Induction of heme-oxygenase-1 (HO-1) does not enhance adiponectin production in human adipocytes: evidence against a direct HO-1 - Adiponectin axis

Adiponectin is a salutary adipokine and hypoadiponectinemia is implicated in the aetiology of obesity-related inflammation and cardiometabolic disease making therapeutic strategies to increase adiponectin attractive. Emerging evidence, predominantly from preclinical studies, suggests induction of heme-oxygenase-1 (HO-1) increases adiponectin production and reduces inflammatory tone. Here, we aimed to test whether induction of HO-1 enhanced adiponectin production from mature adipocytes. Treatment of human adipocytes with cobalt protoporphyrin (CoPP) or hemin for 24-48 h increased HO-1 expression and activity without affecting adiponectin expression and secretion. Treatment of adipocytes with TNFα reduced adiponectin secretion and increased expression and secretion of additional pro-inflammatory cytokines, IL-6 and MCP-1, as well as expression of sXBP-1, a marker of ER stress. HO-1 induction failed to reverse these effects. These results demonstrate that induction of HO-1 does not directly enhance adiponectin production or ameliorate the pro-inflammatory effects of TNFα and argue against a direct HO-1 - adiponectin axis. © 2015 Elsevier Ireland Ltd

Mechanisms underlying the diminished sensitivity to prolactin negative feedback during lactation: Reduced STAT5 signaling and up-regulation of cytokine-inducible SH2 domain-containing protein (CIS) expression in tuberoinfundibular dopaminergic neurons

Hyperprolactinaemia during lactation is a consequence of the sucking stimulus and in part due to reduced prolactin (PRL) negative feedback. To date, the mechanisms involved in this diminished sensitivity to PRL feedback are unknown but may involve changes in PRL signal transduction within tuberoinfundibular dopaminergic (TIDA) neurons. Therefore, we investigated signal transducers and activators of transcription (STAT) 5 signaling in the TIDA neurons of lactating rats. Dual-label confocal immunofluorescence studies were used to determine the intracellular distribution of STAT5 within TIDA neurons in the dorsomedial arcuate nucleus. In lactating rats with pups removed for 16 h, injection of ovine PRL significantly (P < 0.05) increased the STAT5 nuclear/cytoplasmic ratio compared with vehicle-treated mothers. In contrast, ovine PRL injection did not increase the STAT5 nuclear/cytoplasmic ratio in lactating mothers with pups, demonstrating that PRL signal transduction through STAT5 is reduced in TIDA neurons in the presence of pups. To investigate possible mechanisms involved in reduced PRL signaling, we examined the expression of suppressors of cytokine signaling (SOCS) proteins. Northern analysis on whole hypothalamus showed that CIS (cytokine-inducible SH2 domain-containing protein), but not SOCS1 or SOCS3, mRNA expression was significantly (P < 0.01) up-regulated in suckled lactating rats. Semiquantitative RT-PCR on arcuate nucleus micropunches also showed up-regulation of CIS transcripts. Immunofluorescence studies demonstrated that CIS is expressed in all TIDA neurons in the dorsomedial arcuate nucleus, and the intensity of CIS staining in these neurons is significantly (P < 0.05) increased in lactating rats with sucking pups. Together, these results support the hypothesis that loss of sensitivity to PRL-negative feedback during lactation is a result of increased CIS expression in TIDA neurons

Fibroblast growth factor-1 (FGF-1) promotes adipogenesis by downregulation of carboxypeptidase A4 (CPA4) – a negative regulator of adipogenesis implicated in the modulation of local and systemic insulin sensitivity

