Regulation of lipid dysmetabolism and neuroinflammation linked with Alzheimer's disease through modulation of Dgat2.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaque accumulation, cognitive decline, lipid dysregulation, and neuroinflammation. Mutations in the Amyloid Precursor Protein (APP), and accumulation of A contribute to AD, however, underlying mechanisms linking beta amyloid to lipid metabolism and neuroinflammation remain unclear. Using models, we demonstrate that and lead to progressive locomotor impairments, disrupted sleep activity, memory deficits, lipid dysregulation, loss of synaptic integrity, and neuroinflammation.

The Interplay of Genetic Predisposition, Circadian Misalignment, and Metabolic Regulation in Obesity.

Purpose Of Review: This review explores the complex interplay between genetic predispositions to obesity, circadian rhythms, metabolic regulation, and sleep. It highlights how genetic factors underlying obesity exacerbate metabolic dysfunction through circadian misalignment and examines promising interventions to mitigate these effects.

Recent Findings: Genome-wide association Studies (GWAS) have identified numerous Single Nucleotide Polymorphisms (SNPs) associated with obesity traits, attributing 40-75% heritability to body mass index (BMI).

Direct Cryosectioning of Drosophila Heads for Enhanced Brain Fluorescence Staining and Immunostaining.

Immunostaining Drosophila melanogaster brains is essential for exploring the mechanisms behind complex behaviors, neural circuits, and protein expression patterns. Traditional methods often involve challenges such as performing complex dissection, maintaining tissue integrity, and visualizing specific expression patterns during high-resolution imaging. We present an optimized protocol that combines cryosectioning with fluorescence staining and immunostaining.

A conserved role for ALG10/ALG10B and the -glycosylation pathway in the sleep-epilepsy axis.

Congenital disorders of glycosylation (CDG) comprise a class of inborn errors of metabolism resulting from pathogenic variants in genes coding for enzymes involved in the asparagine-linked glycosylation of proteins. Unexpectedly to date, no CDG has been described for , encoding the alpha-1,2-glucosyltransferase catalyzing the final step of lipid-linked oligosaccharide biosynthesis. Genome-wide association studies (GWAS) of human traits in the UK Biobank revealed significant SNP associations with short sleep duration, reduced napping frequency, later sleep timing and evening diurnal preference as well as cardiac traits at a genomic locus containing a pair of paralogous enzymes and .

Apolipoprotein E Induces Lipid Accumulation Through Dgat2 That Is Prevented with Time-Restricted Feeding in .

Apolipoprotein E (ApoE) is the leading genetic risk factor for late-onset Alzheimer's disease (AD), which is the leading cause of dementia worldwide. Most people have two ApoE-ε3 (ApoE3) alleles, while ApoE-ε2 (ApoE2) is protective from AD, and ApoE-ε4 (ApoE4) confers AD risk. How these alleles modulate AD risk is not clearly defined, and ApoE's role in lipid metabolism is also not fully known.

Time-restricted feeding mediated modulation of microbiota leads to changes in muscle physiology in Drosophila obesity models.

Recent research has highlighted the essential role of the microbiome in maintaining skeletal muscle physiology. The microbiota influences muscle health by regulating lipid metabolism, protein synthesis, and insulin sensitivity. However, metabolic disturbances such as obesity can lead to dysbiosis, impairing muscle function.

Automated assessment of cardiac dynamics in aging and dilated cardiomyopathy Drosophila models using machine learning.

The Drosophila model is pivotal in deciphering the pathophysiological underpinnings of various human ailments, notably aging and cardiovascular diseases. Cutting-edge imaging techniques and physiology yield vast high-resolution videos, demanding advanced analysis methods. Our platform leverages deep learning to segment optical microscopy images of Drosophila hearts, enabling the quantification of cardiac parameters in aging and dilated cardiomyopathy (DCM).

Diurnal expression of Dgat2 induced by time-restricted feeding maintains cardiac health in the Drosophila model of circadian disruption.

Circadian disruption is associated with an increased risk of cardiometabolic disorders and cardiac diseases. Time-restricted feeding/eating (TRF/TRE), restricting food intake within a consistent window of the day, has shown improvements in heart function from flies and mice to humans. However, whether and how TRF still conveys cardiac benefits in the context of circadian disruption remains unclear.

Time-restricted feeding regulates lipid metabolism under metabolic challenges.

Dysregulation of lipid metabolism is a commonly observed feature associated with metabolic syndrome and leads to the development of negative health outcomes such as obesity, diabetes mellitus, non-alcoholic fatty liver disease, or atherosclerosis. Time-restricted feeding/eating (TRF/TRE), an emerging dietary intervention, has been shown to promote pleiotropic health benefits including the alteration of diurnal expression of genes associated with lipid metabolism, as well as levels of lipid species. Although TRF likely induces a response in multiple organs leading to the modulation of lipid metabolism, a majority of the studies related to TRF effects on lipids have focused only on individual tissues, and furthermore there is a lack of insight into potential underlying mechanisms.

When a calorie is not just a calorie: Diet quality and timing as mediators of metabolism and healthy aging.

An epidemic of obesity has affected large portions of the world, increasing the risk of developing many different age-associated diseases, including cancer, cardiovascular disease, and diabetes. In contrast with the prevailing notion that "a calorie is just a calorie," there are clear differences, within and between individuals, in the metabolic response to different macronutrient sources. Recent findings challenge this oversimplification; calories from different macronutrient sources or consumed at different times of day have metabolic effects beyond their value as fuel.

Automated evaluation of cardiac contractile dynamics and aging prediction using machine learning in a model.

The model has proven tremendously powerful for understanding pathophysiological bases of several human disorders including aging and cardiovascular disease. Relevant high-speed imaging and high-throughput lab assays generate large volumes of high-resolution videos, necessitating next-generation methods for rapid analysis. We present a platform for deep learning-assisted segmentation applied to optical microscopy of hearts and the first to quantify cardiac physiological parameters during aging.

Time-restricted feeding promotes muscle function through purine cycle and AMPK signaling in Drosophila obesity models.

Obesity caused by genetic and environmental factors can lead to compromised skeletal muscle function. Time-restricted feeding (TRF) has been shown to prevent muscle function decline from obesogenic challenges; however, its mechanism remains unclear. Here we demonstrate that TRF upregulates genes involved in glycine production (Sardh and CG5955) and utilization (Gnmt), while Dgat2, involved in triglyceride synthesis is downregulated in Drosophila models of diet- and genetic-induced obesity.

Mitochondrial epigenetic modifications and nuclear-mitochondrial communication: A new dimension towards understanding and attenuating the pathogenesis in women with PCOS.

Mitochondrial DNA (mtDNA) epigenetic modifications have recently gained attention in a plethora of complex diseases, including polycystic ovary syndrome (PCOS), a common cause of infertility in women of reproductive age. Herein we discussed mtDNA epigenetic modifications and their impact on nuclear-mitochondrial interactions in general and the latest advances indicating the role of mtDNA methylation in the pathophysiology of PCOS. We highlighted epigenetic changes in nuclear-related mitochondrial genes, including nuclear transcription factors that regulate mitochondrial function and may be involved in the development of PCOS or its related traits.

Circadian-mediated regulation of cardiometabolic disorders and aging with time-restricted feeding.

Circadian rhythms are present throughout biology, from the molecular level to complex behaviors such as eating and sleeping. They are driven by molecular clocks within cells, and different tissues can have unique rhythms. Circadian disruption can trigger obesity and other common metabolic disorders such as aging, diabetes, and cardiovascular disease, and circadian genes control metabolism.

A Skeletal Muscle-Centric View on Time-Restricted Feeding and Obesity under Various Metabolic Challenges in Humans and Animals.

Nearly 50% of adults will suffer from obesity in the U.S. by 2030.

Author Correction: Time-restricted feeding restores muscle function in Drosophila models of obesity and circadian-rhythm disruption.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Time-Restricted Eating to Prevent and Manage Chronic Metabolic Diseases.

Molecular clocks are present in almost every cell to anticipate daily recurring and predictable changes, such as rhythmic nutrient availability, and to adapt cellular functions accordingly. At the same time, nutrient-sensing pathways can respond to acute nutrient imbalance and modulate and orient metabolism so cells can adapt optimally to a declining or increasing availability of nutrients. Organismal circadian rhythms are coordinated by behavioral rhythms such as activity-rest and feeding-fasting cycles to temporally orchestrate a sequence of physiological processes to optimize metabolism.

Suppression of myopathic lamin mutations by muscle-specific activation of AMPK and modulation of downstream signaling.

Laminopathies are diseases caused by dominant mutations in the human LMNA gene encoding A-type lamins. Lamins are intermediate filaments that line the inner nuclear membrane, provide structural support for the nucleus and regulate gene expression. Drosophila melanogaster models of skeletal muscle laminopathies were developed to investigate the pathological defects caused by mutant lamins and identify potential therapeutic targets.

Prolonged cross-bridge binding triggers muscle dysfunction in a model of myosin-based hypertrophic cardiomyopathy.

K146N is a dominant mutation in human β-cardiac myosin heavy chain, which causes hypertrophic cardiomyopathy. We examined how muscle responds to this mutation and integratively analyzed the biochemical, physiological and mechanical foundations of the disease. ATPase assays, actin motility, and indirect flight muscle mechanics suggest at least two rate constants of the cross-bridge cycle are altered by the mutation: increased myosin attachment to actin and decreased detachment, yielding prolonged binding.

Increasing autophagy and blocking Nrf2 suppress laminopathy-induced age-dependent cardiac dysfunction and shortened lifespan.

Mutations in the human LMNA gene cause a collection of diseases known as laminopathies. These include myocardial diseases that exhibit age-dependent penetrance of dysrhythmias and heart failure. The LMNA gene encodes A-type lamins, intermediate filaments that support nuclear structure and organize the genome.

TRiC/CCT chaperonins are essential for maintaining myofibril organization, cardiac physiological rhythm, and lifespan.

We recently reported that CCT chaperonin subunits are upregulated in a cardiac-specific manner under time-restricted feeding (TRF) [Gill S et al. (2015) Science 347, 1265-1269], suggesting that TRiC/CCT has a heart-specific function. To understand the CCT chaperonin function in cardiomyocytes, we performed its cardiac-specific knock-down in the Drosophila melanogaster model.