Biology subjects

Kovary, K. M.

Publications and source records attributed to Kovary, K. M..

4 recordsLinked to original sources

bioRxiv2022

A dynamic HIF1alpha-PPARgamma circuit controls a paradoxical adipocyte regulatory landscape

Hypoxia-induced upregulation of HIF1 triggers adipose tissue dysfunction and insulin resistance in obese patients. HIF1 closely interacts with PPAR{gamma}, the master regulator of adipocyte differentiation and lipid accumulation, but there are conflicting results how this co-regulation controls the excessive lipid accumulation that drives adipocyte dysfunction. Using single-cell imaging and modeling, we find that, surprisingly, HIF1 both promotes and represses lipid accumulation during adipogenesis. We show that the opposing roles of HIF1 are isolated from each other and depend on when HIF1 increases relative to the positive-feedback mediated upregulation of PPAR{gamma} that drives adipocyte differentiation. A theoretical model incorporating our findings resolves conflicting prior results and suggests that three network nodes before and after the isolation step have to be synergistically targeted in therapeutic strategies to revert hypoxia-mediated adipose tissue dysfunction in obesity. TeaserA systems biology approach detangles the effect of hypoxic and adipogenic regulators on lipid accumulation in adipocytes.

systems biology↗

bioRxiv2020

Flattened circadian glucocorticoid oscillations cause obesity due to increased lipid turnover and lipid uptake

Chronic stressors flatten diurnal glucocorticoid oscillations, resulting in obesity, insulin resistance, and diabetes. How such flattened diurnal glucocorticoid oscillations increase fat storage is unknown. Here we investigated the consequences in mice and found that flattening of glucocorticoid oscillations results not only in body weight gain, mainly due to increases in white fat depot mass, but also leads to hyperinsulinemia and fat accumulation in brown adipose tissue. A transcriptomic analysis of white and brown adipose tissues revealed that flattened glucocorticoid oscillations cause dysregulated lipid metabolism with a prominent role of the fatty acid transporter Cd36 and insulin-driven adipocyte hypertrophy. Indeed, Cd36 knockout mice are partially protected against the adverse effects of flattened GC oscillations including body weight gain and lipid accumulation in the brown and visceral white fat depots. These results show the molecular mechanisms how flattened glucocorticoid oscillations can cause obesity and diabetes.

physiology↗

bioRxiv2019

Stochastic and coincident control of terminal cell differentiation and cell cycle exit

Terminal differentiation is essential for the development and maintenance of tissues in all multi-cellular organisms and is associated with a permanent exit from the cell cycle. Failure to permanently exit the cell cycle can result in cancer and disease. However, the molecular mechanisms and timing that coordinates differentiation commitment and cell cycle exit are not yet understood. Here using adipogenesis as a model system to track differentiation commitment in live cells, we show that a rapid switch mechanism engages exclusively in G1 to trigger a simultaneous commitment to differentiate and permanently exit from the cell cycle. We identify a signal integration mechanism whereby the strengths of both mitogen and differentiation stimuli control a molecular competition between cyclin D1 and PPARG-induced expression of the CDK inhibitor p21 which in turn regulates if and when the differentiation switch is triggered and when the proliferative window closes. In this way, the differentiation control system is able to couple mitogen and differentiation stimuli to sustain a long-term balance between terminally differentiating cells and maintaining the progenitor cell pool, a parameter of critical importance for enabling proper development of tissue domains and organs. HIGHLIGHTSO_LIProgenitor cells both commit to terminally differentiate and permanently exit the cell cycle at a precise time in G1 as a result of a competition process that can last over multiple cell cycles. C_LIO_LIPositive-feedback driven expression of PPARG and the parallel induction of p21 triggers a rapid commitment to terminally differentiate and then maintains a postmitotic adipocyte state. C_LIO_LIOpposing mitogen and adipogenic signals are funneled into a molecular competition in G1 phase that controls if and when cells commit to differentiate, which in turn regulates the number of differentiated cells produced while allowing for the maintenance of sufficient progenitor cells. C_LI

cell biology↗

bioRxiv2018

Expression variation and covariation impair analog and enable binary signaling control

Due to noise in the synthesis and degradation of proteins, the concentrations of individual vertebrate signaling proteins were estimated to vary with a coefficient of variation (CV) of approximately 25% between cells. This high variation enables population-level regulation of cell functions but abolishes accurate single-cell signal transmission. Here we measure cell-to-cell variability of relative protein abundance using quantitative proteomics of individual Xenopus laevis eggs and cultured human cells and show that variation is typically much lower, in the range of 5-15%, compatible with accurate single-cell transmission. Furthermore, we show that MEK and ERK expression covary which improves controllability of the fraction of cells that activate bimodal ERK signaling, arguing that covariation has a role in facilitating population-level control of binary cell-fate decisions. Together, our experimental and model data argues for a control principle whereby low covariation limits signaling noise for accurate control analog single-cell signaling. In contrast, increased covariation widens the stimulus-range over which external inputs can regulate binary cell activation, thereby enabling accurate control of the fraction of activated cells at the population level.

systems biology↗