A family history of type 2 diabetes increases risk factors associated with overfeeding

Aims/hypothesis: The purpose of the study was to test prospectively whether healthy individuals with a family history of type 2 diabetes are more susceptible to adverse metabolic effects during experimental overfeeding. Methods: We studied the effects of 3 and 28 days of overfeeding by 5,200 kJ/day in 41 sedentary individuals with and without a family history of type 2 diabetes (FH+ and FH− respectively). Measures included body weight, fat distribution (computed tomography) and insulin sensitivity (hyperinsulinaemic–euglycaemic clamp). Results: Body weight was increased compared with baseline at 3 and 28 days in both groups (p<0.001), FH+ individuals having gained significantly more weight than FH− individuals at 28 days (3.4±1.6 vs 2.2±1.4 kg, p<0.05). Fasting serum insulin and C-peptide were increased at 3 and 28 days compared with baseline in both groups, with greater increases in FH+ than in FH− for insulin at +3 and +28 days (p<0.01) and C-peptide at +28 days (p<0.05). Fasting glucose also increased at both time points, but without a significant group effect (p=0.1). Peripheral insulin sensitivity decreased in the whole cohort at +28 days (54.8±17.7 to 50.3±15.6 μmol min−1 [kg fat-free mass]−1, p=0.03), and insulin sensitivity by HOMA-IR decreased at both time points (p<0.001) and to a greater extent in FH+ than in FH− (p=0.008). Liver fat, subcutaneous and visceral fat increased similarly in the two groups (p<0.001). Conclusions: Overfeeding induced weight and fat gain, insulin resistance and hepatic fat deposition in healthy individuals. However, individuals with a family history of type 2 diabetes gained more weight and greater insulin resistance by HOMA-IR. The results of this study suggest that healthy individuals with a family history of type 2 diabetes are predisposed to adverse effects of overfeeding.D. Samocha-Bonet, L.V. Campbell, A. Viardot, J. Freund, C.S. Tam, J.R. Greenfield and L.K. Heilbron

Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated &lsquo;omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease

Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples

Recent research has uncovered an important role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9,246 families with autism spectrum disorder, intellectual disability, or developmental delay, we found that ∼1/3 of de novo variants are independently present as standing variation in the Exome Aggregation Consortium's cohort of 60,706 adults, and these de novo variants do not contribute to neurodevelopmental risk. We further used a loss-of-function (LoF)-intolerance metric, pLI, to identify a subset of LoF-intolerant genes containing the observed signal of associated de novo protein-truncating variants (PTVs) in neurodevelopmental disorders. LoF-intolerant genes also carry a modest excess of inherited PTVs, although the strongest de novo-affected genes contribute little to this excess, thus suggesting that the excess of inherited risk resides in lower-penetrant genes. These findings illustrate the importance of population-based reference cohorts for the interpretation of candidate pathogenic variants, even for analyses of complex diseases and de novo variation

Limited evolutionary responses to harvesting regime in the intensive production of algae

Plastic changes in the growth and productivity of algae in response to environment and stocking density are well established. In contrast, the capacity for such changes to persist once environmental differences cease, potentially signalling an evolutionary response, have rarely been tested for algae in intensive production systems. We tested whether continuous differences in harvesting regime (a high stocking density/low-yield regime versus low stocking density/high-yield regime) generated changes in biomass productivity and other growth metrics within several strains of the clonal macroalga Oedogonium (Chlorophyta, Oedogoniales) and whether such changes persisted once differential harvesting yields ceased. We found considerable plasticity in growth rate and biomass productivity over a 12-week period of active selection (i.e. repeated high-yield and low-yield harvesting of clonal lineages within strains) and that strains responded differently to this selection pressure over time. While small, but significant, differences in growth rates of clonal lineages exposed to high-yield vs low-yield harvesting regimes were maintained after prolonged culture under a common selection regime (i.e. medium-yield harvesting), differences in biomass productivity were not. There was no evidence for positive or negative effects of maintaining multiple strains in polyculture on growth and biomass productivity. Overall, we detected limited potential for evolutionary responses to harvesting regime in the main commercial trait of interest—biomass productivity. This outcome is important for commercial cultivation in intensive production systems, since it identifies a low risk that harvesting practices will impact negatively on biomass productivity in the longer term