Biology subjects

Gavrilova, O.

Publications and source records attributed to Gavrilova, O..

8 recordsLinked to original sources

bioRxiv2026

Thermoregulatory roles of preoptic area histamine H1 receptor-expressing neurons

The preoptic area (POA) is a key regulator of body temperature, orchestrating behavioral and physiological thermoregulatory functions, including fever, torpor, and homeostatic responses to ambient temperature. Histamine regulates body temperature across animal taxa, including mammals, lower vertebrates, and invertebrates. Hrh1, which encodes the histamine H1 receptor, is expressed in several neuronal populations in the POA with limited overlap with other POA thermoregulatory neurons. Acute activation of POAHrh1 neurons increased body temperature and physical activity. Acute inhibition attenuated the dark phase increase in body temperature without affecting physical activity. There was no effect of inhibition on body temperature during the light phase, fever, cold exposure, or warm exposure. Assessing behavioral thermoregulation, we found that POAHrh1 neurons stimulated nest building in both sexes, possibly contributing to cold-induced nesting behavior. Through projections to the arcuate, dorsomedial hypothalamic and tuberomammillary nuclei, POAHrh1 neurons can increase body temperature and physical activity. Overall, POAHrh1 neurons participate in several thermoregulatory functions, including daily body temperature rhythm regulation, physical activity, and nest building behavior.

neuroscience↗

bioRxiv2026

P2Y14 receptor agonist impairs, and antagonist improves whole-body glucose homeostasis and liver steatosis

Knockout of the UDP-glucose-activated P2Y14 receptor (P2Y14R) in adipocytes or whole-body has been reported to provide metabolic benefits in obese mice. We hypothesized that selective P2Y14R activation would lead to metabolic impairments, whereas pharmacological antagonism would improve metabolic deficits in diet-induced obese (DIO) mice. Here, we investigated the metabolic effects of a synthetic P2Y14R agonist, UDP-like methylene-bridged MRS2905. Acute P2Y14R activation with MRS2905 triggered a robust and prolonged hyperglycemic effect in lean and obese mice with impaired glucose homeostasis. Moreover, MRS2905 treatment of obese mice lowered fasting plasma insulin and increased glucagon levels, along with upregulation of liver JNK phosphorylation and the expression of rate-limiting gluconeogenic genes. The MRS2905-induced hyperglycemic effect was blunted in whole-body P2Y14R knockout mice compared with wild-type control. In contrast, a potent P2Y14R antagonist mono-ester prodrug (MRS4779) partially reversed the agonist-induced hyperglycemia and restored proper glucose homeostasis after acute treatment. Chronic MRS4779 administration in DIO mice reduced fat mass and improved various metabolic parameters including liver steatosis. Additionally, we examined the roles of P2Y14R in hepatocytes of DIO mice. Here, we report that P2Y14R was upregulated in liver and hepatocytes from obese mice compared to lean mice. Overnight fasting also upregulated hepatic P2Y14R expression. P2Y14R deletion from hepatocytes in DIO mice improved fasting blood glucose level and lipid metabolism without improving glucose homeostasis. These results suggest a novel P2Y14R function in hepatic lipid metabolism, and P2Y14R antagonists may prove useful for the treatment of obesity and obesity-related metabolic disorders.

