Biology subjects

Baur, J. A.

Publications and source records attributed to Baur, J. A..

11 recordsLinked to original sources

bioRxiv2026

Impaired glycolysis in bone underlies age-related bone loss in mice

Bone loss and metabolic dysregulation often coexist in older adults, yet the relationship between age-related changes in bone cell metabolism and bone-forming activity remains unclear. By modeling both conditions in aged mice and using in vivo stable-isotope tracing, we demonstrated that age-related decline in bone formation was coupled with an intrinsic impairment of glycolysis within bone tissue. Impaired glycolysis was associated with reduced protein levels of key glycolysis enzymes, and transcriptomics analyses revealed compensatory upregulation of glycolysis genes in aged bone. Metabolic intervention through long-term caloric restriction prevented age-related trabecular bone loss. Furthermore, osteoblast-specific genetic enhancement of glycolysis, via overexpression of HIF1 or the rate-limiting enzyme PFKFB3, significantly improved osteoblast function and increased bone mass in aged mice. Together, the study identifies glycolytic decline as a cell-autonomous driver of osteoblast deficiency and provides proof of principle that reactivating glycolysis can promote bone accrual in aging.

physiology↗

bioRxiv2026

Tyrosine phosphorylation and dimerization cooperatively activate NAMPT to enable NAD+ synthesis in cancer

Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway, is frequently upregulated in cancer, yet mechanisms regulating its catalytic activity remain undefined. We identify NAMPT as a direct substrate of multiple proto-oncogenic tyrosine kinases, including ALK, insulin receptor, IGF1R, and PDGFRA. Phosphoproteomics identified NAMPT Y188 as the major phosphorylation site, including the oncogenic fusion kinase NPM1::ALK. NAMPT interacted with NPM1::ALK in the cytoplasm, nucleus, and mitochondria, while Y188 phosphorylation enhanced catalytic activity, NMN/NAD biosynthesis, and downstream metabolism. Conversely, the Y188F mutant reduced enzymatic activity, proliferation, and clonogenicity, whereas disrupting dimerization similarly impaired phosphorylation and function. Interactome analyses showed phosphorylation and dimerization cooperatively remodel NAMPT-associated networks, enriching phosphorylated dimers for metabolic/redox regulators and monomeric NAMPT for ribosome biogenesis. NAMPT inhibition suppressed the growth of both ALK inhibitor-sensitive and -resistant lymphoma cells and enhanced the efficacy of ALK inhibition, revealing kinase-dependent NAMPT activation as a metabolic vulnerability in oncogene-driven cancers.

cancer biology↗

bioRxiv2026

Metabolic responses to physiological stressors assessed using continuous glucose monitoring integrated with indirect calorimetry in mice

Continuous glucose monitoring (CGM) in rodents has provided unprecedented temporal resolution of glycemic dynamics in vivo. Even in the absence of deliberate perturbation, glucose levels in mice are dynamic, fluctuating in response to the timing and duration of feeding events, changes in neurological and hormonal states, physical activity, and photoperiod. To obtain a comprehensive view of metabolic adaptations under common experimental conditions, we monitored freely moving mice simultaneously using CGM and indirect calorimetry to quantify glucose, food intake, physical activity and metabolic rate. We characterized glycemic and metabolic responses to routine laboratory interventions, including short-term and overnight fasting, refeeding, tail blood sampling during glucose tolerance tests, changes in ambient temperature to cold or thermoneutral conditions, and access to running wheels. We found that food removal induced a robust, transient stress response characterized by increased blood glucose, body temperature, energy expenditure, and physical activity. However, prolonged fasting ultimately led to hypoglycemia and torpor. The magnitude and variability of glycemic responses to insulin tolerance tests were strongly influenced by fasting duration, and tail-tip blood collection itself elicited substantial hyperglycemia. In contrast to prolonged fasting, refeeding produced relatively modest and transient effects on glucose and energy expenditure. Cold exposure elicited increased energy expenditure along with a sustained hyperglycemic response. Voluntary wheel running induced transient increases in glucose and metabolic activity and promoted a shift toward increased fatty acid oxidation. Together, these findings demonstrate that common laboratory manipulations exert dynamic, often substantial effects on glycemia and whole-body metabolism that are readily revealed by CGM and indirect calorimetry.

