Myostatin Inhibition in Muscle, but Not Adipose Tissue, Decreases Fat Mass and Improves Insulin Sensitivity

Myostatin (Mstn) is a secreted growth factor expressed in skeletal muscle and adipose tissue that negatively regulates skeletal muscle mass. Mstn−/− mice have a dramatic increase in muscle mass, reduction in fat mass, and resistance to diet-induced and genetic obesity. To determine how Mstn deletion causes reduced adiposity and resistance to obesity, we analyzed substrate utilization and insulin sensitivity in Mstn−/− mice fed a standard chow. Despite reduced lipid oxidation in skeletal muscle, Mstn−/− mice had no change in the rate of whole body lipid oxidation. In contrast, Mstn−/− mice had increased glucose utilization and insulin sensitivity as measured by indirect calorimetry, glucose and insulin tolerance tests, and hyperinsulinemic-euglycemic clamp. To determine whether these metabolic effects were due primarily to the loss of myostatin signaling in muscle or adipose tissue, we compared two transgenic mouse lines carrying a dominant negative activin IIB receptor expressed specifically in adipocytes or skeletal muscle. We found that inhibition of myostatin signaling in adipose tissue had no effect on body composition, weight gain, or glucose and insulin tolerance in mice fed a standard diet or a high-fat diet. In contrast, inhibition of myostatin signaling in skeletal muscle, like Mstn deletion, resulted in increased lean mass, decreased fat mass, improved glucose metabolism on standard and high-fat diets, and resistance to diet-induced obesity. Our results demonstrate that Mstn−/− mice have an increase in insulin sensitivity and glucose uptake, and that the reduction in adipose tissue mass in Mstn−/− mice is an indirect result of metabolic changes in skeletal muscle. These data suggest that increasing muscle mass by administration of myostatin antagonists may be a promising therapeutic target for treating patients with obesity or diabetes

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, P-inter= 2.6 x 10(-8)). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDAR-ADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10(-8)), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10(-8)), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10(-4)). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.Peer reviewe

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Exome genotyping and linkage analysis identifies two novel linked regions and replicates two others for myopia in Ashkenazi Jewish families

Abstract Background Myopia is one of most common eye diseases in the world and affects 1 in 4 Americans. It is a complex disease caused by both environmental and genetics effects; the genetics effects are still not well understood. In this study, we performed genetic linkage analyses on Ashkenazi Jewish families with a strong familial history of myopia to elucidate any potential causal genes. Methods Sixty-four extended Ashkenazi Jewish families were previously collected from New Jersey. Genotypes from the Illumina ExomePlus array were merged with prior microsatellite linkage data from these families. Additional custom markers were added for candidate regions reported in literature for myopia or refractive error. Myopia was defined as mean spherical equivalent (MSE) of -1D or worse and parametric two-point linkage analyses (using TwoPointLods) and multi-point linkage analyses (using SimWalk2) were performed as well as collapsed haplotype pattern (CHP) analysis in SEQLinkage and association analyses performed with FBAT and rv-TDT. Results Strongest evidence of linkage was on 1p36(two-point LOD = 4.47) a region previously linked to refractive error (MYP14) but not myopia. Another genome-wide significant locus was found on 8q24.22 with a maximum two-point LOD score of 3.75. CHP analysis also detected the signal on 1p36, localized to the LINC00339 gene with a maximum HLOD of 3.47, as well as genome-wide significant signals on 7q36.1 and 11p15, which overlaps with the MYP7 locus. Conclusions We identified 2 novel linkage peaks for myopia on chromosomes 7 and 8 in these Ashkenazi Jewish families and replicated 2 more loci on chromosomes 1 and 11, one previously reported in refractive error but not myopia in these families and the other locus previously reported in the literature. Strong candidate genes have been identified within these linkage peaks in our families. Targeted sequencing in these regions will be necessary to definitively identify causal variants under these linkage peaks

Transition to density dependence in a reintroduced ecosystem engineer

When does a reintroduced population of animals become self-regulating? Quantifying this is critical in determining when interventions can be tapered off, or when they may need to be reinstated. We tracked the growth trajectory of a reintroduced population to establish whether it was irruptive and/or had transitioned to self-regulation. In 2012, we reintroduced 32 eastern bettongs (Bettongia gaimardi), a potoroid marsupial from Tasmania, Australia, to a 485 ha exotic predator-proof fenced reserve in the Australian Capital Territory. We established a 92 cage trap monitoring network to track population growth between the Austral Autumn 2014 and Summer 2018. We used capture-recapture models to track changes in the population through time, and modelled 'bettong weight', 'pouch occupancy' and 'age of pouch young' with population variation, to establish potential associations with changes in population size. The estimated population grew from 32 individuals in 2012 to 100 in 2014, 192 in Autumn 2016, and then declined to 151 in Summer 2018. Estimated survival of adults was high-above 92% between most sessions. Adult female weights ranged between 0.485 and 2.428 kg, and adult males between 0.470 and 2.775 kg. Our study showed density dependence was achieved over the 6 year period. Low adult mortality, and variable pouch occupancy related to female weight, suggested that food availability had influenced lactation in females, with flow-on impacts on juvenile survival. Long-term, broad-scale population dynamics were probably driven by a mix of direct (e.g. disease, harvesting for other reintroductions), and indirect (i.e. climate dependent availability of nutritious food) influences on population size

Transition to density dependence in a reintroduced ecosystem engineer

When does a reintroduced population of animals become self-regulating? Quantifying this is critical in determining when interventions can be tapered off, or when they may need to be reinstated. We tracked the growth trajectory of a reintroduced population to establish whether it was irruptive and/or had transitioned to self-regulation. In 2012, we reintroduced 32 eastern bettongs (Bettongia gaimardi), a potoroid marsupial from Tasmania, Australia, to a 485 ha exotic predator-proof fenced reserve in the Australian Capital Territory. We established a 92 cage trap monitoring network to track population growth between the Austral Autumn 2014 and Summer 2018. We used capture-recapture models to track changes in the population through time, and modelled ‘bettong weight’, ‘pouch occupancy’ and ‘age of pouch young’ with population variation, to establish potential associations with changes in population size. The estimated population grew from 32 individuals in 2012 to 100 in 2014, 192 in Autumn 2016, and then declined to 151 in Summer 2018. Estimated survival of adults was high—above 92% between most sessions. Adult female weights ranged between 0.485 and 2.428 kg, and adult males between 0.470 and 2.775 kg. Our study showed density dependence was achieved over the 6 year period. Low adult mortality, and variable pouch occupancy related to female weight, suggested that food availability had influenced lactation in females, with flow-on impacts on juvenile survival. Long-term, broad-scale population dynamics were probably driven by a mix of direct (e.g. disease, harvesting for other reintroductions), and indirect (i.e. climate dependent availability of nutritious food) influences on population size