Field potentials were recorded simultaneously from the olfactory bulb (OB), prepyriform cortex (PPC), entorhinal cortex (EC), and dentate gyrus (DG) of rats trained to respond to appetitively reinforced odors. Preafferent anticipatory events in the beta band (12-35 Hz) suggest transmission from EC to OB before the odorant stimulus. Gamma band (35-120 Hz) power in olfactory regions is significantly reduced during stimulus presentation as compared with high values during preafferent expectation. High coherence of OB and PPC gamma activity during the preodorant control period is interrupted before the stimulus and is followed by increased gamma coherence among OB, EC, and DG. These results suggest that olfactory perceptual processing is bidirectional and covers a wide frequency range.

We previously suggested that, in obese animals and humans, white adipose tissue inflammation results from the death of hypertrophic adipocytes; these are then cleared by macrophages, giving rise to distinctive structures we denominated crown-like structures. Here we present evidence that subcutaneous and visceral hypertrophic adipocytes of leptin-deficient (ob/ob and db/db) obese mice exhibit ultrastructural abnormalities (including calcium accumulation and cholesterol crystals), many of which are more common in hyperglycemic db/db versus normoglycemic ob/ob mice and in visceral versus subcutaneous depots. Degenerating adipocytes whose intracellular content disperses in the extracellular space were also noted in obese mice; in addition, increased anti-reactive oxygen species enzyme expression in obese fat pads, documented by RT-PCR and immunohistochemistry, suggests that ultrastructural changes are accompanied by oxidative stress. RT-PCR showed NLRP3 inflammasome activation in the fat pads of both leptin-deficient and high-fat diet obese mice, in which formation of active caspase-1 was documented by immunohistochemistry in the cytoplasm of several hypertrophic adipocytes. Notably, caspase-1 was not detected in FAT-ATTAC transgenic mice, where adipocytes die of apoptosis. Thus, white adipocyte overexpansion induces a stress state that ultimately leads to death. NLRP3-dependent caspase-1 activation in hypertrophic adipocytes likely induces obese adipocyte death by pyroptosis, a proinflammatory programmed cell death.

Hyperinsulinemia. is associated with an overexpression of mRNA for the ob protein leptin in rodent models of genetic obesity, and insulin has been reported to directly stimulate leptin mRNA in rat adipocytes. Human obesity is also associated with increased leptin mRNA as well as plasma levels, but there have been no reports of the effect of insulin on leptin secretion. We, therefore, tested the hypothesis that insulin stimulates leptin secretion in humans. Using a newly developed leptin assay, immunoreactive leptin was measured in fasting and postprandial plasma samples from 27 healthy adults and in samples before and during euglycemic-hyperinsulinemic then stepped hypoglycemic (hourly steps at 85, 75, 65, 55, and 45 mg/dl) clamps from 10 healthy subjects and 11 patients with IDDM. Plasma leptin was correlated (r = 0.84, P = 0.0005) with BMI in obese but not nonobese subjects and with fasting (r = 0.75, P = 0.008) but not postprandial plasma insulin levels. (Leptin levels did not change postprandially.) Euglycemic hyperinsulinemia did not alter leptin levels, nor did hyperinsulinemic hypoglycemia. Thus, because circulating leptin levels are not increased during postprandial hyperinsulinemia or during euglycemic (or hypoglycemic) hyperinsulinemia, we conclude that, at least in the short term, insulin does not increase leptin secretion in humans and that hyperleptinemia in obese individuals is not likely the result of hyperinsulinemia.