physiology↗

bioRxiv2025

AKT signaling in hepatocytes rapidly increases glucose phosphorylation and contribution to glycogen without affecting metabolite pool sizes or glycogen breakdown

Background and aimsHepatic insulin action is essential for whole body glucose homeostasis. Insulins inhibition of glycogen breakdown, suppression of gluconeogenesis, and activation of glycogen synthesis are critical for postprandial glucose disposal. AKT, a serine-threonine kinase and well-established insulin signaling target, regulates hepatic glucose metabolism through transcriptional and posttranslational mechanisms. However, current knowledge about AKTs regulation of hepatic glucose metabolism largely stems from genetic loss of function models, precluding observation of rapid, transcription-independent effects. MethodsStable isotope tracing using [U-13C]-glucose was coupled with pharmacological inhibition of AKT using MK-2206 in primary rat hepatocytes. Bulk metabolomics was performed on AKT knockout livers and primary rat hepatocytes treated with MK-2206. Radiolabeled glucose was used to quantify short-term changes to glycogen synthesis. ResultsMK-2206 treatment decreased glucose contribution to glucose 6-phosphate and uridine diphosphate glucose within minutes without significantly affecting total metabolite pool sizes or changes to glucokinase protein levels. This was accompanied by a decrease in glucose contribution to glycogen, independent of changes to glycogen breakdown or glycogen synthase phosphorylation. ConclusionsTogether, these results demonstrate that AKT acutely regulates glucose contribution to glycogen and its upstream precursors, suggesting a transcription-independent, glucokinase-centered mechanism for glycogen synthesis through the direct pathway.

cell biology↗

bioRxiv2025

Competitive catabolism in systemic mammalian metabolic homeostasis

Systemic metabolic homeostasis maintains circulating nutrient concentrations within physiological ranges. Insulin is central to this process, lowering circulating levels of glucose, free fatty acids, and ketones. Yet, how simultaneous homeostasis of these nutrients is achieved remains unclear. Here we develop a differential equation model of fasting metabolic homeostasis. Grounded in mass action kinetics, this multi-nutrient model reveals how a fixed energy demand naturally leads to competition between major circulating nutrients for oxidation ( competitive catabolism). Perturbative nutrient infusions confirm this emergent behavior. The multi-nutrient model predicts that insulin promotes fasting glucose homeostasis primarily indirectly by slowing lipolysis. It further identifies a physiological circuit by which obesity causes diabetes: Increased fat mass promotes lipolysis, releasing fatty acids into circulation that compete with glucose for oxidation, elevating glucose. Resulting hyperinsulinemia restores proper lipid catabolic flux but not euglycemia. Thus, quantitative modeling reveals a physiological homeostatic circuit through which obesity causes type 2 diabetes.

physiology↗

bioRxiv2024

Long-term NMN treatment increases lifespan and healthspan in mice in a sex dependent manner

Nicotinamide adenine dinucleotide (NAD) is essential for many enzymatic reactions, including those involved in energy metabolism, DNA repair and the activity of sirtuins, a family of defensive deacylases. During aging, levels of NAD+ can decrease by up to 50% in some tissues, the repletion of which provides a range of health benefits in both mice and humans. Whether or not the NAD+ precursor nicotinamide mononucleotide (NMN) extends lifespan in mammals is not known. Here we investigate the effect of long-term administration of NMN on the health, cancer burden, frailty and lifespan of male and female mice. Without increasing tumor counts or severity in any tissue, NMN treatment of males and females increased activity, maintained more youthful gene expression patterns, and reduced overall frailty. Reduced frailty with NMN treatment was associated with increases in levels of Anerotruncus colihominis, a gut bacterium associated with lower inflammation in mice and increased longevity in humans. NMN slowed the accumulation of adipose tissue later in life and improved metabolic health in male but not female mice, while in females but not males, NMN increased median lifespan by 8.5%, possible due to sex-specific effects of NMN on NAD+ metabolism. Together, these data show that chronic NMN treatment delays frailty, alters the microbiome, improves male metabolic health, and increases female mouse lifespan, without increasing cancer burden. These results highlight the potential of NAD+ boosters for treating age-related conditions and the importance of using both sexes for interventional lifespan studies.

