of Occurrence of Plant Species model for the United States [US-PROPS v2]) was developed based on observations of forest understory and grassland plant species presence/absence and associated abiotic characteristics derived from spatial datasets. Improvements to the US-PROPS model, relative to version 1, were mostly focused on inclusion of additional input data, development of custom species-level input datasets, and implementation of methods to address uncertainty. We investigated the application of US-PROPS v2 to evaluate the potential impacts of atmospheric nitrogen (N) and sulfur (S) deposition, and climate change on forest ecosystems at three forested sites located in New Hampshire, Virginia, and Tennessee in the eastern United States. Species-level N and S critical loads (CLs) were determined under ambient deposition at all three modeled sites. The lowest species-level CLs of N deposition at each site were between 2 and 11 kg N/ha/yr. Similarly, the lowest CLs of S deposition, based on the predicted soil pH response, were less than 2 kg S/ha/yr among the three sites. Critical load exceedance was found at all three model sites. The New Hampshire site included the largest percentage of species in exceedance. Simulated warming air temperature typically resulted in lower maximum occurrence probability, which contributed to lower CLs of N and S deposition. The US-PROPS v2 model, together with the PROPS-CLF model to derive CL functions, can be used to develop site-specific CLs for understory plants within broad regions of the United States. This study demonstrates that species-level CLs of N and S deposition are spatially variable according to the climate, light availability, and soil characteristics at a given location. Although the species niche models generally performed well in predicting occurrence probability, there remains uncertainty with respect to the accuracy of reported CLs. As such, the specific CLs reported here should be considered as preliminary estimates.

Factors associated with survival probability in autopsy-proven frontotemporal lobar degeneration.

OBJECTIVE: To examine the clinical and pathological factors associated with survival in autopsy-confirmed frontotemporal lobar degeneration (FTLD). METHODS: The final analysis cohort included 71 patients with pathologically proven FTLD, excluding patients with clinical motor neuron disease (MND), evaluated at the University of Pennsylvania or at the University of California, San Francisco. We assessed clinical and demographic features; cognitive functioning at presentation; genetic markers of disease; and graded anatomical distribution of tau, ubiquitin and amyloid pathology. RESULTS: The tau-negative group (n = 35) had a median survival time of 96 months (95% CI: 72-114 months), whereas the tau-positive group (n = 36) had a median survival time of 72 months (95% CI: 60-84 months). Patients with tau-positive pathology across all brain regions had shorter survival than those with tau-negative pathology in univariate Cox regression analyses (Hazard ratio of dying = 2.003, 95% CI = 1.209-3.318, p = 0.007). CONCLUSIONS: Tau-positive pathology represents a significant risk to survival in FTLD, whereas tau-negative pathology is associated with a longer survival time when clinical MND is excluded.

Feasibility of coupled empirical and dynamic modeling to assess climate change and air pollution impacts on temperate forest vegetation of the eastern United States.

Changes in climate and atmospheric nitrogen (N) deposition caused pronounced changes in soil conditions and habitat suitability for many plant species over the latter half of the previous century. Such changes are expected to continue in the future with anticipated further changing air temperature and precipitation that will likely influence the effects of N deposition. To investigate the potential long-term impacts of atmospheric N deposition on hardwood forest ecosystems in the eastern United States in the context of climate change, application of the coupled biogeochemical and vegetation community model VSD+PROPS was explored at three sites in New Hampshire, Virginia, and Tennessee. This represents the first application of VSD+PROPS to forest ecosystems in the United States. Climate change and elevated (above mid-19th century) N deposition were simulated to be important factors for determining habitat suitability. Although simulation results suggested that the suitability of these forests to support the continued presence of their characteristic understory plant species might decline by the year 2100, low data availability for building vegetation response models with PROPS resulted in uncertain results at the extremes of simulated N deposition. Future PROPS model development in the United States should focus on inclusion of additional foundational data or alternate candidate predictor variables to reduce these uncertainties.

Evidence for delayed development of the glucagon receptor of adenylate cyclase in the fetal and neonatal rat heart.

