👤 Marcus-Oliver Schupp

High-sugar diets cause human metabolic diseases, yet several bird lineages convergently adapted to feeding on sugar-rich nectar or fruits. We investigated the underlying molecular mechanisms in hummingbirds, parrots, honeyeaters, and sunbirds by generating nine new genomes and 90 tissue-specific transcriptomes. Comparative screens revealed an excess of repeated selection in both protein-coding and regulatory sequences in sugar-feeding birds, suggesting reuse of genetic elements. Sequence or expression changes in sugar-feeders affect genes involved in blood pressure regulation and lipid, amino acid, and carbohydrate metabolism, with experiments showing functional changes in honeyeater hexokinase 3. Show less

Carbohydrate response element-binding protein (ChREBP) is a transcription factor activated by glucose metabolites that orchestrates the expression of genes involved in glycolysis, de novo lipogenesis, and ATP homeostasis. Inadequate ChREBP activity impairs the cellular adaptations to glucose exposure and in humans associates with dyslipidemia, fatty liver disease, and type 2 diabetes. ChREBP activity is regulated by cytosolic-nuclear translocation involving its low-glucose inhibitory domain (LID). Whether this domain is targeted by post-translational lysine acetylation is unknown. Here we report a novel LID acetylation site that controls activity and protein interactions of ChREBP. Mutation of this residue increased glucose-induced activity and target gene expression of ChREBP. Mechanistically, mutant ChREBP protein showed more nuclear localization and enhanced genomic binding to a target promoter. Interactions with proteins that exhibit differential binding upon glucose exposure were attenuated by the mutation, demonstrating the importance of the LID in the formation of the protein interactome. Particularly interactions with 14-3-3 proteins, factors that regulate cytosolic/nuclear trafficking of ChREBP, were reduced, whereas interactions with proteins of the nucleosome remodeling deacetylase complex (NuRD) were increased. These molecular insights may shape new therapeutic strategies to target ChREBP activity and counteract metabolic diseases. Show less

The liver integrates multiple metabolic pathways to warrant systemic energy homeostasis. An excessive lipogenic flux due to chronic dietary stimulation contributes to the development of hepatic steatosis, dyslipidemia and hyperglycemia. Here we show that the oxidoreductase retinol saturase (RetSat) is involved in the development of fatty liver. Hepatic RetSat expression correlates with steatosis and serum triglycerides (TGs) in humans. Liver-specific depletion of RetSat in dietary obese mice lowers hepatic and circulating TGs and normalizes hyperglycemia. Mechanistically, RetSat depletion reduces the activity of carbohydrate response element binding protein (ChREBP), a cellular hexose-phosphate sensor and inducer of lipogenesis. Defects upon RetSat depletion are rescued by ectopic expression of ChREBP but not by its putative enzymatic product 13,14-dihydroretinol, suggesting that RetSat affects hepatic glucose sensing independent of retinol conversion. Thus, RetSat is a critical regulator of liver metabolism functioning upstream of ChREBP. Pharmacological inhibition of liver RetSat may represent a therapeutic approach for steatosis.Fatty liver is one of the major features of metabolic syndrome and its development is associated with deregulation of systemic lipid and glucose homeostasis. Here Heidenreich et al. show that retinol saturase is implicated in hepatic lipid metabolism by regulating the activity of the transcription factor ChREBP. Show less

Carbohydrate response element binding protein (ChREBP) regulates cellular glucose and lipid homeostasis. Although ChREBP is highly expressed in many key metabolic tissues, the role of ChREBP in most of those tissues and the consequent effects on whole-body glucose and lipid metabolism are not well understood. Therefore, we generated a transgenic mouse that overexpresses a constitutively active ChREBP isoform under the control of the fatty acid binding protein 4-Cre-driven promoter (FaChOX). Weight gain was blunted in male, but not female, FaChOX mice when placed on either a normal chow diet or an obesogenic Western diet. Respiratory exchange ratios were increased in Western diet-fed FaChOX mice, indicating a shift in whole-body substrate use favoring carbohydrate metabolism. Western diet-fed FaChOX mice showed improved insulin sensitivity and glucose tolerance in comparison with controls. Hepatic triglyceride content was reduced in Western diet-fed FaChOX mice in comparison with controls, suggesting protection from fatty liver. Epididymal adipose tissue exhibited differential expression of genes involved in differentiation, browning, metabolism, lipid homeostasis, and inflammation between Western diet-fed FaChOX mice and controls. Our findings support a role for ChREBP in modulating adipocyte differentiation and adipose tissue metabolism and inflammation as well as consequent risks for obesity and insulin resistance. Show less