Mixing of hydrothermal fluids and seawater at the ocean floor, combined with slow reaction kinetics for oxidation/reduction reactions, provides a source of metabolic energy for chemolithotrophic microorganisms which are the primary biomass producers for an extensive submarine ecosystem that is essentially independent of photosynthesis. Thermodynamic models are used to explore geochemical constraints on the amount of metabolic energy potentially available from chemosynthetic reactions involving S, C, Fe, and Mn compounds during mixing of hydrothermal fluids with seawater. For the vent fluid used in the calculations (EPR 21 degrees N OBS), the model indicates that mixing environments are favorable for oxidation of H2S, CH4, Fe2+ and Mn2+ only below approximately 38 degrees C, with methanogenesis and reduction of sulfate or S degrees favored at higher temperatures, suggesting that environments dominated by mixing provide habitats for mesophilic (but not thermophilic) aerobes and thermophilic (but not mesophilic) anaerobes. A maximum of approximately 760 cal per kilogram vent fluid is available from sulfide oxidation while between 8 and 35 cal/kg vent fluid is available from methanotrophy, methanogenesis, oxidation of Fe or Mn, or sulfate reduction. The total potential for chemosynthetic primary production at deep-sea hydrothermal vents globally is estimated to be about 10(13) g biomass per year, which represents approximately 0.02% of the global primary production by photosynthesis in the oceans. Thermophilic methanogens and sulfate- and S degree-reducers are likely to be the predominant organisms in the walls of vent chimneys and in the diffuse mixing zones beneath warm vents, where biological processes may contribute to the high methane concentrations of vent fluids and heavy 34S/32S ratios of vent sulfide minerals. The metabolic processes taking place in these systems may be analogs of the first living systems to evolve on the Earth.

BACKGROUND

The complications of atherosclerosis are a major cause of death and disability in type 2 diabetes. Defective clearance of apoptotic cells by macrophages (efferocytosis) is thought to lead to increased necrotic core formation and inflammation in atherosclerotic lesions.

OBJECTIVE

To determine whether there is defective efferocytosis in a mouse model of obesity and atherosclerosis.

RESULTS

We quantified efferocytosis in peritoneal macrophages and in atherosclerotic lesions of obese ob/ob or ob/ob;Ldlr(-/-) mice and littermate controls. Peritoneal macrophages from ob/ob and ob/ob;Ldlr(-/-) mice showed impaired efferocytosis, reflecting defective phosphatidylinositol 3-kinase activation during uptake of apoptotic cells. Membrane lipid composition of ob/ob and ob/ob;Ldlr(-/-) macrophages showed an increased content of saturated fatty acids (FAs) and decreased omega-3 FAs (eicosapentaenoic acid and docosahexaenoic acid) compared to controls. A similar defect in efferocytosis was induced by treating control macrophages with saturated free FA/BSA complexes, whereas the defect in ob/ob macrophages was reversed by treatment with eicosapentaenoic acid/BSA or by feeding ob/ob mice a fish oil diet rich in omega-3 FAs. There was also defective macrophage efferocytosis in atherosclerotic lesions of ob/ob;Ldlr(-/-) mice and this was reversed by a fish oil-rich diet.

CONCLUSIONS

The findings suggest that in obesity and type 2 diabetes elevated levels of saturated FAs and/or decreased levels of omega-3 FAs contribute to decreased macrophage efferocytosis. Beneficial effects of fish oil diets in atherosclerotic cardiovascular disease may involve improvements in macrophage function related to reversal of defective efferocytosis and could be particularly important in type 2 diabetes and obesity.

OBJECTIVE

Although total fat body mass (FM) is considered to be one of the major determinants of bone mass, the mechanism by which FM and bone mass are positively correlated remains unclear. Leptin, the product of the obese (ob) gene, is secreted from adipocytes and its plasma levels are known to be positively correlated with %fat (FM divided by total body weight). There is recent evidence suggesting that leptin directly stimulates osteoblastic differentiation. Thus it is possible that the anabolic action of this hormone on bone may participate in the positive correlation between FM and bone mass. In this study, we analysed the relationships between either plasma leptin levels or %fat vs. bone mineral density (BMD) values as well as the presence of vertebral compression fractures, and evaluated whether or not plasma leptin levels were associated with BMD or bone fragility in a manner independent of FM.

METHODS

One hundred and thirty-nine postmenopausal women (age 48-78 years, mean 62.5), who visited our outpatient clinic for the evaluation of osteoporosis.

METHODS

Plasma concentrations of leptin after an overnight fast were measured by radioimmunoassay. BMD values were measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine, femoral neck and whole body. Distal one-third of radius BMD was measured by single photon absorptiometry (SPA). Vertebral fractures were assessed by lateral thoracic and lumbar spine radiographs.

