Biology subjects

Yeh, C.-Y.

Publications and source records attributed to Yeh, C.-Y..

15 recordsLinked to original sources

bioRxiv2026

Dietary sugar type determines the response to protein restriction in females, but not males

Low protein (LP) diets improve metabolic health in rodents and humans. In rodents, LP diets are typically implemented by replacing protein with carbohydrates like sucrose or cornstarch, keeping diets isocaloric. However, humans can choose from many different types of carbohydrate, and how dietary carbohydrate quality - the precise composition of the dietary sugars - impacts the response to dietary protein remains largely unexplored. Here, mice were fed control (21% protein) or LP (7% protein) diets with four different carbohydrate sources: sucrose, a 1:1 glucose/fructose mixture, glucose, or fructose. While LP diets improved metabolic health across all groups in male mice, carbohydrate quality also significantly altered specific health outcomes, with fructose-fed mice having the lowest body weight and adiposity of all control diets. In female mice, responses to LP diets were influenced by carbohydrate quality, with certain sugars inducing a stronger metabolic response to LP diets than previously seen. Finally, in female APP/PS1 mice, a model of Alzheimer's disease, we find that although LP diets reduce A-beta; plaque burden irrespective of carbohydrate type, dietary sugar type does influence spatial memory. Together, these results demonstrate that while dietary protein is a critical determinant of metabolic and neurological health, carbohydrate quality influences these outcomes in a sex-specific manner.

physiology↗

bioRxiv2026

Female resistance to the metabolic benefits of protein restriction is reversed by ovariectomy in mice

Dietary protein intake mediates healthy aging in diverse species, with consumption of a low protein (LP) diet improving metabolic health in both humans and mice. In mice, the benefits of LP diets are sex-specific, with males exhibiting a stronger response to a LP diet than females. The reason for this sexually dimorphic response is unknown, but we hypothesized that sex hormones might be responsible for this difference. Here, we tested the role of sex hormones in the response to a LP diet by feeding intact and gonadectomized mice of both sexes either a Control (21% of calorie from protein) or LP (7% of calories from protein) diet, and assessing the effects on weight, body composition, glycemic control, and energy balance over the course of three months, followed by molecular and histological analysis of tissues from each group. We confirm that males show a stronger metabolic response to an LP diet than females, but that ovariectomy sensitizes female mice to the metabolic effects of an LP diet, making them respond more similarly to males; conversely, castration does not substantially impact the response of males to an LP diet. Molecularly, we find that gonadectomy and sex are important interactors that mediate the response of mechanistic target of rapamycin (mTOR) signaling, lipid homeostasis, and thermogenesis to an LP diet. Together, this data shows that the resistance of female mice to an LP diet is mediated by ovarian hormones and suggests the possibility that older female humans might receive enhanced benefits from LP diet feeding.

physiology↗

bioRxiv2025

Low-intensity transcranial focused ultrasound engages parvalbumin-positive GABAergic interneurons in a humanized mouse model of chronic pain: from electrophysiology to cellular investigation

BackgroundLow-intensity transcranial focused ultrasound (tFUS) offers high spatial specificity and deep brain penetration, showing great promise as a non-invasive stimulation technology for modulating brain activity and behavior. Recent studies show that specific tFUS parameters targeted to pain-processing brain circuits can significantly alter pain-related behaviors in rodent models and humans. However, a comprehensive understanding of how tFUS influences brain networks and cellular mechanisms is essential to optimize efficacy and facilitate safe translation to clinical pain therapies. ObjectiveWe aimed to evaluate the modulation of inhibitory neural circuits induced by tFUS of 40 Hz pulse repetition frequency (PRF) in a humanized mouse model of chronic pain, integrating local and network-level electrophysiological investigations, molecular analyses, and histological assessment to confirm safety. Methods and ResultsWe used a 128-element random array transducer for stimulation, along with a non-invasive and flexible 30-channel electroencephalography (EEG) to assess local evoked responses, topographical brain activity, and global brain dynamics including excitation and inhibition (E/I) balance. To further assess tFUS neuromodulation effects at the cellular level, we performed immunohistochemistry (IHC) analysis and found that tFUS significantly increased the activity of inhibitory neurons as indicated by elevated expression of Glutamate Decarboxylase 67 (GAD67) and Parvalbumin (PV). Finally, safety was evaluated in the same brain samples used for mechanistic analysis, with blinded histological assessment revealing no signs of tissue damage. ConclusionsThese findings provide new evidence that tFUS non-invasively engages PV GABAergic inhibitory circuits in a chronic pain mouse model, supporting its development as a robust neuromodulation strategy. TopicsChronic pain; Transcranial focused ultrasound; Non-invasive brain neuromodulation; GABAergic neural circuit modulation HighlightsO_LIMulti-modal assessment of low-intensity tFUS in a humanized chronic pain model. C_LIO_LI40 Hz tFUS enhances inhibition, mirroring optogenetic PV neuron activation. C_LIO_LIRepeated tFUS restored chronic pain-disrupted E/I balance. C_LIO_LIMulti-session tFUS upregulates GAD67 and PV interneuron expressions. C_LI