Reduced de novo lipogenesis in adipose tissue, often observed in obese individuals, is thought to contribute to insulin resistance. Besides trapping excess glucose and providing for triglycerides and energy storage, endogenously synthesized lipids can function as potent signaling molecules. Indeed, several specific lipids and their molecular targets that mediate insulin sensitivity have been recently identified. Here, we report that carbohydrate-response element-binding protein (ChREBP), a transcriptional inducer of glucose use and de novo lipogenesis, controls the activity of the adipogenic master regulator peroxisome proliferator-activated receptor (PPAR)γ. Expression of constitutive-active ChREBP in precursor cells activated endogenous PPARγ and promoted adipocyte differentiation. Intriguingly, ChREBP-constitutive-active ChREBP expression induced PPARγ activity in a fatty acid synthase-dependent manner and by trans-activating the PPARγ ligand-binding domain. Reducing endogenous ChREBP activity by either small interfering RNA-mediated depletion, exposure to low-glucose concentrations, or expressing a dominant-negative ChREBP impaired differentiation. In adipocytes, ChREBP regulated the expression of PPARγ target genes, in particular those involved in thermogenesis, similar to synthetic PPARγ ligands. In summary, our data suggest that ChREBP controls the generation of endogenous fatty acid species that activate PPARγ. Thus, increasing ChREBP activity in adipose tissue by therapeutic interventions may promote insulin sensitivity through PPARγ. Show less

The GTPase ADP-ribosylation factor-related protein 1 (ARFRP1) is located at the trans-Golgi compartment and regulates the recruitment of Arf-like 1 (ARL1) and its effector golgin-245 to this compartment. Here, we show that liver-specific knockout of Arfrp1 in the mouse (Arfrp1(liv-/-)) resulted in early growth retardation, which was associated with reduced hepatic insulin-like growth factor 1 (IGF1) secretion. Accordingly, suppression of Arfrp1 in primary hepatocytes resulted in a significant reduction of IGF1 release. However, the hepatic secretion of IGF-binding protein 2 (IGFBP2) was not affected in the absence of ARFRP1. In addition, Arfrp1(liv-/-) mice exhibited decreased glucose transport into the liver, leading to a 50% reduction of glycogen stores as well as a marked retardation of glycogen storage after fasting and refeeding. These abnormalities in glucose metabolism were attributable to reduced protein levels and intracellular retention of the glucose transporter GLUT2 in Arfrp1(liv-/-) livers. As a consequence of impaired glucose uptake into the liver, the expression levels of carbohydrate response element binding protein (ChREBP), a transcription factor regulated by glucose concentration, and its target genes (glucokinase and pyruvate kinase) were markedly reduced. Our data indicate that ARFRP1 in the liver is involved in the regulation of IGF1 secretion and GLUT2 sorting and is thereby essential for normal growth and glycogen storage. Show less

Vasculogenesis, the de novo formation of blood vessels from precursor cells is critical for a developing embryo. However, the signals and events that dictate the formation of primary axial vessels remain poorly understood. In this study, we use ets-related protein-1 (etsrp), which is essential for vascular development, to analyze the early stages of vasculogenesis in zebrafish. We found etsrp(+) cells of the head, trunk and tail follow distinct developmental sequences. Using a combination of genetic, molecular and chemical approaches, we demonstrate that fli(+)etsrp(+) hemato-vascular progenitors (FEVPs) are proliferating at the lateral plate mesoderm (LPM). The Shh-VEGF-Notch-Hey2 signaling pathway controls the proliferation process, and experimental modulation of single components of this pathway alters etsrp(+) cell numbers at the LPM. This study for the first time defines factors controlling proliferation, and cell numbers of pre-migratory FEVPs in zebrafish. Show less