SUMMARY
Recent studies find that sugar tastes less intense to humans with obesity, but whether this sensory change is a cause or a consequence of obesity is unclear. To tackle this question, we study the effects of a high sugar diet on sweet taste sensation and feeding behavior in Drosophila melanogaster. On this diet, fruit flies have lower taste responses to sweet stimuli, overconsume food, and develop obesity. Excess dietary sugar, but not obesity or dietary sweetness alone, caused taste deficits and overeating via the cell-autonomous action of the sugar sensor O-linked N-Acetylglucosamine (O-GlcNAc) transferase (OGT) in the sweet-sensing neurons. Correcting taste deficits by manipulating the excitability of the sweet gustatory neurons or the levels of OGT protected animals from diet-induced obesity. Our work demonstrates that the reshaping of sweet taste sensation by excess dietary sugar drives obesity and highlights the role of glucose metabolism in neural activity and behavior.
Mutations targeting as few as four residues lining the access tunnel extended the half‐life of an enzyme in 40 % dimethyl sulfoxide from minutes to weeks and increased its melting temperature by 19 °C. Protein crystallography and molecular dynamics revealed that the tunnel residue packing is a key determinant of protein stability and the active‐site accessibility for cosolvent molecules (red dots).
Diets rich in sugar, salt, and fat alter taste perception and food preference, contributing to obesity and metabolic disorders, but the molecular mechanisms through which this occurs are unknown. Here, we show that in response to a high sugar diet, the epigenetic regulator Polycomb Repressive Complex 2.1 (PRC2.1) persistently reprograms the sensory neurons of Drosophila melanogaster flies to reduce sweet sensation and promote obesity. In animals fed high sugar, the binding of PRC2.1 to the chromatin of the sweet gustatory neurons is redistributed to repress a developmental transcriptional network that modulates the responsiveness of these cells to sweet stimuli, reducing sweet sensation. Half of these transcriptional changes persist despite returning the animals to a control diet, causing a permanent decrease in sweet taste. Our results uncover a new epigenetic mechanism that, in response to the dietary environment, regulates neural plasticity and feeding behavior to promote obesity.
A time-dependent fluorescence shift method, biomimetic colorimetric assays, and molecular dynamics simulations have been performed in search of explanations why arginine rich peptides with intermediate lengths of about 10 amino acids translocate well through cellular membranes, while analogous lysine rich peptides do not. First, we demonstrate that an important factor for efficient peptide adsorption, as the first prerequisite for translocation across the membrane, is the presence of negatively charged phospholipids in the bilayer. Second, we observe a strong tendency of adsorbed arginine (but not lysine) containing peptides to aggregate at the bilayer surface. We suggest that this aggregation of oligoarginines leads to partial disruption of the bilayer integrity due to the accumulated large positive charge at its surface, which increases membrane-surface interactions due to the increased effective charge of the aggregates. As a result, membrane penetration and translocation of medium length oligoarginines becomes facilitated in comparison to single arginine and very long polyarginines, as well as to lysine containing peptides.
Transcriptional regulation allows cells to match their gene expression profiles to their current requirements based on environment, cellular physiological state, and extracellular signals. DNA binding transcription factors are major agents of transcriptional regulation, and bind to DNA with a factor-specific sequence preference to exert regulatory effects. A crucial step in unraveling the logic of a regulatory network is determining the sequence-specific binding affinity landscapes for the transcription factors in it. While such landscapes can be measured experimentally, the ability to predict them computationally would both reduce the effort required to obtain the needed data, and provide additional insight into the key interactions shaping protein-DNA interactions. Here we apply free energy calculations based on all-atom molecular dynamics simulations to predict the changes in binding free energy for all single base pair perturbations of the binding sites for four eukaryotic transcription factors for which high-quality experimental data exist. We find that the simulated results both vastly overestimate the magnitude of changes in binding free energy, and frequently predict the incorrect signs. These simulations will nevertheless serve as a jumping-off point for refining our current representation of protein-DNA interactions to allow quantitative reproduction of experimental data on such systems in the future.
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