bioengineering↗

bioRxiv2025

Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice

Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced intake of dietary branched-chain amino acids (BCAAs; leucine, valine and isoleucine), and restriction of the BCAAs is sufficient to extend healthspan and lifespan in mice. While the BCAAs have often been considered as a group, it has become apparent that they have distinct metabolic roles, and we recently found that restriction of isoleucine is sufficient to extend the healthspan and lifespan of male and female mice. Here, we test the effect of lifelong restriction of the BCAA valine on healthy aging. We find that valine restriction (Val-R) improves metabolic health in C57BL/6J mice, promotes leanness and glycemic control across ages, and reduces frailty, cancer prevalence, and senescent cell burden in multiple tissues in both sexes. Val-R reduces glial activation in the brain in a male-specific manner, and extends the lifespan of male, but not female, mice by 23%. To investigate the molecular mechanisms engaged by Val-R with aging, we conducted multi-tissue transcriptional profiling and gene network analysis. While Val-R had a greater molecular impact in the liver, muscle, and brown adipose tissue of females, the enrichment of genes associated with phenotypic traits was stronger in males. Assessing novel gene relationships across tissues, we identified a liver gene module enriched in mitochondrial-related pathways as a central hub. Assessing mitochondrial function, we identified a Val-R-induced male-specific increase in mitochondrial respiration. Our results demonstrate for the first time that Val-R improves multiple aspects of healthspan in mice of both sexes and extends lifespan in males, and suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.

physiology↗

bioRxiv2025

Restriction of individual branched-chain amino acids has distinct effects on the development and progression of Alzheimers disease in 3xTg mice

Dietary protein is a critical regulator of metabolic health and aging in diverse species. Recent discoveries have determined that many benefits of a low protein diet are the result of reduced consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Intriguingly, each BCAA has distinct physiological and molecular effects, with restriction of isoleucine alone being sufficient to improve metabolic health and extend the lifespan of mice. While restriction of protein or all three BCAAs improves cognition in mouse models of Alzheimers disease (AD), the impact of restricting each individual BCAA on the progression and development of AD is unknown. Here, we investigate the effect of restricting each individual BCAA on metabolic health, AD pathology, molecular signaling, and cognition in the 3xTg mouse model. We find that restriction of isoleucine and valine, but not leucine, promotes metabolic health. Restriction of each BCAA had distinct effects on AD pathology and molecular signaling, with transcriptomic analysis of the brain revealing both distinct and shared, and highly sex-specific, molecular impacts of restricting each BCAA. Restricting any of the three BCAAs improved short-term memory in males, with isoleucine restriction having the strongest effect, while restricting valine had the greatest cognitive benefits in females. We identify a set of significantly altered pathways strongly associated with reduced AD pathology and improved cognitive performance in males. Our findings suggest that restricting any of the BCAAs, particularly isoleucine or valine, may form the basis of a novel sex-specific approach to prevent or delay the progression of AD.

