Hematological and acute-phase responses to diet-induced obesity in IL-6 KO mice

Obesity is associated with chronic inflammation and elevated levels of IL-6. The role of IL-6 in induction of acute-phase proteins and modulation of haematological responses has been demonstrated in models of inflammation and aging, but not in obesity. We hypothesized that IL-6 is necessary to regulate the acute-phase response and hematological changes associated with diet-induced obesity (DIO) in mice. Feeding a 60% kcal/fat diet for 13 weeks to C57BL6 WT male mice induced a significant increase in IL-6 expression in visceral adipose tissue (VAT), but not liver, compared to mice fed chow diet. Significantly elevated IL-6 levels were present in the peritoneal lavage fluid, but not plasma, of DIO compared to lean mice. A comparable degree of obesity, hepatomegaly, hyperleptinemia, VAT inflammation and insulin resistance was observed in DIO WT and IL-6 KO mice compared to WT and KO mice fed chow diet. Significant leukocytosis was observed in DIO WT but not DIO KO mice compared to lean groups. A significant reduction in platelet counts, without alterations in platelet size, percentage of circulating reticulated platelets and number of bone marrow megakaryocytes, was present in DIO KO mice compared to each other group. Hepatic expression of thrombopoietin was comparable in each group, with DIO WT and KO mice having reduced VAT expression compared to lean mice. Lean KO mice had significantly elevated plasma levels of thrombopoietin compared to each other group, whereas liver-associated thrombopoietin levels were comparable in each group. Deficiency of IL-6 resulted in blunted hepatic induction of the acute-phase protein serum amyloid A-1, whereas expression of hepcidin-1 and -2, LPS-binding protein, ceruloplasmin, plasminogen activator inhibitor-1 and thrombospondin-1 was IL-6- independent. In conclusion, in the absence of overt metabolic alterations, IL-6 modulates leukocytosis,thrombopoiesis induction of SAA-1, but not other acute-phase proteins in obese mice

Rosiglitazone Improves Survival and Hastens Recovery from Pancreatic Inflammation in Obese Mice

Obesity increases severity of acute pancreatitis (AP) by unclear mechanisms. We investigated the effect of the PPAR-gamma agonist rosiglitazone (RGZ, 0.01% in the diet) on severity of AP induced by administration of IL-12+ IL-18 in male C57BL6 mice fed a low fat (LFD) or high fat diet (HFD), under the hypothesis that RGZ would reduce disease severity in HFD-fed obese animals. In both LFD and HFD mice without AP, RGZ significantly increased body weight and % fat mass, with significant upregulation of adiponectin and suppression of erythropoiesis. In HFD mice with AP, RGZ significantly increased survival and hastened recovery from pancreatic inflammation, as evaluated by significantly improved pancreatic histology, reduced saponification of visceral adipose tissue and less severe suppression of erythropoiesis at Day 7 post-AP. This was associated with significantly lower circulating and pancreas-associated levels of IL-6, Galectin-3, osteopontin and TIMP-1 in HFD + RGZ mice, particularly at Day 7 post-AP. In LFD mice with AP, RGZ significantly worsened the degree of intrapancreatic acinar and fat necrosis as well as visceral fat saponification, without affecting other parameters of disease severity or inflammation. Induction of AP lead to major suppression of adiponectin levels at Day 7 in both HFD and HFD + RGZ mice. In conclusion, RGZ prevents development of severe AP in obese mice even though it significantly increases adiposity, indicating that obesity can be dissociated from AP severity by improving the metabolic and inflammatory milieu. However, RGZ worsens selective parameters of AP severity in LFD mice

Experimental design.

<p>Timing of LFD and HFD feeding with and without RGZ, administration of vehicle or IL-12+ IL-18 (2 injections, 24 h apart), and termination of the experiment is shown.</p

Effect of RGZ on adipokine levels in mice with AP.

<p>Mice in the LFD (green columns), LFD + RGZ (orange columns), HFD (blue columns) or HFD + RGZ (pink columns) groups received two injections of IL-12+ IL-18 and were evaluated at Day 1 and Day 7. Control mice received vehicle. Circulating levels of leptin (<b>A</b>) and adiponectin (APN) (<b>B</b>) were measured by ELISA. Data are mean +/− SEM of 8–12 mice per group.</p

Effect of RGZ on hematological parameters in mice with AP.

