An extensive phenotypic characterization of the hTNFα transgenic mice

<p>Abstract</p> <p>Background</p> <p>Tumor necrosis factor alpha (TNFα) is implicated in a wide variety of pathological and physiological processes, including chronic inflammatory conditions, coronary artery disease, diabetes, obesity, and cachexia. Transgenic mice expressing human TNFα (hTNFα) have previously been described as a model for progressive rheumatoid arthritis. In this report, we describe extensive characterization of an hTNFα transgenic mouse line.</p> <p>Results</p> <p>In addition to arthritis, these hTNFα transgenic mice demonstrated major alterations in body composition, metabolic rate, leptin levels, response to a high-fat diet, bone mineral density and content, impaired fertility and male sexual function. Many phenotypes displayed an earlier onset and a higher degree of severity in males, pointing towards a significant degree of sexual dimorphism in response to deregulated expression of TNFα.</p> <p>Conclusion</p> <p>These results highlight the potential usefulness of this transgenic model as a resource for studying the progressive effects of constitutively expressed low levels of circulating TNFα, a condition mimicking that observed in a number of human pathological conditions.</p

An extensive phenotypic characterization of the hTNFα transgenic mice-2

<p><b>Copyright information:</b></p><p>Taken from "An extensive phenotypic characterization of the hTNFα transgenic mice"</p><p>http://www.biomedcentral.com/1472-6793/7/13</p><p>BMC Physiology 2007;7():13-13.</p><p>Published online 10 Dec 2007</p><p>PMCID:PMC2222242.</p><p></p>pendently increased endogenous TNFα in WT and TG mice similarly. WT (open bars) and TG mice (closed bars) were injected with the indicated doses of LPS (μg/mouse) as shown on the X-axis. (A) Human and (B) mouse TNFα levels were measured using ELISA assays. Data are presented as means ± SEM, n = 5 for each genotype and dose combination. ND – non-detectable

An extensive phenotypic characterization of the hTNFα transgenic mice-0

<p><b>Copyright information:</b></p><p>Taken from "An extensive phenotypic characterization of the hTNFα transgenic mice"</p><p>http://www.biomedcentral.com/1472-6793/7/13</p><p>BMC Physiology 2007;7():13-13.</p><p>Published online 10 Dec 2007</p><p>PMCID:PMC2222242.</p><p></p>pendently increased endogenous TNFα in WT and TG mice similarly. WT (open bars) and TG mice (closed bars) were injected with the indicated doses of LPS (μg/mouse) as shown on the X-axis. (A) Human and (B) mouse TNFα levels were measured using ELISA assays. Data are presented as means ± SEM, n = 5 for each genotype and dose combination. ND – non-detectable

GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent

<div><p>GPR40 agonists are effective antidiabetic agents believed to lower glucose through direct effects on the beta cell to increase glucose stimulated insulin secretion. However, not all GPR40 agonists are the same. Partial agonists lower glucose through direct effects on the pancreas, whereas GPR40 AgoPAMs may incorporate additional therapeutic effects through increases in insulinotrophic incretins secreted by the gut. Here we describe how GPR40 AgoPAMs stimulate both insulin and incretin secretion in vivo over time in diabetic GK rats. We also describe effects of AgoPAMs in vivo to lower glucose and body weight beyond what is seen with partial GPR40 agonists in both the acute and chronic setting. Further comparisons of the glucose lowering profile of AgoPAMs suggest these compounds may possess greater glucose control even in the presence of elevated glucagon secretion, an unexpected feature observed with both acute and chronic treatment with AgoPAMs. Together these studies highlight the complexity of GPR40 pharmacology and the potential additional benefits AgoPAMs may possess above partial agonists for the diabetic patient.</p></div

GLP-1R^-/- mice vs. wild type mice during an IPGTT.

<p>After treatment with MK-2305 at 10 mg/kg or AP1 at 30 mg/kg and a dextrose challenge, blood glucose excursion was reduced to similar levels in both the knockout and wild type mice compared to the respective vehicle groups (A, B). AP1 administered at a maximally efficacious dose increased insulin following the dextrose challenge in both knockout and wild type mice, but a much greater effect was seen in the wild type mice (C, D). The partial agonist MK-2305 administered at a maximally efficacious dose showed no effect in insulin for either the knockout or wild type mice. Data are mean ± SEM with analysis via ANOVA followed by Tukey’s posttest. ^ <i>P < 0</i>.<i>05</i> vs. GLP-1R^-/- Vehicle; * <i>P < 0</i>.<i>05</i> vs. WT Vehicle; ⁺ <i>P < 0</i>.<i>05</i> vs. GLP-1R^-/- AP1.</p

GK rat glucose, body weight, and food intake are affected by 28 days treatment with AgoPAMs or partial agonist.

<p>All compounds were dosed at maximal efficacious doses. Fed blood glucose levels were significantly reduced by GPR40 AgoPAMs compared to vehicle controls on days 10 through 28 of treatment, but only on day 28 by the partial agonist (P < 0.05, A). On day 28 of study, fed and fasted blood glucose was significantly reduced with GPR40 partial and AgoPAM treatments compared to vehicle controls (P < 0.05, B). Additionally, AP1 significantly reduced fed blood glucose compared to the partial agonist (P < 0.05, B). Decreased levels of food intake were observed with AgoPAM treatment days 10 through 28 (P < 0.05), while the partial agonist did not reduce food intake until day 17 (P < 0.05, C). The effects of AgoPAMs on food intake were associated with decreases in body weight (P < 0.05, D) whereas MK-8666 had no effect on body weight. Data are mean ± SEM with analysis via ANOVA followed by Tukey’s posttest. * <i>P < 0</i>.<i>05</i> vs. Vehicle, ⁺ <i>P < 0</i>.<i>05</i> vs. MK-8666.</p

Acute treatment with GPR40 partial agonists and AgoPAMs in GK rats.

<p>One hour post-acute treatment with vehicle, TAK-875 at 100 mg/kg, AP1 at 30 mg/kg, or AP3 at 10 mg/kg, blood glucose dropped to its lowest levels (A) at the same time insulin peaked (B) in GK rats. All compounds were dosed at maximal efficacious doses. Acute treatment with the AgoPAMs produced a significant 24 hr increase in glucagon, while the glucagon increase of TAK-875 was not significant and was of a shorter duration (C). Data are mean ± SEM with analysis via ANOVA followed by Tukey’s posttest. * <i>P < 0</i>.<i>05</i> vs. Vehicle, ⁺ <i>P < 0</i>.<i>05</i> vs. TAK-875.</p

Summary of [3H]L358 and [3H]AP9 ([3H]25,) binding to WT human GPR40.

<p>Each compound was profiled multiple times (n = 2–13). N.A. specifies that a compound augmented the binding of specified radioligand in line with the positive cooperativity between the partial agonist and AgoPAM binding sites.</p

Skeletal muscle 13C-glycogen levels following a 13C-GTT in GK rats chronically treated with GPR40 partial agonist (MK-8666) or AgoPAM (AP1).

<p>Data are mean ± SEM with analysis via ANOVA followed by Tukey’s posttest. * <i>P < 0</i>.<i>05</i> vs. Vehicle; ⁺ <i>P < 0</i>.<i>05</i> vs. MK-8666.</p