physiology↗

bioRxiv2025

Ketogenesis is dispensable for the metabolic adaptations to caloric restriction

Caloric restriction (CR) extends the health and lifespan of diverse species. When fed once daily, CR-treated mice rapidly consume their food and endure a prolonged fast between meals. As fasting is associated with a rise in circulating ketone bodies, we investigated the role of ketogenesis in CR using mice with whole-body ablation of Hmgcs2, the rate-limiting enzyme producing the main ketone body {beta}-hydroxybutyrate ({beta}HB). Here, we report that Hmgcs2 is largely dispensable for many metabolic benefits of CR, including CR-driven changes in adiposity, glycemic control, liver autophagy, and energy balance. Although we observed sex-specific effects of Hmgcs2 on insulin sensitivity, fuel selection, and adipocyte gene expression, the overall physiological response to CR remained robust in mice lacking Hmgcs2. To gain insight into why the deletion of Hmgcs2 does not disrupt CR, we measured fasting {beta}HB levels as mice initiated a CR diet. Surprisingly, as mice adapt to CR, they no longer engage high levels of ketogenesis during the daily fast. Our work suggests that the metabolic benefits of long-term CR are not mediated by ketogenesis.

physiology↗

bioRxiv2024

Enhanced Pooling for Weakly Supervised Gigapixel WSI Training Improves Classification and Lesion Localization

A robust artificial intelligence-assisted workflow for tumor assessment in pathology requires not only accurate classification but also precise lesion localization. While current weakly supervised learning methods significantly reduce the need for extensive annotations and leverage large quantities of annotation-free whole-slide images (WSIs) to enhance classification robustness, they often fall short in segmentation accuracy. We attribute this limitation to the optimization goals in classification, which tend to focus solely on the most representative features--an approach that is particularly inefficient for WSIs with gigapixel resolution. To address this challenge, we introduce a novel approach based on streaming convolution, an end-to-end method for WSI training. Our contributions include the Rectified LogSumExp (ReLSE) pooling method and adaptive pseudo annotation generation for self-training, both designed to encourage models to learn from sub-representative features. Using only slide-level annotations from the CAMELYON16 dataset, our method achieves a significant improvement in metastasis localization, with a patch-level recall from 53.88% to 79.18% at a precision of 80%. This conclusion also holds for a dataset collected from Taipei Veterans General Hospital (TVGH), used in the assessment of lung cancer lymph node metastasis with a recall improved from 42.98% to 72.27%. The proposed method can also be integrated with additional manual annotations. Experiment results showed the semi-supervised model (recall: 91.12%) could even outperform the strongly supervised model (recall: 81.80%) on the TVGH dataset.

bioinformatics↗

bioRxiv2024

Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer&aposs disease

Caloric restriction (CR) is a widely recognized geroprotective intervention that slows or prevents Alzheimers disease (AD) in animal models. CR is typically implemented via feeding mice a single meal per day; as CR mice rapidly consume their food, they are subject to a prolonged fast between meals. While CR has been shown to improve metabolic and cognitive functions and suppress pathological markers in AD mouse models, the specific contributions of fasting versus calorie reduction remains unclear. Here, we investigated the contribution of fasting and energy restriction to the beneficial effects of CR on AD progression. To test this, we placed 6-month-old 3xTg mice on one of several diet regimens, allowing us to dissect the effects of calories and fasting on metabolism, AD pathology, and cognition. We find that energy restriction alone, without fasting, was sufficient to improve glucose tolerance and reduce adiposity in both sexes, and to reduce A{beta} plaques and improve aspects of cognitive performance in females. However, we find that a prolonged fast between meals is necessary for many of the benefits of CR, including improved insulin sensitivity, reduced phosphorylation of tau, decreased neuroinflammation, inhibition of mTORC1 signaling, and activation of autophagy, as well as for the full cognitive benefits of CR. Finally, we find that fasting is essential for the benefits of CR on survival in male 3xTg mice. Overall, our results demonstrate that fasting is required for the full benefits of a CR diet on the development and progression of AD in 3xTg mice, and suggest that both when and how much we eat influences the development and progress of AD.

physiology↗

bioRxiv2024

Acarbose ameliorates Western diet-induced metabolic and cognitive impairments in the 3xTg mouse model of Alzheimer's disease