<p>Mice received two injections of IL -12+ IL-18 and were evaluated at Day 1 and Day 7. Control mice received vehicle. Circulating while blood cells (WBC) (<b>A</b>), % neutrophils (<b>B</b>), % lymphocytes (<b>C</b>) and % monocytes (<b>D</b>) as well as red blood cells (RBC) (<b>E</b> absolute value, <b>F</b> % change from baseline), concentration of hemoglobin (<b>G</b> absolute value, <b>H</b> % change from baseline), and hematocrit (<b>I</b> absolute value, <b>I</b> % change from baseline) were quantified in blood obtained from LFD (green columns), LFD + RGZ (orange columns), HFD (blue columns) or HFD + RGZ (pink columns) groups. Data are mean +/− SEM of 8–12 mice per group.</p

Genome-Wide Association Study of Grain Polyphenol Concentrations in Global Sorghum [<i>Sorghum bicolor</i> (L.) Moench] Germplasm

Identifying natural variation of health-promoting compounds in staple crops and characterizing its genetic basis can help improve human nutrition through crop biofortification. Some varieties of sorghum, a staple cereal crop grown worldwide, have high concentrations of proanthocyanidins and 3-deoxyanthocyanidins, polyphenols with antioxidant and anti-inflammatory properties. We quantified total phenols, proanthocyanidins, and 3-deoxyanthocyanidins in a global sorghum diversity panel (<i>n</i> = 381) using near-infrared spectroscopy (NIRS), and characterized the patterns of variation with respect to geographic origin and botanical race. A genome-wide association study (GWAS) with 404,628 SNP markers identified novel quantitative trait loci for sorghum polyphenols, some of which colocalized with homologues of flavonoid pathway genes from other plants, including an orthologue of maize (<i>Zea mays</i>) <i>Pr1</i> and a homologue of <i>Arabidopsis</i> (<i>Arabidopsis thaliana</i>) <i>TT16</i>. This survey of grain polyphenol variation in sorghum germplasm and catalog of flavonoid pathway loci may be useful to guide future enhancement of cereal polyphenols

Effect of RGZ on the pancreatic inflammatory infiltrate.

<p>Mice received two injections of IL -12+ IL-18 and were evaluated at Day 1 and Day 7. Control mice received vehicle. Infiltration by neutrophils (<b>A</b>), macrophages (<b>B</b>) and lymphocytes (<b>C</b>) was quantified by a pathologist in sections of pancreas obtained from LFD (green columns), LFD + RGZ (orange columns), HFD (blue columns) or HFD + RGZ (pink columns) groups. Data are mean +/− SEM of 8–12 mice per group.</p

Effect of RGZ in control mice.

<p>Body and pancreas weight, % fat mass, average daily food intake during the last week of feeding with the various diets, plasma levels of leptin, adiponectin, glucose, insulin, triglycerides (TG) and amylase, were measured in LFD and HFD groups with or without RGZ. Data are mean +/− SEM of 6–8 mice per group.</p>a<p>p<0.001 <i>vs.</i> LFD groups;</p>b<p>p<0.05,</p>c<p>p<0.001 <i>vs.</i> respective group without RGZ by ANOVA.</p

Effect of RGZ on survival from AP in LFD and HFD mice.

<p>Mice in the LFD (green line), LFD + RGZ (orange line), HFD (blue line) or HFD + RGZ (pink line) received two injections of IL-12+ IL-18 at 150 and 750 ng/mouse each, respectively and survival monitored for 15 days. No further lethality was observed after Day 7. Data are from 10–15 mice per group.</p

Effect of RGZ on pancreatic and circulating inflammatory mediators.

<p>Mice received two injections of IL -12+ IL-18 and were evaluated at Day 1 and Day 7. Control mice received vehicle. Levels of by IL-6 (<b>A–B</b>), osteopontin (OPN) (<b>C–D</b>), TIMP1 (<b>E–F</b>) and Galectin-3 (Gal3) (<b>G–H</b>) were quantified in pancreatic homogenates (<b>A, C, E, G</b>) and plasma (<b>B, D, F, H</b>) obtained from LFD (green columns), LFD + RGZ (orange columns), HFD (blue columns) or HFD + RGZ (pink columns) groups. Data are mean +/− SEM of 8–12 mice per group.</p