RESULTS

Although neither plasma leptin levels nor %fat correlated with age, there was a significant positive correlation between plasma leptin levels and %fat (r = 0.563, P < 0.001). Plasma leptin levels were significantly and positively correlated with BMD values at all skeleton sites measured, and multiple regression analysis revealed that this positive relationship was still observed with BMD values of the femoral neck and of the whole body, even after %fat and age were taken into account. Moreover, plasma leptin levels but not %fat were significantly lower in women with vertebral fractures than in those without fractures. When multiple logistic regression analysis was performed with either plasma leptin value or %fat employed as independent variables, plasma leptin values but not %fat were selected as an index affecting the presence of vertebral fractures.

CONCLUSIONS

Our study showed that plasma leptin levels but not %fat are associated with BMD and the presence of vertebral fractures in postmenopausal women, suggesting that circulating leptin might play a physiological role in maintaining bone mass as well as better bone quality.

Wound-healing disorders are a therapeutic problem of extensive clinical importance. Leptin-deficient ob/ob mice are characterized by a severely delayed wound healing that has been explained by the mild diabetic phenotype of these animals. Here we demonstrate that systemically and topically supplemented leptin improved re-epithelialization of wounds in ob/ob mice. Leptin completely reversed the atrophied morphology of the migrating epithelial tongue observed at the wound margins of leptin-deficient animals into a well-organized hyperproliferative epithelium. Moreover, topically supplemented leptin accelerated normal wound-healing conditions in wild-type mice. As assessed by immunohistochemistry, proliferating keratinocytes located at the wound margins specifically expressed the leptin-receptor subtype ObRb during repair. Additionally, leptin mediated a mitogenic stimulus to the human keratinocyte cell line HaCaT and human primary keratinocytes in vitro. Therefore, leptin might represent an effective novel therapeutic factor to improve impaired wound-healing conditions.

The Saami are regarded as extreme genetic outliers among European populations. In this study, a high-resolution phylogenetic analysis of Saami genetic heritage was undertaken in a comprehensive context, through use of maternally inherited mitochondrial DNA (mtDNA) and paternally inherited Y-chromosomal variation. DNA variants present in the Saami were compared with those found in Europe and Siberia, through use of both new and previously published data from 445 Saami and 17,096 western Eurasian and Siberian mtDNA samples, as well as 127 Saami and 2,840 western Eurasian and Siberian Y-chromosome samples. It was shown that the "Saami motif" variant of mtDNA haplogroup U5b is present in a large area outside Scandinavia. A detailed phylogeographic analysis of one of the predominant Saami mtDNA haplogroups, U5b1b, which also includes the lineages of the "Saami motif," was undertaken in 31 populations. The results indicate that the origin of U5b1b, as for the other predominant Saami haplogroup, V, is most likely in western, rather than eastern, Europe. Furthermore, an additional haplogroup (H1) spread among the Saami was virtually absent in 781 Samoyed and Ob-Ugric Siberians but was present in western and central European populations. The Y-chromosomal variety in the Saami is also consistent with their European ancestry. It suggests that the large genetic separation of the Saami from other Europeans is best explained by assuming that the Saami are descendants of a narrow, distinctive subset of Europeans. In particular, no evidence of a significant directional gene flow from extant aboriginal Siberian populations into the haploid gene pools of the Saami was found.

Type I NOS expression increases in OB neurons during VSV infection. Immunocytochemical staining of NB41A3 cells indicates constitutive expression of interferon (IFN)-gamma receptor and type I NOS. IFN-gamma treatment of NB41A3 cells increased NO production and type I NOS protein. In vitro replication of VSV, polio virus type I, and Herpes Simplex virus type I (HSV-1) is significantly inhibited by IFN-gamma induced type I NOS and antagonized by NOS inhibitors. In contrast, while IFN-gamma treatment inhibited influenza and Sindbis virus replication, a different pathway(s) was involved. The isoform-selective NOS inhibitor. 7-nitroindazole (7NI) was used to treat mice, resulting in a 10-fold higher titer of virus in brain homogenates, and abrogated the recovery-promoting effect of interleukin-12 treatment. Thus, IFN-gamma induced type I NOS activity may play an important role in host immunity against neurotropic viral infections.