pharmacology and toxicology↗

bioRxiv2023

PPP1R3B is a metabolic switch that shifts hepatic energy storage from lipid to glycogen

Obesity is a growing worldwide epidemic that carries numerous metabolic complications including increased risk of type 2 diabetes (T2D), cardiovascular disease (CVD), and non-alcoholic fatty liver disease (NAFLD). Multiple genome-wide association studies (GWAS) have associated the PPP1R3B locus with cardiometabolic traits including fasting glucose and insulin levels (T2D traits), plasma lipids (CVD traits), and indications of hepatic steatosis and liver damage (NAFLD traits)1-5. The PPP1R3B gene encodes the glycogen regulatory protein PPP1R3B (also known as GL) which has an established role in liver glycogen metabolism and plasma glucose homeostasis6,7. The metabolic and NAFLD GWAS single nucleotide polymorphisms (SNPs) in this region, which are all in high linkage disequilibrium, result in increased liver PPP1R3B expression and hepatic glycogen accumulation, but have provided conflicting results on the impacts on hepatic steatosis and liver damage. Here we investigate the consequences of both Ppp1r3b overexpression and deletion in mouse and cell models and find that dysregulated Ppp1r3b expression in either direction promotes metabolic dysfunction and liver injury. Hepatocyte overexpression of Ppp1r3b increases hepatic glycogen storage, prolongs fasting blood glucose levels, and confers protection from hepatic steatosis, but increases plasma ALT in aged animals. Conversely, deletion of hepatocyte Ppp1r3b eliminates hepatic glycogen, causes impaired glucose disposal, and results in hepatic steatosis with age or high sucrose diet. We investigated the metabolic pathways contributing to steatosis and found that Ppp1r3b deletion and diminished glycogenesis diverts the storage of exogenous glucose to hepatic triglycerides (TG), and stored liver lipids are preferentially used for energy during fasting through lipid oxidation and ketogenesis. Further, we interrogated two large human biobank cohorts and found carriers of SNPs associated with increased PPP1R3B expression have increased plasma glucose, decreased hepatic fat, and lower plasma lipids, while putative loss-of-function (pLoF) variant carriers have increased hepatic fat and elevated plasma ketones and lipids, consistent with the results seen in our mouse models. These findings suggest hepatic PPP1R3B serves as a metabolic switch favoring hepatic energy storage as glycogen instead of TG.

molecular biology↗

bioRxiv2022

Regulation of metabolic health by dietary histidine in mice

Low protein (LP) diets are associated with a decreased risk of diabetes in humans, and a low protein diet promotes leanness and glycemic control in both rodents and humans. While the effects of a LP diet on glycemic control are mediated by reduced dietary levels of the branched- chain amino acids (BCAAs), we have observed that reducing dietary levels of the other six essential amino acids leads to changes in body composition. Here, we find that dietary histidine plays a key role in the response to a LP diet in male C57BL/6J mice. Specifically reducing dietary levels of histidine by 67% reduces weight gain of young, lean male mice, reducing both adipose and lean mass gain, without altering glucose metabolism. Specifically reducing dietary histidine rapidly reverses diet-induced obesity and hepatic steatosis in diet-induced obese male mice, increasing insulin sensitivity; this normalization of metabolic health was associated not with caloric restriction or increased activity, but with increased energy expenditure. We find that the effects of histidine restriction surprisingly does not require the energy balance hormone Fgf21. Histidine restriction started in mid-life promoted leanness and glucose tolerance in aged males but not females, but did not affect frailty or lifespan in either sex. Finally, we demonstrate that variation in dietary histidine levels helps to explain body mass index differences in humans. Overall, our findings demonstrate that dietary histidine is a key regulator of weight and body composition in male mice and in humans, and suggest that reducing dietary levels of histidine may be a highly translatable option for the treatment of obesity. Key PointsO_LIProtein restriction (PR) promotes metabolic health in rodents and humans and extends rodent lifespan. C_LIO_LIRestriction of specific individual essential amino acids can recapitulate the benefits of PR. C_LIO_LIReduced histidine promotes leanness and increased energy expenditure in mice. C_LIO_LIReduced histidine does not extend the lifespan of mice when begun in mid-life. C_LIO_LIDietary levels of histidine are positively associated with BMI in humans. C_LI