physiology↗

bioRxiv2026

Copper Import via CTR1 Supports the β3-Adrenergic Thermogenic Program

Adaptive thermogenesis requires coordinated activation of mitochondrial oxidation and metabolic remodeling, yet the signals driving this coordination are incompletely understood. Here, we show that cold exposure and {beta}3-adrenergic receptor ({beta}3-AR) stimulation upregulate the high-affinity copper (Cu) importer CTR1 and promote Cu accumulation in thermogenic adipose tissues. Adipocyte-specific Ctr1 knockout (ACKO) mice exhibit markedly reduced energy expenditure and develop severe hypothermia during acute cold challenge. Proteomic analysis of brown adipose tissue (BAT) from ACKO mice reveals coordinated suppression of oxidative phosphorylation and thermogenic metabolic programs, accompanied by attenuation of lipolytic pathways. Cu deficiency also impairs cold- and {beta}3-AR-induced lipolytic activation, including reduced HSL phosphorylation and lipid clearance in both BAT and inguinal white adipose tissue (iWAT). Although BAT-specific Ctr1 deletion (BCKO) leaves acute {beta}3-adrenergic responses largely intact, these mice still exhibit cold intolerance, indicating that BAT Cu homeostasis is indispensable for sustaining thermogenic capacity during cold challenge. Treatment with the Cu ionophore elesclomol partially restores mitochondrial oxidative capacity and improves cold tolerance in ACKO mice. Together, these findings identify CTR1-dependent Cu import as a dynamically regulated component of the {beta}3-adrenergic thermogenic program and establish intracellular Cu availability as a key determinant of thermogenic capacity during adaptive thermogenesis.

molecular biology↗

bioRxiv2025

Disease-associated mutations in the STAT5B SH2 domain reprogram hepatic cholesterol and lipid metabolism

Growth hormone (GH) signaling through STAT5B is a central regulator of hepatic metabolism, yet the functional consequences of disease-associated STAT5B variants remain poorly understood. Here, we analyzed mice carrying STAT5BY665F (gain-of-function) and STAT5BY665H (loss-of-function) variants and dissect their impact on metabolic regulation. STAT5BY665F mice developed hepatic lipid accumulation, hypercholesterolemia, and enhanced insulin sensitivity, whereas STAT5BY665H mice displayed reduced body weight and impaired insulin responsiveness. Transcriptomic analyses revealed that STAT5BY665F activated lipid, cholesterol, and immune transcriptional programs, while STAT5BY665H failed to induce these pathways. Notably, STAT5BY665F substantially feminized male liver gene expression, inducing 77% of female-biased genes while repressing 51% of male-biased genes, thereby mimicking the persistent STAT5B activation characteristic of female livers. ChIP-seq demonstrated extensive STAT5BY665F enhancer occupancy at metabolic and immune loci, contrasting with the minimal chromatin engagement of STAT5BY665H. Beyond the liver, STAT5BY665F broadly reprogrammed adipose tissue gene expression, activating lipid metabolism and immune regulatory networks, whereas STAT5BY665H exerted more restricted effects. Together, these findings illustrate how alterations in STAT5B activity affect enhancer activation and can lead to changes in metabolic function and hepatic sexual dimorphism.

genomics↗

bioRxiv2025

Histone Chaperone HIRA facilitates transcription elongation to regulate insulin sensitivity and obesity-associated adipose expansion

Adipose tissue is essential for maintaining glucose and lipid homeostasis in mammals. However, epigenomic mechanisms underlying adipose tissue function remain largely unclear. Here, we identify the histone chaperon HIRA as a novel epigenomic regulator of adipose tissue function. Adipose tissue-specific knockout of Hira in mice impairs insulin sensitivity and restrains adipose tissue expansion during high-fat diet-induced obesity. Mechanistically, HIRA is required for the expression of Adipoq, encoding the adipokine adiponectin, and lipid metabolism genes in adipose tissue. Genomic mapping reveals that HIRA binds to promoters and enhancers of Adipoq and lipid metabolism genes in adipocytes. Acute HIRA depletion using the dTAG system, followed by nascent RNA-Seq and ChIP-Seq, demonstrates that while HIRA is largely dispensable for enhancer activation and coactivator binding, it promotes transcription of target genes by facilitating RNA polymerase II pause release and subsequent elongation likely independently of H3.3 deposition. Our findings uncover a novel mechanism by which HIRA regulates transcription and establish HIRAs critical role in insulin sensitivity and lipid metabolism, providing a potential therapeutic target for obesity and insulin resistance. Significance StatementDysregulated adipose tissue function leads to metabolic disorders including obesity and insulin resistance, yet the epigenomic mechanisms that maintain its normal function are incompletely understood. This study identifies the histone chaperone HIRA as a critical regulator of insulin sensitivity and obesity-associated adipose expansion. We show that HIRA directly controls adiponectin and lipid metabolism gene expression in adipocytes by promoting RNA polymerase II pause release, rather than transcription initiation or enhancer activation, and likely in a manner independent of H3.3 deposition. These findings uncover a novel mechanism of HIRA in regulating gene expression and highlight its critical role in insulin sensitivity and lipid metabolism in adipocytes.