E. coli ribonucleotide reductase (RNR) catalyzes the conversion of nucleoside diphosphates (NDPs) to dNDPs and is composed of two homodimeric subunits: R1 and R2. R1 binds NDPs and contains binding sites for allosteric effectors that control substrate specificity and turnover rate. R2 contains a diiron-tyrosyl radical (Y(*)) cofactor that initiates nucleotide reduction. Pre-steady-state experiments with wild type R1 or C754S/C759S-R1 and R2 were carried out to determine which step(s) are rate-limiting and whether both active sites of R1 can catalyze nucleotide reduction. Rapid chemical quench experiments monitoring dCDP formation gave k(obs) of 9 +/- 4 s(-1) with an amplitude of 1.7 +/- 0.4 equiv. This amplitude, generated in experiments with pre-reduced R1 (3 or 15 microM) in the absence of reductant, indicates that both monomers of R1 are active. Stopped-flow UV-vis spectroscopy monitoring the concentration of the Y(*) failed to reveal any changes from 2 ms to seconds under similar conditions. These pre-steady-state experiments, in conjunction with the steady-state turnover numbers for dCDP formation of 2-14 s(-1) at RNR concentrations of 0.05-0.4 microM (typical assay conditions), reveal that the rate-determining step is a physical step prior to rapid nucleotide reduction and rapid tyrosine reoxidation to Y(*). Steady-state experiments conducted at RNR concentrations of 3 and 15 microM, typical of pre-steady-state conditions, suggest that, in addition to the slow conformational change(s) prior to chemistry, re-reduction of the active site disulfide to dithiol or a conformational change accompanying this process can also be rate-limiting.

In agreement with evidence that estrogens slow the rate of bone remodeling by suppressing the production of both osteoclasts and osteoblasts, loss of estrogens leads to an increase in the number of osteoclast as well as early osteoblast progenitors (CFU-osteoblasts; CFU-OBs) in the murine bone marrow. Here we show that CFU-OBs are early transit-amplifying progenitors, i.e., dividing cells capable of limited self-renewal, and that 17 beta-estradiol acts in vivo and in vitro to attenuate their self-renewal by approximately 50%. Consistent with a direct receptor-mediated action of estrogens on early mesenchymal cell progenitors, anti-estrogen receptor-alpha (anti-ER alpha) Ab's stain a small number of marrow cells that exhibit characteristics of primitive undifferentiated cells, including a high nucleus/cytoplasm ratio and lack of lineage-specific biochemical markers; the effect of 17 beta-estradiol on CFU-OB self-renewal is absent in mice lacking ER alpha. Because both osteoblasts and the stromal/osteoblastic cells that are required for osteoclast development are derived from CFU-OBs, suppression of the self-renewal of this common progenitor may represent a key mechanism of the anti-remodeling effects of estrogens.

Osteoblast differentiation and bone formation (osteogenesis) are regulated by transcriptional and post-transcriptional mechanisms. Recently, microRNAs (miRNAs) were identified as novel key regulators of human stromal (skeletal, mesenchymal) stem cells (hMSC) differentiation. Here, we identified miRNA-34a (miR-34a) and its target protein networks as modulator of osteoblastic (OB) differentiation of hMSC. miRNA array profiling and further validation by quantitative RT-PCR revealed that miR-34a was upregulated during OB differentiation of hMSC, and in situ hybridization confirmed its OB expression in vivo. Overexpression of miR-34a inhibited early commitment and late OB differentiation of hMSC in vitro, whereas inhibition of miR-34a by anti-miR-34a enhanced these processes. Target prediction analysis and experimental validation confirmed Jagged1 (JAG1), a ligand for Notch 1, as a bona fide target of miR-34a. siRNA-mediated reduction of JAG1 expression inhibited OB differentiation. Moreover, a number of known cell cycle regulator and cell proliferation proteins, such as cyclin D1, cyclin-dependent kinase 4 and 6 (CDK4 and CDK6), E2F transcription factor three, and cell division cycle 25 homolog A were among miR-34a targets. Furthermore, in a preclinical model of in vivo bone formation, overexpression of miR-34a in hMSC reduced heterotopic bone formation by 60%, and conversely, in vivo bone formation was increased by 200% in miR-34a-deficient hMSC. miRNA-34a exhibited unique dual regulatory effects controlling both hMSC proliferation and OB differentiation. Tissue-specific inhibition of miR-34a might be a potential novel therapeutic strategy for enhancing in vivo bone formation.

OBJECTIVE

To investigate the cardiovascular autonomic function in pediatric obesity of different duration by using standard time domain, spectral heart rate variability (HRV), and nonlinear methods.

METHODS

Fifty obese children (13.9 +/- 1.7 years) were compared with 12 lean subjects (12.9 +/- 1.6 years). Obese children were classified as recent obese (ROB) (<4 years), intermediate obese (IOB) (4 to 7 years), and long-term obese (OB) (>7 years). In all participants, we performed blood pressure (BP) measurements, laboratory tests, and 24-hour electrocardiogram/ambulatory BP monitoring. The spectral power was quantified in total power, very low-frequency (LF) power, high-frequency (HF) power, and LF to HF ratio. Total, long-term, and short-term time domain HRV were calculated. Poincaré plot and quadrant methods were used as nonlinear techniques.

RESULTS

All obese groups had higher casual and ambulatory BP and higher glucose, homeostasis model assessment, and triglyceride levels. All parameters reflecting parasympathetic tone (HF band, root mean square successive difference, proportion of successive normal-to-normal intervals, and scatterplot width) were significantly and persistently reduced in all obese groups in comparison with lean controls. LF normalized units, LF/HF, and cardiac acceleration (reflecting sympathetic activation) were significantly increased in the ROB group. In IOB and OB groups, LF, but not nonlinear, measures were similar to lean controls, suggesting biphasic behavior of sympathetic tone, whereas nonlinear analysis showed a decreasing trend with the duration of obesity. Long-term HRV measures were significantly reduced in ROB and IOB.

CONCLUSIONS

Autonomic nervous system changes in adolescent obesity seem to be related to its duration. Nonlinear methods of scatterplot and quadrant analysis permit assessment of autonomic balance, despite measuring different aspects of HRV.

The transcription factor cAMP response element-binding protein (CREB) is involved in multiple aspects of neuronal development and plasticity. Here, we demonstrate that CREB regulates specific phases of adult neurogenesis in the subventricular zone/olfactory bulb (SVZ/OB) system. Combining immunohistochemistry with bromodeoxyuridine treatments, cell tracer injections, cell transplants, and quantitative analyses, we show that although CREB is expressed by the SVZ neuroblasts throughout the neurogenic process, its phosphorylation is transient and parallels neuronal differentiation, increasing during the late phase of tangential migration and decreasing after dendrite elongation and spine formation. In vitro, inhibition of CREB function impairs morphological differentiation of SVZ-derived neuroblasts. Transgenic mice lacking CREB, in a null CREM genetic background, show reduced survival of newborn neurons in the OB. This finding is further supported by peripheral afferent denervation experiments resulting in downregulation of CREB phosphorylation in neuroblasts, the survival of which appears heavily impaired. Together, these findings provide evidence that CREB regulates differentiation and survival of newborn neurons in the OB.

OBJECTIVE

Progress in identification of effective therapies for diabetic nephropathy continues to be limited by the lack of ideal animal models. Here we review the current status of some leading murine models of this disorder.

RESULTS

A consensus statement of the Animals Models of Diabetic Complications Consortium sets forth guidelines and standards for measuring renal function and structural parameters necessary for validating murine models of diabetic nephropathy. Two murine models exploiting endothelial nitric oxide synthase (eNOS) deficiency as a major susceptibility factor for development of diabetic nephropathy are among the very few options for studying features of advanced diabetic nephropathy. Akita and OVE26 mice with mutations that result in Type I diabetes are also useful models of diabetic nephropathy. The recently described BTBR ob/ob (leptin deficient) mouse with Type II diabetes demonstrates key features of early podocyte loss and mesangiolysis characteristic of human diabetic nephropathy.

CONCLUSIONS

While there are many murine models of mesangial matrix expansion in the setting of diabetes, few progress to develop advanced diabetic lesions. Mice with eNOS deficiency, OVE26 mice, and the recently described BTBR ob/ob mouse currently appear to be the best murine models of advanced disease. A model that allows testing of interventions that modulate podocyte loss and regeneration, such as the BTBR ob/ob mouse, may be of particular benefit in developing therapeutics for diabetic nephropathy.

