Zbtb16 has a role in brown adipocyte bioenergetics.

OBJECTIVE: A better understanding of the processes influencing energy expenditure could provide new therapeutic strategies for reducing obesity. As the metabolic activity of the brown adipose tissue (BAT) and skeletal muscle is an important determinant of overall energy expenditure and adiposity, we investigated the role of genes that could influence cellular bioenergetics in these two tissues. DESIGN: We screened for genes that are induced in both the BAT and skeletal muscle during acute adaptive thermogenesis in the mouse by microarray. We used C57BL/6J mice as well as the primary and immortalized brown adipocytes and C2C12 myocytes to validate the microarray data. Further characterization included gene expression, mitochondrial density, cellular respiration and substrate utilization. We also used a Hybrid Mouse Diversity Panel to assess in vivo effects on obesity and body fat content. RESULTS: We identified the transcription factor Zbtb16 (also known as Plzf and Zfp14) as being induced in both the BAT and skeletal muscle during acute adaptive thermogenesis. Zbtb16 overexpression in brown adipocytes led to the induction of components of the thermogenic program, including genes involved in fatty acid oxidation, glycolysis and mitochondrial function. Enhanced Zbtb16 expression also increased mitochondrial number, as well as the respiratory capacity and uncoupling. These effects were accompanied by decreased triglyceride content and increased carbohydrate utilization in brown adipocytes. Natural variation in Zbtb16 mRNA levels in multiple tissues across a panel of >100 mouse strains was inversely correlated with body weight and body fat content. CONCLUSION: Our results implicate Zbtb16 as a novel determinant of substrate utilization in brown adipocytes and of adiposity in vivo.

TCF7L2 is associated with high serum triacylglycerol and differentially expressed in adipose tissue in families with familial combined hyperlipidaemia.

AIMS/HYPOTHESIS: Common DNA variants of the transcription factor 7-like 2 gene (TCF7L2) are associated with type 2 diabetes. Familial combined hyperlipidaemia (FCHL) is characterised by hypertriacylglycerolaemia, hypercholesterolaemia, or both. Additionally, disturbances in glucose metabolism are commonly seen in FCHL. Therefore, we hypothesised that TCF7L2 may contribute to the genetic susceptibility for this common dyslipidaemia. METHODS: We investigated the effect of the TCF7L2 variants, rs7903146 and rs12255372, on FCHL and its component traits triacylglycerol (TG), total cholesterol (TC) and apolipoprotein B (ApoB) in 759 individuals from 55 Mexican families. As a replication sample, 719 individuals from 60 Finnish FCHL families were analysed. We also used quantitative RT-PCR to evaluate the transcript levels of TCF7L2 in 47 subcutaneous fat biopsies from unrelated Mexican FCHL and normolipidaemic participants. RESULTS: Significant evidence for association was observed for high TG for the T alleles of rs7903146 and rs12255372 (p = 0.005 and p = 0.01) in Mexican FCHL families. No evidence for association was observed for FCHL, TC, ApoB or glucose in Mexicans. When testing rs7903146 and rs12255372 for replication in Finnish FCHL families, these single nucleotide polymorphisms were associated with TG (p = 0.01 and p = 0.007). Furthermore, we observed statistically significant decreases in the mRNA levels (p = 0.0002) of TCF7L2 in FCHL- and TG-affected individuals. TCF7L2 expression was not altered by the SNP genotypes. CONCLUSIONS/INTERPRETATION: These data show that rs7903146 and rs12255372 are significantly associated with high TG in FCHL families from two different populations. In addition, significantly decreased expression of TCF7L2 was observed in TG- and FCHL-affected individuals.