Fibroblast growth factor-1 (FGF-1) promotes differentiation of human preadipocytes into mature adipocytes via modulation of a BMP and Activin Membrane-Bound Inhibitor (BAMBI)/Peroxisome proliferator-activated receptor (PPAR?)-dependent network. Here, we combined transcriptomic and functional investigations to identify novel downstream effectors aligned with complementary analyses of gene expression in human adipose tissue to explore relationships with insulin sensitivity. RNA-Seq and qRT-PCR analysis revealed significant down-regulation of carboxypeptidase A4 (CPA4) following FGF-1 treatment or induction of differentiation of human preadipocytes in a BAMBI/PPAR?-independent manner. siRNA-mediated knockdown of CPA4 resulted in enhanced differentiation of human preadipocytes. Furthermore, expression of CPA4 in subcutaneous adipose tissue correlated negatively with indices of local and systemic (liver and muscle) insulin sensitivity. These results identify CPA4 as a negative regulator of adipogenesis that is down-regulated by FGF-1 and a putative deleterious modulator of local and systemic insulin sensitivity. Further investigations are required to define the molecular mechanism(s) involved and potential therapeutic opportunities

Exoplanet Science Priorities from the Perspective of Internal and Surface Processes for Silicate and Ice Dominated Worlds

The geophysics of extrasolar planets is a scientific topic often regarded as standing largely beyond the reach of near-term observations. This reality in no way diminishes the central role of geophysical phenomena in shaping planetary outcomes, from formation, to thermal and chemical evolution, to numerous issues of surface and near-surface habitability. We emphasize that for a balanced understanding of extrasolar planets, it is important to look beyond the natural biases of current observing tools, and actively seek unique pathways to understand exoplanet interiors as best as possible during the long interim prior to a time when internal components are more directly accessible. Such pathways include but are not limited to: (a) enhanced theoretical and numerical modeling, (b) laboratory research on critical material properties, (c) measurement of geophysical properties by indirect inference from imprints left on atmospheric and orbital properties, and (d) the purpose-driven use of Solar System object exploration expressly for its value in comparative planetology toward exoplanet-analogs. Breaking down barriers that envision local Solar System exploration, including the study of Earth's own deep interior, as separate from and in financial competition with extrasolar planet research, may greatly improve the rate of needed scientific progress for exoplanet geophysics. As the number of known rocky and icy exoplanets grows in the years ahead, we expect demand for expertise in 'exogeoscience' will expand at a commensurately intense pace. We highlight key topics, including: how water oceans below ice shells may dominate the total habitability of our galaxy by volume, how free-floating nomad planets may often attain habitable subsurface oceans supported by radionuclide decay, and how deep interiors may critically interact with atmospheric mass loss via dynamo-driven magnetic fields

Circadian Desynchrony Promotes Metabolic Disruption in a Mouse Model of Shiftwork

Shiftwork is associated with adverse metabolic pathophysiology, and the rising incidence of shiftwork in modern societies is thought to contribute to the worldwide increase in obesity and metabolic syndrome. The underlying mechanisms are largely unknown, but may involve direct physiological effects of nocturnal light exposure, or indirect consequences of perturbed endogenous circadian clocks. This study employs a two-week paradigm in mice to model the early molecular and physiological effects of shiftwork. Two weeks of timed sleep restriction has moderate effects on diurnal activity patterns, feeding behavior, and clock gene regulation in the circadian pacemaker of the suprachiasmatic nucleus. In contrast, microarray analyses reveal global disruption of diurnal liver transcriptome rhythms, enriched for pathways involved in glucose and lipid metabolism and correlating with first indications of altered metabolism. Although altered food timing itself is not sufficient to provoke these effects, stabilizing peripheral clocks by timed food access can restore molecular rhythms and metabolic function under sleep restriction conditions. This study suggests that peripheral circadian desynchrony marks an early event in the metabolic disruption associated with chronic shiftwork. Thus, strengthening the peripheral circadian system by minimizing food intake during night shifts may counteract the adverse physiological consequences frequently observed in human shift workers

Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer.