The effects, in vivo, of epinephrine, glucagon, and dibutyryl cyclic adenosine 3',5'-monophosphate (cyclic AMP) on the glycogen content of rat heart and liver and, in vitro, upon adenylate cyclase activity in homogenates of rat heart and liver were determined during the latter third of gestation and the neonatal period. Hepatic glycogen was depleted by epinephrine, glucagon, and dibutyryl cyclic adenosine 3',5'-monophosphate, but myocardial glycogen was depleted only by epinephrine and dibutyryl cyclic AMP in the neonates. Hepatic adenylate cyclase activity was augmented by both epinephrine (10(-5) M) and glucagon (10(-5) M), and myocardial cyclase was increased only by epinephrine in tissue obtained from 16, 18, and 20 day fetal rats. Myocardial adenylate cyclase responsiveness to glucagon was present in tissue obtained from rats 4 wk of age and older. It is concluded that in contrast to hepatic adenylate cyclase, myocardial adenylate cyclase in the rat is not responsive to glucagon during gestation and that responsiveness to glucagon and the associated ability of glucagon to deplete myocardial glycogen do not develop until well after birth.

Responsiveness to glucagon in fetal hearts. Species variability and apparent disparities between changes in beating, adenylate cyclase activation, and cyclic AMP concentration.

Previous studies of the ability of the immature heart to respond to glucagon have yielded conflicting results. To test the possibility that the apparent discrepancies might be explained in part by species variability, isolated hearts of fetal mice and rats (13-22 days' gestational age) were studied under identical conditions in vitro. Changes in atrial rate and ventricular contractility were measured in spontaneously beating hearts exposed to glucagon, and activation of adenylate cyclase was assayed in cardiac homogenates. In mice of 16 days' gestational age or less, there was no change in heart rate in response to glucagon; at 17-18 days, minimal responsiveness was present; and after 19 days, 10muM glucagon caused an increase in spontaneous atrial rate of 30 +/- 4% (SEM) (P less than 0.001). Measurement of the extent and speed of volume displacement of the isotonically contracting hearts with a specially constructed capacitance transducer revealed that ventricular inotropic responsiveness also appeared after 17-19 days. Cardiac stores of glycogen were reduced in older hearts exposed to glucagon, but not in those aged less than 16 days. In contrast, glucagon failed to activate adenylate cyclase in homogenates of hearts of fetal mice at any age. Furthermore, glucagon failed to elicit an increase in the concentration of cyclic AMP in spontaneously beating hearts that developed tachycardia. Responses in hearts of fetal rats were distinctly different from those in mouse hearts: at no age was there any change in heart rate, strength of contraction, glycogen content, or adenylate cyclase activation. Thus, there are major species differences in cardiac pharmacological maturation. Although the mouse heart develops the ability to increase its rate and strength of contraction and to undergo glycogenolysis in response to glucagon well before birth, the rat heart does not. In addition, there is an apparent disparity in late fetal mouse hearts between the ability of glucagon to induce functional responses and its ability to stimulate adenylate cyclase and increase cyclic AMP levels. It is impossible, of course, to rule out absolutely the possibility that localized increases in a critical cyclic AMP pool were present but too small to measure in the entire tissue. Nevertheless, the most obvious interpretation of our results is that they are compatible with the hypothesis that glucagon may exert some of its hemodynamic effects independently from the adenylate cyclase-cyclic AMP system in the late-fetal mouse heart.

Development of glucagon sensitivity in neonatal rat liver.