Age is the greatest risk factor for Alzheimers disease (AD) as well as for other disorders that increase the risk of AD such as diabetes and obesity. There is growing interest in determining if interventions that promote metabolic health can prevent or delay AD. Acarbose is an anti-diabetic drug that not only improves glucose homeostasis, but also extends the lifespan of wild-type mice. Here, we test the hypothesis that acarbose will not only preserve metabolic health, but also slow or prevent AD pathology and cognitive deficits in 3xTg mice, a model of AD, fed either a Control diet or a high-fat, high-sucrose Western diet (WD). We find that acarbose decreases the body weight and adiposity of WD-fed 3xTg mice, increasing energy expenditure while also stimulating food consumption, and improves glycemic control. Both male and female WD-fed 3xTg mice have worsened cognitive deficits than Control-fed mice, and these deficits are ameliorated by acarbose treatment. Molecular and histological analysis of tau and amyloid pathology identified sex-specific effects of acarbose which are uncoupled from the dramatic improvements in cognition, suggesting that the benefits of acarbose on AD are largely driven by improved metabolic health. In conclusion, our results suggest that acarbose may be a promising intervention to prevent, delay, or even treat AD, especially in individuals consuming a Western diet.

physiology↗

bioRxiv2024

Dietary isoleucine content defines the metabolic and molecular response to a Western diet

The amino acid composition of the diet has recently emerged as a critical regulator of metabolic health. Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans, and reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice. However, it is unknown how sex, strain, and dietary isoleucine intake may interact to impact the response to a Western Diet (WD). Here, we find that although the magnitude of the effect varies by sex and strain, reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice of both sexes from the deleterious metabolic effects of a WD, while increasing dietary levels of isoleucine impairs aspects of metabolic health. Despite broadly positive responses across all sexes and strains to reduced isoleucine, the molecular response of each sex and strain is highly distinctive. Using a multi-omics approach, we identify a core sex- and strain-independent molecular response to dietary isoleucine, and identify mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype. Intriguingly, the metabolic effects of reduced isoleucine in mice are not associated with FGF21 - and we find that in humans plasma FGF21 levels are likewise not associated with dietary levels of isoleucine. Finally, we find that foods contain a range of isoleucine levels, and that consumption of dietary isoleucine is lower in humans with healthy eating habits. Our results demonstrate that the dietary level of isoleucine is critical in the metabolic and molecular response to a WD, and suggest that lowering dietary levels of isoleucine may be an innovative and translatable strategy to protect from the negative metabolic consequences of a WD.

physiology↗

bioRxiv2023

Restricting dietary protein or dietary isoleucine improves metabolic health in aged mice

In defiance of the paradigm that calories from all sources are equivalent, we and others have shown that dietary protein is a dominant regulator of healthy aging. The restriction of protein or the branched-chain amino acid isoleucine promotes healthspan and extends lifespan when initiated in young or adult mice. However, many interventions are less efficacious or even deleterious when initiated in aged animals. Here, we investigate the physiological, metabolic, and molecular consequences of consuming a diet with a 67% reduction of all amino acids (Low AA), or of isoleucine alone (Low Ile), in male and female C57BL/6J.Nia mice starting at 20 months of age. We find that both diet regimens effectively reduce adiposity and improve glucose tolerance, which were benefits that were not mediated by reduced calorie intake. Both diets improve specific aspects of frailty, slow multiple molecular indicators of aging rate, and rejuvenate the aging heart and liver at the molecular level. These results demonstrate that Low AA and Low Ile diets can drive youthful physiological and molecular signatures, and support the possibility that these dietary interventions could help to promote healthy aging in older adults.

physiology↗

bioRxiv2022

Resistance exercise protects mice from protein-induced metabolic dysfunction

Low protein (LP) diets extend the lifespan of diverse species, and are associated with improved metabolic health in both rodents and humans. Paradoxically, many athletes and bodybuilders consume high protein (HP) diets and protein supplements, yet are both fit and metabolically healthy. Here, we examine this paradox using weight pulling, a validated progressive resistance exercise training regimen, in mice fed either an LP diet or an isocaloric HP diet. We find that despite having lower food consumption than the LP group, HP-fed mice gain significantly more fat mass than LP-fed mice when not exercising, while weight pulling protected HP-fed mice from this excess fat accretion. The HP diet augmented exercise-induced hypertrophy of the forearm flexor complex, and weight pulling ability increased more rapidly in the exercised HP-fed mice. Surprisingly, exercise did not protect from HP-induced changes in glycemic control. Our results confirm that HP diets can augment muscle hypertrophy and accelerate strength gain induced by resistance exercise without negative effects on fat mass, and also demonstrate that LP diets may be advantageous in the sedentary. Our results highlight the need to consider both dietary composition and activity, not simply calories, when taking a precision nutrition approach to health.