While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20-1.79, P=1.68x10−4). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92-1.18, P=0.49), 0.94 (95% CI: 0.84-1.05, P= 0.27), and 0.98 (95% CI: 0.85-1.12, P=0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR=0.69, 95% CI: 0.49-0.99, P=0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia. This article is protected by copyright. All rights reserved

TOI-836 : a super-Earth and mini-Neptune transiting a nearby K-dwarf

Funding: TGW, ACC, and KH acknowledge support from STFC consolidated grant numbers ST/R000824/1 and ST/V000861/1, and UKSA grant ST/R003203/1.We present the discovery of two exoplanets transiting TOI-836 (TIC 440887364) using data from TESS Sector 11 and Sector 38. TOI-836 is a bright (T = 8.5 mag), high proper motion (∼200 mas yr−1), low metallicity ([Fe/H]≈−0.28) K-dwarf with a mass of 0.68 ± 0.05 M⊙ and a radius of 0.67 ± 0.01 R⊙. We obtain photometric follow-up observations with a variety of facilities, and we use these data-sets to determine that the inner planet, TOI-836 b, is a 1.70 ± 0.07 R⊕ super-Earth in a 3.82 day orbit, placing it directly within the so-called ‘radius valley’. The outer planet, TOI-836 c, is a 2.59 ± 0.09 R⊕ mini-Neptune in an 8.60 day orbit. Radial velocity measurements reveal that TOI-836 b has a mass of 4.5 ± 0.9 M⊕, while TOI-836 c has a mass of 9.6 ± 2.6 M⊕. Photometric observations show Transit Timing Variations (TTVs) on the order of 20 minutes for TOI-836 c, although there are no detectable TTVs for TOI-836 b. The TTVs of planet TOI-836 c may be caused by an undetected exterior planet.Publisher PDFPeer reviewe

TOI-836: A super-Earth and mini-Neptune transiting a nearby K-dwarf

We present the discovery of two exoplanets transiting TOI-836 (TIC 440887364) using data from TESS Sector 11 and Sector 38. TOI-836 is a bright ($T = 8.5$ mag), high proper motion ($\sim\,200$ mas yr$^{-1}$), low metallicity ([Fe/H]$\approx\,-0.28$) K-dwarf with a mass of $0.68\pm0.05$ M$_{\odot}$ and a radius of $0.67\pm0.01$ R$_{\odot}$. We obtain photometric follow-up observations with a variety of facilities, and we use these data-sets to determine that the inner planet, TOI-836 b, is a $1.70\pm0.07$ R$_{\oplus}$ super-Earth in a 3.82 day orbit, placing it directly within the so-called 'radius valley'. The outer planet, TOI-836 c, is a $2.59\pm0.09$ R$_{\oplus}$ mini-Neptune in an 8.60 day orbit. Radial velocity measurements reveal that TOI-836 b has a mass of $4.5\pm0.9$ M$_{\oplus}$ , while TOI-836 c has a mass of $9.6\pm2.6$ M$_{\oplus}$. Photometric observations show Transit Timing Variations (TTVs) on the order of 20 minutes for TOI-836 c, although there are no detectable TTVs for TOI-836 b. The TTVs of planet TOI-836 c may be caused by an undetected exterior planet

Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer

Background: Observational studies have associated adiposity with an increased risk of colorectal cancer (CRC). However, such studies do not establish a causal relationship. To minimise bias from confounding we performed a Mendelian randomisation (MR) analysis to examine the relationship between adiposity and CRC. Methods: We used SNPs associated with adult body mass index (BMI), waist-hip ratio (WHR), childhood obesity and birth weight as instrumental variables in a MR analysis of 9254 CRC cases and 18 386 controls. Results: In the MR analysis, the odds ratios (ORs) of CRC risk per unit increase in BMI, WHR and childhood obesity were 1.23 (95% CI: 1.02-1.49, P = 0.033), 1.59 (95% CI: 1.08-2.34, P = 0.019) and 1.07 (95% CI: 1.03-1.13, P = 0.018), respectively. There was no evidence for association between birth weight and CRC (OR = 1.22, 95% CI: 0.89-1.67, P = 0.22). Combining these data with a concurrent MR-based analysis for BMI and WHR with CRC risk (totalling to 18 190 cases, 27 617 controls) provided increased support, ORs for BMI and WHR were 1.26 (95% CI: 1.10-1.44, P = 7.7 x 10(-4)) and 1.40 (95% CI: 1.14-1.72, P = 1.2 x 10(-3)), respectively. Conclusions: These data provide further evidence for a strong causal relationship between adiposity and the risk of developing CRC highlighting the urgent need for prevention and treatment of adiposity.Peer reviewe