The ontogenesis of the hepatic glucagon-sensitive adenylate cyclase system has been studied in the rat. With a partially purified liver membrane preparation, fetal adenylate cyclase was less responsive to glucagon than the enzyme from neonatal or adult livers. Similar results were obtained in gently prepared liver homogenates, suggesting that destruction of essential components of the fetal liver membrane did not account for the relative unresponsiveness of the adenylate cyclase enzyme to glucagon. Investigation of other factors that might account for diminished fetal hepatic responsiveness to glucagon indicate (a) minimal glucagon degradation by fetal membranes relative to 8-day or adult tissue; and (b) available adenylate cyclase enzyme, as suggested by a 13-fold increase over basal cyclic AMP formation with NaF in fetal liver membranes. These results indicate that neither enhanced glucagon degradation nor adenylate cyclase enzyme deficiency accounts for the relative insensitivity of the fetal hepatic adenylate cyclase system to glucagon. In early neonatal life, hepatic adenylate cyclase responsiveness to glucagon rapidly developed and was maximal 6 days after birth. These changes were closely paralleled by a fivefold increase in glucagon binding and the kinetically determined Vmax for cyclic AMP formation. These observations suggest that (a) fetal hepatic unresponsiveness to glucagon may be explained by a limited number of glucagon receptor sites; (b) during the neonatal period, the development of glucagon binding is expressed primarily as an increase in adenylate cyclase Vmax; (c) the ontogenesis of hepatic responsiveness to glucagon may be important in the resolution of neonatal hypoglycemia.

Effects of dibutyryl cyclic adenosine 3',5'-monophosphate and parathyroid extract on calcium and phosphorus metabolism in hypoparathyroidism and pseudohypoparathyroidism.

It has been proposed previously that the metabolic defect in pseudohypoparathyroidism which accounts for parathyroid hormone unresponsiveness is an absence or abnormal form of the adenyl cyclase system in kidney and presumably in bone. To determine whether there is an associated defect in the response mechanism to cyclic adenosine 3',5'-monophosphate (cyclic AMP), the effects of parathyroid extract (PTE), and dibutyryl cyclic AMP were compared in patients with either surgical hypoparathyroidism or pseudohypoparathyroidism. PTE and dibutyryl cyclic AMP both increased serum and urinary calcium, lowered the serum phosphorus, and increased urinary phosphorus in patients with hypoparathyroidism. PTE also increased urinary cyclic AMP in these patients. PTE increased serum and urinary calcium and urinary phosphorus but did not alter serum phosphorus or urinary cyclic AMP in the patients with pseudohypoparathyroidism. Dibutyryl cyclic AMP increased the serum and urinary calcium, lowered the serum phosphorus, and increased urinary phosphorus in all the patients with pseudohypoparathyroidism. The results indicate that (a) dibutyryl cyclic AMP can reproduce the effects of parathyroid hormone on calcium and phosphorus metabolism in man, (b) the response mechanism to cyclic AMP appears to be intact in pseudohypoparathyroidism, and (c) PTE apparently produces some of its characteristic effects on calcium and phosphorus metabolism in pseudohypoparathyroidism in the absence of an increase in urinary cyclic AMP.

Enlarged vestibular aqueducts and other inner-ear abnormalities in patients with Down syndrome.

BACKGROUND: Histopathological anomalies of inner-ear structures in individuals with Down syndrome have been well documented; however, few studies have examined the radiological features. METHODS: A retrospective study was conducted of temporal bone computed tomography images in 38 individuals (75 ears) with Down syndrome to evaluate the prevalence of inner-ear abnormalities and assess vestibular aqueduct widths. RESULTS: Inner-ear anomalies were identified in 20 of the 38 individuals (52.6 per cent). Seven of the 75 temporal bones (9.3 per cent) were found to have higher than previously reported. A dilated internal auditory canal and vestibule were more common among the present study group, while prior studies have demonstrated internal auditory canal stenosis and decreased vestibule size. CONCLUSION: Down syndrome patients exhibit a high prevalence of dysplastic inner-ear features that confer substantial risk of sensorineural hearing loss. Computed tomography is a useful screening aid to detect inner-ear abnormalities, particularly enlarged vestibular aqueducts, which cause preventable sensorineural hearing loss in this population.

Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment.

The diagnosis of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) is limited because it is based on non-specific behavioral and neuroimaging findings. The lesions of Alzheimer's disease: amyloid beta (Abeta) deposits, tau pathology and cellular oxidative damage, affect the hippocampus in the earlier stages causing memory impairment. In a 2-year longitudinal study of MCI patients and normal controls, we examined the hypothesis that cerebrospinal fluid (CSF) markers for these pathological features improve the diagnostic accuracy over memory and magnetic resonance imaging (MRI)-hippocampal volume evaluations. Relative to control, MCI patients showed decreased memory and hippocampal volumes and elevated CSF levels of hyperphosphorylated tau and isoprostane. These two CSF measures consistently improved the diagnostic accuracy over the memory measures and the isoprostane measure incremented the accuracy of the hippocampal volume achieving overall diagnostic accuracies of about 90%. Among MCI patients, over 2 years, longitudinal hippocampal volume losses were closely associated with increasing hyperphosphorylated tau and decreasing amyloid beta-42 levels. These results demonstrate that CSF biomarkers for AD contribute to the characterization of MCI.