In this study, we investigated hepatic fibrogenesis caused by long-term thioacetamide (TAA) administration in ob/ob mice, a naturally occurring leptin deficient animal. In the lean littermates, prominent hepatic fibrosis, as well as positive staining for alpha smooth muscle actin (alpha-SMA), was induced by treatment with TAA (200 microg/g, IP, 3 times per week) for 4 to 8 weeks as expected. In sharp contrast, almost no hepatic fibrosis developed in ob/ob mice given the equivalent doses of TAA, where specific staining for alpha-SMA barely was detected. Induction of alpha1(I) procollagen mRNA caused by TAA also was prevented in ob/ob mice almost completely. Further, transforming growth factor beta (TGF-beta) mRNA was increased in the liver after TAA treatment for 4 weeks in lean littermates, which also was prevented in ob/ob mice. Interestingly, fibrotic septa in the hepatic lobules, as well as increases in alpha1(I) procollagen mRNA, was observed in ob/ob mice, when they were injected with recombinant murine leptin (1 microg/g daily) in combination with TAA treatment. Leptin per se did not cause any fibrotic changes in the liver in ob/ob mice. These findings clearly indicated that leptin deficiency is responsible for the resistance to TAA-induced profibrogenic responses in ob/ob mice. In conclusion, leptin appears to promote profibrogenic responses in the liver, in part, by up-regulation of TGF-beta.

The functions of Wingless-Int (Wnt) signaling, studied intensely in embryonic brain development, have been comparatively little investigated in the postnatal brain. We report remarkably patterned gene expression of Wnt signaling components in postnatal mouse cerebral cortex, lasting into young adulthood. Wnt genes are expressed in gene-specific regional and lamina patterns in each of the major subdivisions of the cerebral cortex: the olfactory bulb (OB), the hippocampal formation, and the neocortex. Genes encoding Frizzled (Fz) Wnt receptors, or secreted Frizzled-related proteins (sFrps), are also expressed in regional and lamina patterns. These findings suggest that Wnt signaling is active and regulated in the postnatal cortex and that different cortical cell populations have varying requirements for a Wnt signal. The OB, in particular, shows gene expression of a large variety of Wnt signaling components, making it a prime target for future functional studies. The penultimate components of the canonical Wnt pathway are the Tcf/Lef1 transcription factors, which regulate transcription of Wnt signaling target genes. Surprisingly, we found little Tcf/Lef1 expression in the postnatal neocortex. These observations suggest that noncanonical Wnt pathways predominate, which will require functional testing. However, Lef1 is widely expressed in the dorsal thalamus, and Wnt ligands and receptors are expressed, respectively, in cortical areas and thalamic nuclei that are interconnected. Thus, canonical Wnt signaling could be utilized in a major cortical input by Fz- and Lef1-expressing thalamic cells that innervate the Wnt-expressing cortex.

BACKGROUND

Obesity is a more potent cardiovascular risk factor (CVRF) in men than in women. Because traditional CVRFs cannot fully account for this sex difference, we tested the hypothesis that compared with men, women exhibit more robust endothelial function independent of obesity and that this sex difference is abrogated by diabetes.

RESULTS

We studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (Mch) and the endothelium-independent vasodilator sodium nitroprusside (SNP) in groups of lean, obese (OB), and type II diabetic (DM) premenopausal women and age- and body mass index-matched men. LBF response to intrafemoral administration of L-NMMA, an inhibitor of nitric oxide synthase, was also assessed in normal men and women. Maximum LBF increments in response to Mch were 347+/-57% versus 231+/-22% in lean women versus men (P<0.05) and 203+/-25% versus 111+/-17% in OB women versus men (P<0.01), respectively. In DM, maximum LBF increments in response to Mch were 104+/-24% and 138+/-33% in women and men, respectively, (P=NS). LBF decrements in response to L-NMMA were 34.9+/-4.1% and 17.1+/-4.2% in women and men, respectively (P<0.01). The response to SNP was not different between sexes and groups.

