Biology subjects

Nygard, M.

Publications and source records attributed to Nygard, M..

3 recordsLinked to original sources

bioRxiv2024

Loss of RREB1 reduces adipogenesis and improves insulin sensitivity in mouse and human adipocytes

There are multiple independent genetic signals at the Ras-responsive element binding protein 1 (RREB1) locus associated with type 2 diabetes risk, fasting glucose, ectopic fat, height, and bone mineral density. We have previously shown that loss of RREB1 in pancreatic beta cells reduces insulin content and impairs islet cell development and function. However, RREB1 is a widely expressed transcription factor and the metabolic impact of RREB1 loss in vivo remains unknown. Here, we show that male and female global heterozygous knockout (Rreb1+/-) mice have reduced body length, weight, and fat mass on high-fat diet. Rreb1+/- mice have sex- and diet-specific decreases in adipose tissue and adipocyte size; male mice on high-fat diet had larger gonadal adipocytes, while males on standard chow and females on high-fat diet had smaller, more insulin sensitive subcutaneous adipocytes. Mouse and human precursor cells lacking RREB1 have decreased adipogenic gene expression and activated transcription of genes associated with osteoblast differentiation, which was associated with Rreb1+/- mice having increased bone mineral density in vivo. Finally, human carriers of RREB1 T2D protective alleles have smaller adipocytes, consistent with RREB1 loss-of-function reducing diabetes risk.

physiology↗

bioRxiv2023

Coherent feedback leads to robust background compensation in oscillatory and non-oscillatory homeostats

When in an integral feedback controller a step perturbation is applied at a constant background, the controlled variable (described here as A) will in general respond with decreased response amplitudes {Delta}A as backgrounds increase. The controller variable E will at the same time provide the necessary compensatory flux to move A back to its set-point. A typical example of decreased response amplitudes at increased backgrounds is found in retinal light adaptation. Due to remarks in the literature that retinal light adaptation would also involve a compensation of backgrounds we became interested in conditions how background compensation could occur. In this paper we describe how background influences can be robustly eliminated. When such a background compensation is active, oscillatory controllers will respond to a defined perturbation with always the same (damped or undamped) frequency profile, or in the non-oscillatory case, with the same response amplitude {Delta}A, irrespective of the background level. To achieve background compensation we found that two conditions need to apply: (i) an additional set of integral controllers (here described as I1 and I2) have to be employed to keep the manipulated variable E at a defined set-point, and (ii), I1 and I2 need to feed back to the A-E signaling axis directly through the controlled variable A. In analogy to a similar feedback applied in quantum control theory, we term these feedback conditions as coherent feedback. When analyzing retinal light adaptations in more detail, we find no evidence in the presence of background compensation mechanisms. Although robust background compensation, as described theoretically here, appears to be an interesting regulatory property, relevant biological or biochemical examples still need to be identified.

systems biology↗

bioRxiv2023

Homeostasis at different backgrounds: The roles of overlayed feedback structures in vertebrate photoadaptation

We have studied the resetting behavior of eight basic integral controller motifs with respect to different but constant backgrounds. We found that the controllers split symmetrically into two classes: one class, based on derepression of the compensatory flux, leads to more rapid resetting kinetics as backgrounds increase. The other class, which directly activates the compensatory flux, shows a slowing down in the resetting at increased backgrounds. We found a striking analogy between the resetting kinetics of vertebrate photoreceptors and controllers based on derepression, i.e. vertebrate rod or cone cells show decreased sensitivities and accelerated response kinetics as background illuminations increase. The central molecular model of vertebrate photoadaptation consists of an overlay of three negative feedback loops with cytosolic calcium [Formula], cyclic guanosine monophosphate (cGMP) and cyclic nucleotide-gated (CNG) channels as components. While in one of the feedback loops the extrusion of [Formula] by potassium-dependent sodium-calcium exchangers (NCKX) can lead to integral control with cGMP as the controlled variable, the expected robust perfect adaptation of cGMP is lost, because of the two other feedback loops. They avoid that [Formula] levels become too high and toxic. Looking at psychophysical laws, we found that in all of the above mentioned basic controllers Webers law is followed when a "just noticeable difference" (threshold) of 1% of the controlled variables set-point was considered. Applying comparable threshold pulses or steps to the photoadaptation model we find, in agreement with experimental results, that Webers law is followed for relatively high backgrounds, while Stephens power law gives a better description when backgrounds are low. Limitations of our photoadaption model, in particular with respect to potassium/sodium homeostasis, are discussed. Finally, we discuss possible implication of background perturbations in biological controllers when compensatory fluxes are based on activation.

systems biology↗