Actin synthesis and polymerization in the liver of fed and fasted rats bearing a Walker 256 carcinoma.

The effect of tumor growth on the amount, state of polymerization, and synthesis of liver actin was investigated in fed and fasted rats bearing a Walker 256 carcinoma. The increase in liver size in the tumor-bearing animal was accompanied by a rise in the total amount of actin and protein, although the amounts present per g liver fell in both cases. Soluble actin increased in both concentration and total amount in the tumor-bearing animals. While the ratio of total actin to total protein in liver was unaltered by tumor growth, the ratio of soluble actin to total actin was increased. The incorporation of [3H]leucine into liver actin relative to that into liver protein, in vivo, was not affected by tumor growth, but the radioactivity incorporated into soluble actin relative to total actin in the livers of the tumor-bearing rats was increased. Liver polysome preparations from tumor-bearing rats showed an increased ability to synthesize actin and total protein, whereas polysomes from skeletal muscle of tumor-bearing rats exhibited a decreased synthesis of actin and total protein. These results suggest that, in the liver of the tumor-bearing rat, while there is an increase in actin synthesis in parallel with a net increase in protein synthesis, there is a decrease in the polymerization of action. In livers of both control and tumor-bearing rats, the consumption of a meal was accompanied by a decrease in soluble actin relative to total actin and an increase in the synthesis of action relative to total protein.

Response of skeletal muscle RNA polymerases I and II to tumour growth.

The muscle wasting which occurs in animals bearing a transplantable tumour is accompanied by a decrease in the level of protein synthesis and a loss in RNA. This paper examines the behaviour of RNA polymerases I and II (EC 2.7.7.6) in nuclei isolated from skeletal muscle of rats bearing a Walker 256 carcinoma. Marked decreases were observed in template-engaged RNA polymerase I and II activities and in free RNA polymerase I activity. Free RNA polymerase II activity was unaltered. When assays were carried out at high (NH4)2SO4 concentration or in the presence of heparin the diminished RNA polymerase I activity was still apparent, but heparin and high ionic strength overcame the inhibition of RNA polymerase II. Loss of RNA polymerase I activity was associated with a decrease in the number of template-engaged enzyme molecules and in the polynucleotide elongation rate. The number of template-engaged RNA polymerase II molecules was unaltered by tumour growth, but the polynucleotide elongation rate was significantly reduced. No evidence was obtained for any alteration in ribonuclease activity in nuclei or whole muscles of tumour-bearing rats. These results demonstrate an effect of the tumor on transcription in skeletal muscle of its host.

Glucocorticoid-mediated muscle atrophy: alterations in transcriptional activity of skeletal muscle nuclei.

Glucocorticoid-induced muscle atrophy is associated with a decrease in the level of protein synthesis and a loss of RNA. This paper reports the behaviour of RNA polymerase I- and RNA polymerase II-directed transcription (EC 2.7.7.6) in nuclei isolated from skeletal muscles of rats given a catabolic dose of dexamethasone acetate (5 mg per Kg body weight) over a period of 4 days. Both activities were altered by the dexamethasone treatment. In the case of RNA polymerase I-mediated transcription there was a loss of template-engaged enzymes indicating the existence of an inhibition of initiation of transcription while the rate of elongation of bound enzymes was unaltered. The number of RNA polymerase II-chromatin bound enzymes was increased, but the mean polynucleotide elongation rate was reduced. The possibility that glucocorticoids may impair the elongation stage of transcription in skeletal muscle by increasing the frequency of premature termination of transcripts is discussed. No evidence was obtained for any increase in ribonuclease activity in muscle nuclei of dexamethasone-treated animals.

