Metabolomic Profiling Reveals Mitochondrial-Derived Lipid Biomarkers That Drive Obesity-Associated Inflammation

Obesity has reached epidemic proportions worldwide. Several animal models of obesity exist, but studies are lacking that compare traditional lard-based high fat diets (HFD) to “Cafeteria diets" (CAF) consisting of nutrient poor human junk food. Our previous work demonstrated the rapid and severe obesogenic and inflammatory consequences of CAF compared to HFD including rapid weight gain, markers of Metabolic Syndrome, multi-tissue lipid accumulation, and dramatic inflammation. To identify potential mediators of CAF-induced obesity and Metabolic Syndrome, we used metabolomic analysis to profile serum, muscle, and white adipose from rats fed CAF, HFD, or standard control diets. Principle component analysis identified elevations in clusters of fatty acids and acylcarnitines. These increases in metabolites were associated with systemic mitochondrial dysfunction that paralleled weight gain, physiologic measures of Metabolic Syndrome, and tissue inflammation in CAF-fed rats. Spearman pairwise correlations between metabolites, physiologic, and histologic findings revealed strong correlations between elevated markers of inflammation in CAF-fed animals, measured as crown like structures in adipose, and specifically the pro-inflammatory saturated fatty acids and oxidation intermediates laurate and lauroyl carnitine. Treatment of bone marrow-derived macrophages with lauroyl carnitine polarized macrophages towards the M1 pro-inflammatory phenotype through downregulation of AMPK and secretion of pro-inflammatory cytokines. Results presented herein demonstrate that compared to a traditional HFD model, the CAF diet provides a robust model for diet-induced human obesity, which models Metabolic Syndrome-related mitochondrial dysfunction in serum, muscle, and adipose, along with pro-inflammatory metabolite alterations. These data also suggest that modifying the availability or metabolism of saturated fatty acids may limit the inflammation associated with obesity leading to Metabolic Syndrome

Renal Artery Stenosis in Patients with Resistant Hypertension: Stent It or Not?

After three large neutral trials in which renal artery revascularization failed to reduce cardiovascular and renal morbidity and mortality, renal artery stenting became a therapeutic taboo. However, this is probably unjustified as these trials have important limitations and excluded patients most likely to benefit from revascularization. In particular, patients with severe hypertension were often excluded and resistant hypertension was either poorly described or not conform to the current definition. Effective pharmacological combination treatment can control blood pressure in most patients with renovascular hypertension. However, it may also induce further renal hypoperfusion and thus accelerate progressive loss of renal tissue. Furthermore, case reports of patients with resistant hypertension showing substantial blood pressure improvement after successful revascularization are published over again. To identify those patients who would definitely respond to renal artery stenting, properly designed randomized clinical trials are definitely needed

The effectiveness of a Mesoamerican 'paper park' in conserving cloud forest avifauna

Mesoamerican cloud forests are important centres of biodiversity, but are under severe pressure from anthropogenic activities. Protected areas have been established to conserve remaining areas of this habitat, but it is debatable how effective these under-resourced 'paper parks' are in preserving biodiversity. This study investigates this issue utilising species-level data, examining composition of avifaunal communities within an undermanaged cloud forest park. Research was conducted in the Parque Nacional Cusuco, North-West Honduras. Results indicate that overall avian species richness is greater in the less heavily protected buffer zone than the nominally inviolate core zone. However, core zone areas are shown to be effective in preserving threatened and range-restricted species. Results therefore demonstrate that buffer zone forest has a comparably reduced conservation value, but the overall park system appears to be effective in conserving the core zone. These findings should be taken into account when considering extensions to protected area networks in Mesoamerica

Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension

Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure. Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants. Results: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (P<5×10-8). Among them, a rare intergenic variant at novel locus, LOC100506274, was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; P=4.99×10-8) but not stage-2 analysis (P=0.11). Furthermore, a novel common variant at the known INSR locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; P=4.18×10-7) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; P=7.28×10-23). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (P<1×10-6and P<1×10-4, respectively). Discussion: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification