Biology subjects

Puglielli, L.

Publications and source records attributed to Puglielli, L..

6 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

Acetyl-CoA availability regulates neuronal metabolism, growth, and synaptic activity

The metabolite acetyl-CoA plays a central role in cellular metabolic homeostasis. As part of the secretory pathway, acetyl-CoA is imported into the endoplasmic reticulum (ER) by a membrane-bound transporter AT-1 (SLC33A1). AT-1 has been linked to peripheral neuropathy (heterozygous mutations), developmental delay with premature death (homozygous mutations) and intellectual disability with progeria (duplication). These phenotypes can be reproduced in the mouse. Here, we show that AT-1 overexpression in primary neurons impacts diverse phenotypes related to neuronal function and plasticity. At the gene level, AT-1 induces brain aging signatures, and key differences in ribosomal and synaptic processes were identified in both the transcriptome and the proteome. Changes in mitochondria-associated pathways were reflected in an increase in expression of mitochondrial master regulator PGC-1 and its target genes. Functionally, marked differences in mitochondrial membrane potential, architecture, and respiration were detected. Tracing experiments indicated altered glucose utilization in glycogen storage and nucleotide production. Shifts in redox metabolism were linked to differences in levels of NAD-dependent SIRT1 and CtBP2, with consequences for acetylated lysine modification. Depletion of lipid stores was associated with greater plasticity in fuel substrate utilization and a major shift in cellular lipid composition. These broad-scale changes in metabolism were coincident with reduced expression of synaptic proteins and reduced activity among synaptic networks, indicating that neuronal electrophysiology and network communication are coordinated at least in part through neuronal acetyl-CoA metabolism.

cell biology↗

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↗

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↗

bioRxiv2020

Deficient ER acetyl-CoA import in acinar cells leads to chronic pancreatitis

Maintaining endoplasmic reticulum (ER) proteostasis is essential for pancreatic acinar cell function. Under conditions of severe ER stress, activation of pathogenic unfolded protein response pathways play a central role in the development and progression of pancreatitis. A key event in this pathogenic response is a loss of the transcription factor spliced XBP1 (XBP1s) and activation of the PERK pathway. Less is known of the consequence of perturbing ER-associated post-translational protein modification during pancreatitis. Here we show that expression of the ER acetyl-CoA transporter AT-1, necessary for ER protein acetylation, lies downstream of XBP1s and is significantly downregulated during the onset of pancreatitis. Genetic deletion of AT-1 in acinar cells of adult pancreas induces chronic ER stress marked by activation of both the XBP1s and PERK pathways, leading to mild/moderate chronic pancreatitis evidenced by accumulation of intracellular trypsin, immune cell infiltration, and fibrosis, but little pancreatic degeneration. Two-day induction of acute on chronic pancreatitis in AT-1 acinar specific knockout mice results in a severe CP phenotype with pronounced pancreatic atrophy. These findings uncover a new layer of complexity of the pathological ER stress response and its impact on pancreatic disease.

pathology↗