CONCLUSIONS

Premenopausal nondiabetic women exhibit more robust endothelium-dependent vasodilation owing to higher rates of nitric oxide release than men. Given the protective vascular action of nitric oxide, this difference may partially explain the lower incidence of macrovascular disease in women. In premenopausal women, DM causes impairment of endothelial function beyond that observed with obesity alone and leads to endothelial dysfunction similar to that observed in DM men. These findings may help explain the similar rates of coronary artery disease and mortality in diabetic men and women.

OBJECTIVE

To review studies of patterns of food intake, as assessed by diet index, factor analysis or cluster analysis, and their associations with body mass index or obesity (BMI/Ob).

METHODS

Systematic literature review MEDLINE search with crosscheck of references.

METHODS

Thirty observational studies relating food intake patterns to anthropometric information were identified and reviewed. Food intake patterns were defined using a diet index, factor or cluster analysis in 12, nine and nine studies, respectively. Measures of body mass were made concurrently with the diet assessment in all studies, and only in a few cases were the primary outcomes related to BMI/Ob.

RESULTS

The food intake patterns identified could, in most factor or cluster analysis studies, be categorised as: (a) meat, fatty, sweet or energy dense foods; (b) vegetables, fruit, whole grain and low-fat foods; or (c) by high alcohol consumption. The diet indexes were designed to capture a high diversity and/or food combinations matching the recommendations. The relationships with BMI/Ob were inconsistent-ten studies found that intake patterns, which we categorised as fatty, sweet or energy dense were positively associated with BMI/Ob, while similar patterns in four other studies were negatively associated with BMI. The significant associations between diet index score and BMI/Ob were consistently negative, while the associations between factor scores or cluster membership and BMI/Ob were less clear in terms of food intake pattern. Men and women had similar food intake patterns, but food intake patterns were less often positively associated with BMI/Ob in women. In 11 studies, there were no significant associations between food intake pattern and BMI/Ob.

CONCLUSIONS

This review showed that no consistent associations could be identified between BMI or Ob and food intake patterns, derived from diet index, factor analysis or cluster analysis. However, the heterogeneity of food intake patterns identified by such analyses and the lack of gold standards for the application of these techniques hampers consistent analysis of a relation between food intake patterns and health.

OBJECTIVE

To compare low-dose (30 Gy) radiotherapy (RT) with observation (OBS) in limited-stage aggressive lymphoma patients achieving complete remission (CR) after chemotherapy, and to measure conversion from partial response (PR) to CR with high-dose (40 Gy) RT.

METHODS

From 1984 to 1992, stage I (with risk factors) and II adults with diffuse aggressive lymphoma in CR after eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) were randomly assigned to 30 Gy involved-field RT or OBS. PR patients received 40 Gy RT.

RESULTS

Among 172 CR patients, the 6-year disease-free survival (DFS) was 73% for low-dose RT versus 56% for OBS (two-sided P = .05). Failure-free survival (two-sided P = .06), and time to progression (two-sided P = .06) also favored RT. Intent-to-treat analyses yielded similar results. No survival differences were observed. Three RT versus 15 OBS patients relapsed in initial disease sites. At 6 years, failure-free survival was 63% in PR patients; conversion to CR did not significantly influence clinical outcome.

CONCLUSIONS

For patients in CR after CHOP, low-dose RT prolonged DFS and provided local control, but no survival benefit was observed. The majority of PR patients were event-free at 6 years despite residual radiographic abnormalities. Future efforts should be directed toward improved imaging and more effective systemic therapies.

Epidemiological data indicate that obesity is a risk factor for asthma. These data are supported by observations in several murine models of obesity. Ob/ob, db/db, and Cpe(fat) mice each exhibit innate airway hyperresponsiveness, a characteristic feature of asthma. These mice also respond more vigorously to common asthma triggers, including ozone. Here we discuss the implications of these data with respect to several mechanisms proposed to explain the relationship between obesity and asthma: 1) common etiologies; 2) comorbidities; 3) mechanical factors; and 4) adipokines. We focus on the role of adipokines, especially TNF-alpha, IL-6, leptin, and adiponectin. Understanding the mechanistic basis for the relationship between obesity and asthma may lead to novel therapeutic strategies for treatment of the obese asthmatic subject.

