Pepper, M. S. | Search bioRxiv

bioRxiv2021

Slc7a8 deletion is protective against diet-induced obesity and attenuates lipid accumulation in multiple organs

Adipogenesis, through adipocyte hyperplasia and/or hypertrophy, leads to increased adiposity, giving rise to obesity. A genome-wide transcriptome analysis of adipogenesis in human adipose derived stromal/stem cells identified SLC7A8 (Solute Carrier Family 7 Member 8) as a potential novel mediator. This study has investigated the role of SLC7A8 in adipose tissue biology using a mouse model of diet-induced obesity. slc7a8 knockout (KO) and wildtype (WT) C57BL/6J mice were fed either a control diet (CD) or a high-fat diet (HFD) for 14 weeks. On HFD, both WT and KO (WTHFD and KOHFD) gained significantly more weight than their CD counterparts. However, KOHFD gained significantly less weight than WT HFD. KOHFD significantly reduced the level of glucose intolerance observed in WTHFD. KOHFD significantly reduced both adipocyte mass and hypertrophy in inguinal, mesenteric, perigonadal and brown adipose depots, with a corresponding decrease in macrophage infiltration. Additionally, KOHFD decreased lipid accumulation in the liver, heart, gastrocnemius muscle, lung, and kidney. This study demonstrates that targeting SLC7A8 protects against diet-induced obesity by reducing lipid accumulation in multiple organs, and thereby has the potential to mitigate the development of obesity-associated comorbidities. Author summaryThe development of obesity can be attributed to adipocyte hypertrophy or hyperplasia leading to increased adiposity. The C57BL/6 mouse is an excellent model used to study metabolic syndromes often associated with obesity development. Mice fed on a high-fat diet are susceptible to weight gain leading to the development of obesity and its associated metabolic syndrome. Here, we report findings from targeting a novel human adipogenic gene (SLC7A8) in condition of obesity development using a mouse model of diet-induced obesity (DIO). The results indicate that deleting slc7a8 in mice significantly protects against DIO and improves glucose metabolism. Also, deficiency in slc7a8 was observed to significantly attenuates adipocyte hypertrophy in white and brown adipose tissues, and reduced lipid accumulation in many organs. Furthermore, inflammation was significantly reduced in adipose tissues and liver of slc7a8 deficient mice in condition of DIO. Overall, results from this study shows that slc7a8 is an important molecular regulator of obesity development and mediates its function by reducing lipid accumulation in multiple organs. Hence, SLC7A8 could serve as a potential therapeutic target to combat the development of obesity and other pathophysiological conditions associated with excess lipid accumulation in organs.

genetics↗

bioRxiv2018

Establishment and equilibrium levels of deleterious mutations in large populations

Analytical and statistical stochastic approaches are used to model and predict the dispersion of mutations through a large population. These approaches are used to quantify the magnitude of a heterozygous selective advantage of a mutation in the presence of a homozygous disadvantage. Random effects such as genetic drift are accounted for, which are likely to extinguish even highly advantageous mutations while the prevalence is still low. Dunbars results regarding the cognitive upper limit of the number of stable social relationships that humans can maintain are used to determine a realistic community size - a reduced local subset of the total population - from which an individual can select mates. This reduction in effective population size has a dramatic effect on the probability of establishing mutations, as well as the eventual equilibrium values that are reached in the case of mutations conferring a heterozygous selective advantage, but a homozygous disadvantage, as in the case of cystic fibrosis and sickle cell disease. The magnitude of this selective advantage can then be estimated based on observed occurrence levels of a specific mutation in a population, without requiring prior information regarding its phenotypic manifestation.\n\nAuthor summaryDeleterious mutations such as cystic fibrosis and sickle cell anemia can disperse through human populations due to the selective advantage that it bestows on heterozygous carriers, depending on environmental conditions. As its prevalence increases, the probability of generating homozygous offspring, with its concomitant selective disadvantage, also grows until an eventual equilibrium is reached between the number of carriers and wild-type individuals. In this work computer modelling is used to combine Dunbars anthropological observations predicting upper bounds to the number of stable human social relationships with observed prevalence levels, to estimate the absolute magnitude of the heterozygous selective advantage bestowed by such a deleterious genetic variation, without requiring knowledge regarding the specific mechanism whereby such an advantage is manifested.

genetics↗