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Adipocyte serine uptake curbs ROS generation and visceral adiposity [Human]

ABSTRACT: Obesity, and visceral adiposity in particular, increases the risk of common metabolic diseases, including type 2 diabetes, cardiovascular disease, and several forms of cancer. However, the molecular mechanisms responsible for regional fat storage remain poorly characterized, preventing therapeutic innovation. We here applied a systematic genome-wide screen and translational approach, where human primary preadipocytes were isolated from liposuction aspirate and differentiated. At day 7 of differentiation, cells were treated with BMS-466442 or vehicle (DMSO) for 24 hours. After incubation, cells were lysed, and RNA was purified, DNase treated, and the RNA integrity number was checked. Subsequently, cDNA libraries were generated via the TruSeq Stranded mRNA Library Prep kit and sequenced by Illumina Hiseq 4000.

ORGANISM(S): Homo sapiens

PROVIDER: GSE135155 | GEO | 2020/01/19

REPOSITORIES: GEO

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Project description:Obesity, and visceral adiposity in particular, increases the risk of common metabolic diseases, including type 2 diabetes, cardiovascular disease, and several forms of cancer. However, the molecular mechanisms responsible for regional fat storage remain poorly characterized, preventing therapeutic innovation. We here applied a systematic genome-wide screen and translational approach, and discovered a novel role for the adipocyte-expressed neutral amino acid transporter SLC7A10/ASC-1 in the regulation of visceral adiposity. Among 65 genes showing both adipose depot-dependent and fat loss-dependent expression, 27 genes further showed significant correlations with waist-to-hip (WHR) ratio adjusted for BMI. Among these ASC-1 was expressed at the highest level in isolated visceral adipocytes. Further, we found decreased ASC-1 mRNA in visceral, and not subcutaneous adipose tissue, in carriers of the KLF14 type 2 diabetes risk allele compared to the protective allele. By profiling amino acid fluxes during adipocyte differentiation in vitro, we found that ASC-1 inhibition by a selective inhibitor decreased adipocyte uptake particularly of serine in mature adipocytes. Interestingly, radiometric amino acid uptake assays showed ASC-1 dependent uptake of the serine D-enantiomere. Using primary human and murine adipocyte models, we uncovered marked effects of inhibiting ASC-1 on mitochondrial respiratory capacity (within hours) and lipid accumulation (within days). Finally, Asc-1 knockout (KO) zebrafish had increased body weight and adipocyte enlargement upon eight-week overfeeding compared to wild-type (WT) fish. RNA sequencing data from zebrafish adipose tissue showed up-regulation of genes involved in fatty acid and lipid metabolism in the ASC-1 KOs, consistent with the increased lipid accumulation in the inhibitor-treated cell models. Additionally, duox, an enzyme involved in ROS generation, showed higher expression in the KOs compared to the WTs. Importantly, we confirmed increased reactive oxygen species (ROS) generation (within minutes and within hours) when inhibiting ASC-1 in our in vitro cell models. Our study points to increased ROS generation and reduced mitochondrial respiratory capacity as central early mechanisms in development of visceral adiposity, and a role for adipocyte D-serine transport via ASC-1 in these processes. Enhancing ASC-1 expression and/or activity in adipocytes, likely through primary effects on one-carbon metabolism and redox balance, is a promising therapeutic strategy for reducing visceral adiposity and related diseases.

Project description:BackgroundVisceral adiposity is an important risk factor for cardiometabolic diseases.ObjectiveTo determine whether the Metabolic Score for Visceral Fat (METS-VF) is more effective than other adiposity indices in predicting visceral fat area (VFA).MethodsIn this single-center and cross-sectional study, we included patients aged 20-50 years, without diabetes and coronary artery disease, who underwent computed tomography (CT) including the third lumbar vertebra. Age, blood pressure, waist circumference (WC), hip circumference, fasting lipids, and glucose were assessed. VFA was measured by cross-sectional examination of CT. The correlation of WC, body mass index (BMI), waist-hip ratio (WHR), lipid accumulation product (LAP), visceral adiposity index (VAI), a body shape index (ABSI), body roundness index (BRI), and METS-VF with VFA was analyzed by correlation analysis. The cut-off values and area under the curve (AUC) for identifying increased VFA (>130 cm2) were determined.ResultsWe included 185 individuals with mean age 38.2 ± 8 and female predominance (58.4%). There was a significant positive correlation between all indices and VFA (p<0.001). ROC analysis revealed that METS-VF and WC demonstrated the highest predictive value for identifying increased VFA. In both men (p=0.001) and women (p<0.001), METS-VF (AUC 0.922 and 0.939, respectively) showed a significant superiority over ABSI (AUC 0.702 and 0.658, respectively), and VAI (AUC 0.731 and 0.725, respectively). Additionally, in women, its superiority over WHR (AUC 0.807) was also statistically significant (p=0.003). We identified a METS-VF cut-off point >6.4 in males >6.5 in females and WC cut-off point >88 cm in males (AUC 0.922), >90.5 cm in females (AUC 0.938).ConclusionMETS-VF is strongly associated with visceral adiposity and better to predict increased VFA. However, its superiority over WC, BMI, BRI, and LAP was not significant. The results emphasize that WC is more appealing as screening indicator for visceral adiposity considering its easy use.Clinical trial registry nameClinicaltrials.gov (http://www.clinicaltrials.gov).Clinical trial registry urlhttps://clinicaltrials.gov/ct2/show/NCT05648409.Clinical trial registry numberNCT05648409.