Plasma membrane associated actin in liver of normal and tumour-bearing rats.

A study was made of the association of actin with different plasma membrane fractions from liver of normal rats and from the enlarged liver of rats bearing a Walker 256 carcinoma where a decrease in the state of polymerisation of cytoplasmic actin has been previously observed. As estimated by the DNAase I inhibition assay, actin constituted approx. 7% and 3%, respectively, of the protein of membrane fractions enriched in lateral or bile-canalicular domains, but only trace amounts were found in the sinusoidal fraction. [3H]Cytochalasin B binding indicated the presence of 20 and 13 pmol of high-affinity binding sites per mg protein in lateral and bile-canalicular fractions, but none in the sinusoidal. Kd for cytochalasin B binding was of the order of 1 nM for lateral and bile-canalicular fractions. Polypeptide profiles obtained by SDS/urea/polyacrylamide gel electrophoresis of non-ionic detergent-insoluble residues differed for all three fractions although some proteins, including actin, occurred as major components of both bile-canalicular and lateral regions. Tumour growth had no effect on the actin content, high-affinity cytochalasin B binding or polypeptide profiles of the three membrane fractions.

Actin and actin-binding proteins in plasma membranes derived from Walker 256 ascites or solid tumour cells.

Plasma membranes from Walker 256 carcinoma cells grown ascitically or as a solid tumour were examined with respect to actin content, [3H]cytochalasin B-binding and the binding of 125I-labelled G-actin to membrane proteins separated by SDS-PAGE. Differences were observed both in cytochalasin B-binding to membrane actin and affinity of 125I-labelled G-actin for specific membrane proteins.

Muscle protein biosynthesis in the tumour-bearing rat. A defect in a post-initiation stage of translation.

1. The decreased ability of polysomes isolated from the gastrocnemius of rats bearing the Walker 256 carcinoma to incorporate L-[14C]leucine into protein persisted in the presence of 5-10-5 M aurin tricarboxylic acid and 1-10-2 M NaF. 2. Poly(U)-directed phenylalanine incorporation by such polysome preparations was less than that of similar preparations from normal rats. 3. The ability of gastrocnemius polysomes from tumour-bearing rats to react with puromycin was markedly decreased. Cycloheximide inhibited peptidyl puromycin formation by polysome preparations from both normal and tumour-bearing rats. 4. The ability of recombined 60 S and 40 S subunits prepared from polysomes of tumour-bearing rats to carry out poly(U)-directed polyphenylalanine synthesis was much reduced when assayed over a wide range of magnesium concentrations. Cross-over experiments with subunits from normal and tumour-bearing animals suggested that this was due to a defect in the smaller ribosomal subunit.

Studies on the regulation of insulin binding by liver plasma membranes from Zucker fatty rats.

The hyperinsulinemia of obese rodents has been associated with a reduced number of hepatic insulin receptors except in hepatocytes from fatty Zucker rats. We isolated liver plasma membranes from 10-11-wk-old lean and fatty Zucker rats, some of which were injected with streptozotocin 2--4 wk earlier. We have determined that although the number of hepatic insulin receptors is not reduced in young hyperinsulinemic fatty Zucker rats, the number of receptors can be increased when the hyperinsulinemia of the fatty rats is reduced by treatment with streptozotocin. In the fatty rats, this reduction in circulating insulin is accompanied by a reduction in plasma triglyceride concentration, consistent with a decreased stimulation of hepatic lipogenesis. Competitive binding curves for insulin were obtained with isolated liver plasma membranes and 125I-insulin. Analysis of these curves for affinity and number of receptors indicated that the number of insulin receptors was unchanged for the fatty control rats relative to the lean control rats but was increased in streptozotocin-treated animals. These data indicate that the regulation of hepatic insulin receptors is altered in the young fatty Zucker rat as characterized by a lack of downregulation of hepatic insulin receptors by hyperinsulinemia and an upregulation of hepatic insulin receptors at insulin concentrations higher than those found in lean rats. An altered state of hepatic insulin receptor regulation may be characteristic of developing obesity.