Anna Dziewulska

Endosomal Sorting Complexes Required for Transport (ESCRTs) are crucial for delivering membrane receptors or intracellular organelles for lysosomal degradation. Yet, how ESCRT dysfunction affects cell metabolism remained elusive. To address this, we analyzed transcriptomes of cells lacking TSG101 or VPS28 proteins, components of ESCRT-I subcomplex. ESCRT-I deficiency reduced the expression of genes encoding enzymes involved in oxidation of fatty acids and amino acids, and increased the expression of genes encoding glycolytic enzymes. Although depletion of ESCRT-I components did not impair mitochondrial biogenesis and ATP-linked respiration it caused intracellular accumulation of lipids and increased lactate production, hallmarks of aerobic glycolysis. Mechanistically, the observed transcriptional reprogramming towards glycolysis in the absence of ESCRT-I occurred due to activation of the canonical NFκB and JNK signaling pathways. Moreover, inhibiting lysosomal activity phenocopied the altered expression of metabolic genes and lipid homeostasis observed for ESCRT-I deficiency, indicating that ESCRT-I restricts glycolysis by mediating lysosomal degradation.

Type 2 diabetes (T2D) is a complex disorder that is caused by a combination of genetic, epigenetic, and environmental factors. High-throughput approaches have opened a new avenue toward a better understanding of the molecular bases of T2D. A genome-wide association studies (GWASs) identified a group of the most common susceptibility genes for T2D (i.e., TCF7L2, PPARG, KCNJ1, HNF1A, PTPN1, and CDKAL1) and illuminated novel disease-causing pathways. Next-generation sequencing (NGS)-based techniques have shed light on rare-coding genetic variants that account for an appreciable fraction of T2D heritability (KCNQ1 and ADRA2A) and population risk of T2D (SLC16A11, TPCN2, PAM, and CCND2). Moreover, single-cell sequencing of human pancreatic islets identified gene signatures that are exclusive to α-cells (GCG, IRX2, and IGFBP2) and β-cells (INS, ADCYAP1, INS-IGF2, and MAFA). Ongoing epigenome-wide association studies (EWASs) have progressively defined links between epigenetic markers and the transcriptional activity of T2D target genes. Differentially methylated regions were found in TCF7L2, THADA, KCNQ1, TXNIP, SOCS3, SREBF1, and KLF14 loci that are related to T2D. Additionally, chromatin state maps in pancreatic islets were provided and several non-coding RNAs (ncRNA) that are key to T2D pathogenesis were identified (i.e., miR-375). The present review summarizes major progress that has been made in mapping the (epi)genomic landscape of T2D within the last few years.

Protein kinase C (PKC) activation induced by diacylglycerols (DAGs) is one of the sequels of the dysregulation of intramuscular lipid metabolism and is thought to play an important role in the development of insulin resistance (IR). We tested the hypothesis that DAGs with different acyl chains have different biological effects and that DAG species enriched in monounsaturated fatty acids (MUFA) act as better activators of PKC. The experiments were performed in vitro on C2C12 myotubes treated with palmitate (16:0), stearate (18:0) or oleate (18:1) and in vivo on the skeletal muscles of rats fed high-fat (HF), high-tristearin (TS) or high-triolein (TO) diets. To define the importance of endogenously synthesized MUFA on DAG-induced PKCθ activation, we performed experiments on stearoyl-CoA desaturase 1 knockout mice (SCD1-/-) as well. The results show that the content of total DAGs and the levels of saturated DAG species are significantly increased in both insulin-resistant (16:0, HF and TO) and highly insulin-sensitive (18:0 and TS) groups. An increase in MUFA-containing DAGs levels was most constantly related to increase in PKCθ membrane translocation and IR. In the muscles of MUFA-deficient SCD1-/- mice, the DAG content and the induction of PKCθ translocation by the HF diet were significantly reduced. Collectively, our data from both the cell and animal experiments show that DAGs composed of 16:1 and/or 18:1, rather than the levels of total or saturated DAGs, are related to PKCθ membrane translocation. Moreover, our results show that the availability of dietary MUFA and/or the activity of endogenous desaturases play an important role in muscle DAG accumulation.