physiology↗

bioRxiv2022

Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice

Low protein (LP) diets promote health and longevity in diverse species. Although the precise components of an LP diet that mediate its beneficial effects have not been defined, reducing dietary levels of the three branched-chain amino acids (BCAAs) leucine, isoleucine and valine promotes metabolic health in both sexes, and increases lifespan while reducing frailty in male, but not female, C57BL/6J mice. Each BCAA has unique metabolic effects, and we recently showed that restriction of isoleucine is both sufficient to promote metabolic health and required for the metabolic benefits of an LP diet in male C57BL/6J mice. Here, we tested the hypothesis that specifically restricting isoleucine could promote healthy aging in genetically heterogenous UM-HET3 mice. We find that a reduced isoleucine diet improves the metabolic health of both young and old HET3 mice, promoting leanness and glycemic control. Restriction of isoleucine starting in adult, 6 month old HET3 mice reprograms hepatic metabolism in a way distinct from an LP diet. Finally, we find that a reduced isoleucine diet reduces frailty and extends the lifespan of both male and female HET3 mice, but to a much greater degree in males. Our results demonstrate that restricting dietary isoleucine can increase health span and longevity in a genetically diverse population of mice, and suggests that reducing dietary levels of isoleucine may have great potential as a geroprotective intervention.

physiology↗

bioRxiv2022

FGF21 has a sex-specific role in calorie-restriction-induced beiging of white adipose tissue in mice

Calorie restriction (CR) promotes healthspan and extends the lifespan of diverse organisms, including mice, and there is intense interest in understanding the molecular mechanisms by which CR functions. Some studies have demonstrated that CR induces fibroblast growth factor 21 (FGF21), a hormone that regulates energy balance and that when overexpressed, promotes metabolic health and longevity in mice, but the role of FGF21 in the response to CR has not been fully investigated. We directly examined the role of FGF21 in the physiological and metabolic response to a CR diet by feeding Fgf21-/-and wild-type control mice either ad libitum (AL) diet or a 30% CR diet for 15 weeks. Here, we find that FGF21 is largely dispensable for CR-induced improvements in body composition and energy balance, but that lack of Fgf21 blunts CR-induced changes aspects of glucose regulation and insulin sensitivity in females. Surprisingly, despite not affecting CR-induced changes in energy expenditure, loss of Fgf21 significantly blunts CR-induced beiging of white adipose tissue in male but not female mice. Our results shed new light on the molecular mechanisms involved in the beneficial effects of a CR diet, clarify that FGF21 is largely dispensable for the metabolic effects of a CR diet, and highlight a sex-dependent role for FGF21 in the molecular adaptation of white adipose tissue to CR.

physiology↗

bioRxiv2019

Glia-derived exosomal miR-274 targets Sprouty in trachea and synaptic boutons to modulate growth and responses to hypoxia

Secreted exosomal miRNAs mediate inter-organ/tissue communication by downregulating gene expression, thereby modulating developmental and physiological functions. However, the source, route, and function have not been formally established for specific miRNAs. Here, we show that glial miR-274 non-cell autonomously modulates the growth of synaptic boutons and tracheal branches. Whereas precursor miR-274 was expressed in glia, mature miR-274 was secreted. miR-274 secretion to circulating hemolymph was detected in exosomes, a process requiring ESCRT components in exosome biogenesis and Rab11 and Syx1A in exosome release. miR-274 downregulated Sprouty to activate MAPK in synaptic boutons and tracheal branches, thereby promoting their growth. Expression of miR-274 solely in glia of a mir-274 null mutant reset normal levels of Sprouty and MAPK, and hemolymphatic exosomal miR-274. mir-274 mutant larvae were hypersensitive to hypoxia, which was suppressed by increasing tracheal branches. Thus, glia-derived miR-274 coordinates growth of synaptic boutons and tracheal branches to modulate larval hypoxia responses.

developmental biology↗