physiology↗

bioRxiv2022

Nicotinamide Riboside alleviates exercise intolerance in ANT1-deficient mice.

Mitochondrial disorders are often characterized by muscle weakness and fatigue. Null mutations in the heart-muscle adenine nucleotide translocator isoform 1 (ANT1) of both humans and mice cause cardiomyopathy and myopathy associated with exercise intolerance and muscle weakness. We have analyzed the exercise physiology of mice deficient in ANT1, demonstrating a peripheral limitation of skeletal muscle mitochondrial respiration. Upon exercise, lack of Nicotinamide adenine dinucleotide+ (NAD+) results in a substrate limitation and stalling of the TCA cycle and mitochondrial respiration. Treatment of ANT1-deficient mice with nicotinamide riboside increased NAD+ levels in skeletal muscle and improved the exercise capacity and mitochondrial respiration. Thus, increasing NAD+ levels with nicotinamide riboside can alleviate the exercise intolerance associated with ANT1-deficiency, indicating the therapeutic potential of NAD+-stimulating compounds in specific mitochondrial myopathies.

physiology↗

bioRxiv2021

NAD precursors cycle between host tissues and the gut microbiome

Nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor in both mammals and microbes. Here we use isotope tracing to investigate the precursors supporting NAD synthesis in the gut microbiome. We find that preferred dietary NAD precursors are absorbed in the proximal part of the gastrointestinal tract and not available to microbes in the distal gut. Instead, circulating host nicotinamide enters the gut lumen and supports gut microbiome NAD synthesis. In addition, the microbiome converts nicotinamide, originating from the host circulation, into nicotinic acid. Host tissues uptake and utilize this microbiome-derived nicotinic acid for NAD synthesis, maintaining circulating nicotinic acid levels even in the absence of dietary consumption. Moreover, the main route from oral nicotinamide riboside, a widely used nutraceutical, to host NAD is via conversion into nicotinic acid by the gut microbiome. Thus, NAD precursors cycle between the host and gut microbiome to maintain NAD homeostasis.

physiology↗

bioRxiv2020

Increased mTOR activity and metabolic efficiency in mouse and human cells containing the African-centric tumor-predisposing p53 variant Pro47Ser

The Pro47Ser variant of p53 exists in African-descent populations, and is associated with increased cancer risk in humans and mice. This variant, hereafter S47, shows altered regulation of the cystine importer Slc7a11, and S47 cells possess increased cysteine and glutathione (GSH) accumulation compared to cells with wild type p53. In this study we show that mice containing the S47 variant have increased mTOR activity, increased oxidative metabolism, larger size, and improved metabolic efficiency. Mechanistically, we show that there is increased association between mTOR and its positive regulator Rheb in S47 cells, due to altered redox state of GAPDH, which normally binds and sequesters Rheb. Compounds that decrease glutathione in S47 cells normalize GAPDH-Rheb complex formation and mTOR activity. The enhanced metabolic efficiency may have been selected for in early Africa, making the S47 variant one of a growing number of cancer-predisposing genetic variants that possesses other positive, potentially selectable attributes.

cancer biology↗