physiology↗

bioRxiv2021

Preoptic BRS3 neurons increase body temperature and heart rate via multiple pathways

The preoptic area (POA) is a key region controlling body temperature (Tb), dictating thermogenic, cardiovascular, and behavioral responses to regulate Tb. Known POA neuronal populations reduce Tb when activated; a population that increases Tb upon activation has not yet been reported. We now identify bombesin-like receptor 3 (BRS3)-expressing POA (POABRS3) neurons as having this missing functionality. BRS3 is an orphan receptor that regulates energy and cardiovascular homeostasis, but the relevant neural circuits are incompletely understood. In mice, we demonstrate that POABRS3 neuronal activation increases Tb, heart rate, and blood pressure sympathetically, via projections to the paraventricular nucleus of the hypothalamus and dorsomedial hypothalamus. Acute POABRS3 inhibition reduces Tb. Long-term inactivation of POABRS3 neurons increased Tb variability with exaggerated Tb changes, overshooting both increases and decreases in Tb set point. BRS3 marks preoptic populations that regulate Tb and heart rate, contribute to cold-defense and fine-tune feedback control of Tb. These findings advance understanding of homeothermy, a defining feature of mammalian biology. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/433948v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@121b5a8org.highwire.dtl.DTLVardef@1d67bforg.highwire.dtl.DTLVardef@865eeborg.highwire.dtl.DTLVardef@1c1d41e_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

neuroscience↗

bioRxiv2020

MED1 is a lipogenesis coactivator required for postnatal adipose expansion

MED1 often serves as a surrogate of the general transcription coactivator complex Mediator for identifying active enhancers. MED1 is required for phenotypic conversion of fibroblasts to adipocytes in vitro but its role in adipose development and expansion in vivo has not been reported. Here we report that MED1 is dispensable for adipose development in mice. Instead, MED1 is required for postnatal adipose expansion and the induction of de novo lipogenesis (DNL) genes after pups switch diet from high-fat maternal milk to carbohydrate-based chow. During adipogenesis, MED1 is dispensable for induction of lineage-determining transcription factors (TFs) PPAR{gamma} and C/EBP but is required for lipid accumulation in the late phase of differentiation. Mechanistically, MED1 controls the induction of DNL genes by facilitating lipogenic TF ChREBP-dependent recruitment of Mediator to active enhancers. Together, our findings identify a cell- and gene-specific regulatory role of MED1 as a lipogenesis coactivator required for postnatal adipose expansion. O_LIMED1 is largely dispensable for adipogenesis and embryonic development of adipose tissue C_LIO_LIMED1 is required for postnatal adipose expansion C_LIO_LIMED1 is required for DNL gene expression in adipocytes C_LIO_LIMED1 controls DNL gene transcription by facilitating ChREBP-dependent Mediator binding to active enhancers C_LI

developmental biology↗

bioRxiv2020

Lack of Adipocyte Purinergic P2Y6 Receptor Greatly Improves Whole Body Glucose Homeostasis

Uridine diphosphate (UDP)-activated purinergic receptor P2Y6 (P2Y6R) plays a crucial role in controlling energy balance through central mechanisms. However, P2Y6Rs roles in peripheral tissues regulating energy and glucose homeostasis remain unexplored. Here, we report the surprising novel finding that adipocyte-specific deletion of P2Y6R protects mice from diet-induced obesity, improving glucose tolerance and insulin sensitivity with reduced systemic inflammation. These changes were associated with reduced JNK signaling, and enhanced expression and activity of PPAR affecting downstream PGC1 levels leading to beiging of white fat. In contrast, P2Y6R deletion in skeletal muscle reduced glucose uptake resulting in impaired glucose homeostasis. Interestingly, whole body P2Y6R KO mice showed metabolic improvements similar to those observed with mice lacking P2Y6R only in adipocytes. Our findings provide compelling evidence that P2Y6R antagonists may prove useful for the treatment of obesity and type 2 diabetes.

physiology↗