The notion that a trade-off exists between immunity and reproduction is now a central concept in theories of sexual selection. However, whether such a trade-off exists between immunity and gamete viability has not been established. Here we show that genetic variance for high levels of an immune response required to fight bacterial infections is associated with genetic variance for low sperm viability. These data have implications for our understanding of sexual selection mechanisms and of reproductive costs in male longevity.

This article is available online at http://www.jlr.org lipoprotein (HDL), and abnormal low density lipoprotein (LDL) metabolism, which signifi cantly increases the risk of cardiovascular disease (CVD), the leading cause of morbidity and mortality in type II diabetes ( 1 ). Increased hepatic very low density lipoprotein (VLDL)/apolipoprotein B (apoB) secretion is a characteristic feature of type II diabetes and a major cause of diabetic dyslipidemia ( 2, 3 ), but molecular mechanisms linking diabetes to hepatic apoB overproduction are only partially understood. In obesity and diabetes, circulating free fatty acids (FFA) are often elevated mainly due to abnormal adipocyte lipolysis ( 3 ). Recent studies showed that elevated plasma and tissue FFAs are critically involved in the development of hyperlipidemia. Current evidence supports that circulating FFA level is an important CVD risk factor in diabetes ( 4, 5 ). In addition, metabolic profi ling studies also showed that the abundant saturated fatty acid palmitate in the plasma is a reliable biomarker for type II diabetes ( 6 ). At the molecular level, increased hepatic FFA uptake provides substrates for hepatic triglyceride synthesis, leading to apoB lipidation and VLDL synthesis and secretion. In addition, elevated FFAs and their lipid intermediates, namely, ceramides and diacylglycerols, cause abnormal activation of protein kinase C (PKC) isoforms and mitogen-activated protein kinases (MAPK), which results in infl ammation and insulin resistance ( 7,8 ). Although it is well known that activation of infl ammatory signaling and impairment of insulin signaling contribute signifi cantly to apoB overproduction and hyperlipidemia in diabetes, the downstream mechanisms are still not fully clear ( 9, 10 ).Abstract Hepatic VLDL overproduction is a characteristic feature of diabetes and an important contributor to diabetic dyslipidemia. Hepatic sortilin 1 (Sort1), a cellular traffi cking receptor, is a novel regulator of plasma lipid metabolism and reduces plasma cholesterol and triglycerides by inhibiting hepatic apolipoprotein B production. Elevated circulating free fatty acids play key roles in hepatic VLDL overproduction and the development of dyslipidemia. This study investigated the regulation of hepatic Sort1 in obesity and diabetes and the potential implications in diabetic dyslipidemia. Results showed that hepatic Sort1 protein was markedly decreased in mouse models of type I and type II diabetes and in human individuals with obesity and liver steatosis, whereas increasing hepatic Sort1 expression reduced plasma cholesterol and triglycerides in mice. Mechanistic studies showed that the saturated fatty acid palmitate activated extracellular signal-regulated kinase (ERK) and inhibited Sort1 protein by mechanisms involving Sort1 protein ubiquitination and degradation. Consistently, hepatic ERK signaling was activated in diabetic mice, whereas blocking ERK signaling by an ERK inhibitor increased hepatic Sort1 protein in mice. These results suggest that increased satu...

We used volumetric quantitative computed tomography (QCT) scans to evaluate volumetric bone density (vBMD), geometry, and strength in the thoracic (T8 to T10) and lumbar (L3 to L5) spine and determined how these parameters varied with age, sex, and spinal region. Participants included 690 participants of the Framingham Study, 40 to 87 years old (mean, 61 years). In both women and men, trabecular vBMD declined with age similarly for lumbar and thoracic regions, whereas cortical vBMD and integral vBMD, vertebral strength, and compressive force declined more at the lumbar spine than thoracic spine (interaction, p < 0.01). Notably, in men, cortical vBMD increased (β = 0.0004, p = 0.01), and vertebral strength did not change (β = 1.9305, p = 0.66) at the thoracic spine with age. In both women and men, vertebral cross‐sectional area increased less and the factor‐of‐risk increased more with age at the lumbar than at the thoracic region (interaction, p < 0.01). For example, in women, the factor‐of‐risk for forward flexion increased (worsened) with age 6.8‐fold more in the lumbar spine (β = 0.0157), compared with the thoracic spine (β = 0.0023). vBMD and vertebral strength declined more and the factor‐of‐risk increased more with age in women than men (interaction, p < 0.01). For instance, integral vBMD for the lumbar spine declined 36% from 40 to 75 years of age in women compared with 18% in men. There was little or no age‐related change in the forces applied to the thoracic vertebrae in either women or men. Age‐related changes were greater in the lumbar spine than in the thoracic region and greater in women than men. Whereas women lost bone density and strength at both the thoracic and lumbar spine, in men, vertebral strength declined only at the lumbar spine. Our study confirms the importance of evaluating determinants of vertebral strength in both the thoracic and lumbar spine and in both women and men to understand mechanisms underlying the structural failure of vertebral bodies with aging. © 2012 American Society for Bone and Mineral Research.

Background: Innate immune signaling requires multiple mechanisms to suppress signaling in the absence of stimulation. Results: TNF receptor associated factor 6 (TRAF6) activity is regulated by reversible arginine methylation. Conclusion: Arginine methylation of TRAF6 inhibits signaling in the absence of Toll-like receptor ligands. Significance: Reversible TRAF6 methylation is a novel mechanism that controls innate immune responses.

Arginine methylation is a common posttranslational modification that has been shown to regulate both gene expression and extranuclear signaling events. We recently reported defects in protein arginine methyltransferase 1 (PRMT1) activity and arginine methylation in the livers of cirrhosis patients with a history of recurrent infections. To examine the role of PRMT1 in innate immune responses , we created a cell type-specific knock-out mouse model. We showed that myeloid-specific PRMT1 knock-out mice demonstrate higher proinflammatory cytokine production and a lower survival rate after cecal ligation and puncture. We found that this defect is because of defective peroxisome proliferator-activated receptor γ (PPARγ)-dependent M2 macrophage differentiation. PPARγ is one of the key transcription factors regulating macrophage polarization toward a more anti-inflammatory and pro-resolving phenotype. We found that PRMT1 knock-out macrophages failed to up-regulate PPARγ expression in response to IL4 treatment resulting in 4-fold lower PPARγ expression in knock-out cells than in wild-type cells. Detailed study of the mechanism revealed that PRMT1 regulates PPARγ gene expression through histone H4R3me2a methylation at the PPARγ promoter. Supplementing with PPARγ agonists rosiglitazone and GW1929 was sufficient to restore M2 differentiation and and abrogated the difference in survival between wild-type and PRMT1 knock-out mice. Taken together these data suggest that PRMT1-dependent regulation of macrophage PPARγ expression contributes to the infection susceptibility in PRMT1 knock-out mice.