Equilibrium binding of human alpha-thrombin to heparin was investigated at pH 7.4 as a function of thrombin and heparin concentrations, NaCl concentration, temperature, and heparin chain length with the extrinsic fluorescence probe, p-aminobenzamidine, or by quantitative affinity chromatography, in order to distinguish between sequence-specific and nonspecific electrostatic modes of binding. Analysis of binding data by a nonspecific binding model developed for protein-nucleic acid interactions, or by the discrete binding site model previously used to analyze the thrombin-heparin interaction, indicated that both models described the binding interaction equally well over the range of thrombin binding densities accessible to measurement. However, the strong dependence of the thrombin-heparin binding interaction on NaCl concentration, its minimal dependence on temperature, and the increase in apparent binding affinity with increasing heparin oligosaccharide chain length were best accounted for by a nonspecific electrostatic association of thrombin with 5 to 6 anionic residues contained in a 3-disaccharide binding site of heparin. This interaction was characterized by an intrinsic dissociation constant (KD,obs) of 6-10 microM at physiological ionic strength. Although the nonspecific binding model satisfactorily described the binding of thrombin to heparin chains ranging in size from 3 to approximately 13 disaccharides in terms of a single intrinsic KD,obs, deviations from this model were apparent with longer heparin chains (approximately 22 to approximately 35 disaccharides) from a progressive decrease in the intrinsic KD,obs of up to 4-fold. Sedimentation equilibrium analyses of thrombin-heparin complexes suggested a second weaker binding site on thrombin for heparin, which accounted for these deviations as well as the observed insolubility of thrombin-heparin complexes at high thrombin binding densities.

OBJECTIVE

We compared acylcarnitine (AcylCN) species, common amino acid and fat oxidation (FOX) byproducts, and plasma amino acids in normal weight (NW; n = 39), obese (OB; n = 64), and type 2 diabetic (n = 17) adolescents.

METHODS

Fasting plasma was analyzed by tandem mass spectrometry, body composition by dual energy X-ray absorptiometry and computed tomography, and total-body lipolysis and substrate oxidation by [(2)H(5)]glycerol and indirect calorimetry, respectively. In vivo insulin sensitivity (IS) was assessed with a 3-h hyperinsulinemic-euglycemic clamp.

RESULTS

Long-chain AcylCNs (C18:2-CN to C14:0-CN) were similar among the three groups. Medium- to short-chain AcylCNs (except C8 and C10) were significantly lower in type 2 diabetes compared with NW, and when compared with OB, C2-, C6-, and C10-CN were lower. Amino acid concentrations were lower in type 2 diabetes compared with NW. Fasting lipolysis and FOX were higher in OB and type 2 diabetes compared with NW, and the negative association of FOX to C10:1 disappeared after controlling for adiposity, Tanner stage, and sex. IS was lower in OB and type 2 diabetes with positive associations between IS and arginine, histidine, and serine after adjusting for adiposity, Tanner stage, and sex.

CONCLUSIONS

These metabolomics results, together with the increased rates of in vivo FOX, are not supportive of defective fatty acid or amino acid metabolism in obesity and type 2 diabetes in youth. Such observations are consistent with early adaptive metabolic plasticity in youth, which over time-with continued obesity and aging-may become dysfunctional, as observed in adults.

Brown adipose tissue (BAT) promotes a lean and healthy phenotype and improves insulin sensitivity. In response to cold or exercise, brown fat cells also emerge in the white adipose tissue (WAT; also known as beige cells), a process known as browning. Here we show that the development of functional beige fat in the inguinal subcutaneous adipose tissue (ingSAT) and perigonadal visceral adipose tissue (pgVAT) is promoted by the depletion of microbiota either by means of antibiotic treatment or in germ-free mice. This leads to improved glucose tolerance and insulin sensitivity and decreased white fat and adipocyte size in lean mice, obese leptin-deficient (ob/ob) mice and high-fat diet (HFD)-fed mice. Such metabolic improvements are mediated by eosinophil infiltration, enhanced type 2 cytokine signaling and M2 macrophage polarization in the subcutaneous white fat depots of microbiota-depleted animals. The metabolic phenotype and the browning of the subcutaneous fat are impaired by the suppression of type 2 cytokine signaling, and they are reversed by recolonization of the antibiotic-treated or germ-free mice with microbes. These results provide insight into the microbiota-fat signaling axis and beige-fat development in health and metabolic disease.