Biology subjects

Lassen, M.

Publications and source records attributed to Lassen, M..

5 recordsLinked to original sources

bioRxiv2025

High-throughput assessment of exercise-induced adaptations and muscle function in health and ageing

Exercise improves metabolic health, enhances insulin sensitivity, and preserves muscle function, making it a core intervention to combat age-related decline and metabolic disorders. However, large-scale genetic and pharmacological screens to uncover exercise-induced adaptations remain challenging in mammalian models due to their complexity and cost. Here, we present the ClimbMaster, a fully automated, computer-controlled platform for assessing exercise-induced adaptations and physical performance in the fruit fly Drosophila. The system uses repeated climbing exercises to simulate endurance training, enabling precise measurements of climbing speed and endurance across different conditions and life stages. Using the ClimbMaster, we demonstrate that exercise improves endurance, promotes fat loss, and enhances insulin-mediated glucose uptake and modulates insulin sensitivity in muscle, highlighting key conserved features of exercise physiology between flies and mammals. We also show that rapamycin, a TOR inhibitor, mitigates age-related performance decline. This platform enables high-throughput screens to investigate genetic and environmental factors influencing muscle health, aging, and insulin resistance, providing a scalable and versatile tool for the identification of novel therapeutic targets to improve healthspan and physical performance.

physiology↗

bioRxiv2024

HR3/RORα-mediated cholesterol sensing regulates TOR signaling

Cells and organisms adjust their growth based on the availability of cholesterol, which is essential for cellular functions. However, the mechanisms by which cells sense cholesterol levels and translate these into growth signals are not fully understood. We report that cholesterol rapidly activates the master growth-regulatory TOR pathway in Drosophila tissues. We identify the nuclear receptor HR3, an ortholog of mammalian ROR, as an essential factor in cholesterol-induced TOR activation. We demonstrate that HR3 binds cholesterol and promotes TOR pathway activation through a non-genomic mechanism acting upstream of the Rag GTPases. Similarly, we find that ROR is necessary for cholesterol-mediated TOR activation in human cells, suggesting that HR3/ROR represents a conserved mechanism for cholesterol sensing that couples cholesterol availability to TOR-pathway activity. These findings advance our understanding of how cholesterol influences cell growth, with implications for cholesterol-related diseases and cancer. HighlightsO_LICholesterol leads to dynamic TOR pathway activation, driving systemic growth C_LIO_LIHR3 in Drosophila binds cholesterol and couples its availability to TOR activation C_LIO_LIHR3 acts upstream of Rag GTPases to activate TOR in response to lysosomal cholesterol C_LIO_LIMammalian HR3 ortholog ROR is required for cholesterol-induced TOR activation C_LI

cell biology↗

bioRxiv2023

A neuronal relay mediates muscle-adipose communication that drives systemic metabolic adaptation to high-sugar diets

Obesity leads to impaired insulin signaling and tissue sensitivity, which drive the onset of type 2 diabetes. Insulin resistance leads to a reduction in cellular glucose uptake, resulting in elevated blood glucose levels, which consequently cause {beta}-cell dysfunction and development of diabetes. Although improving insulin signaling is a key target for restoring whole-body glucose homeostasis and reversing diabetes, the multi-organ mechanisms that regulate insulin signaling and tissue sensitivity are poorly defined. We screened the secretome and receptome in Drosophila to identify the underlying interorgan hormonal crosstalk affecting diet-induced insulin resistance and obesity. We identified complex interplay between muscle, neuronal, and fat tissues, mediated by the conserved BMP and LGR signaling pathways, which augments insulin signaling and improves dietary sugar tolerance. We found that muscle-derived BMP signaling is induced by sugar and governs neuronal Bursicon signaling. Acting through its LGR-family receptor, Bursicon both enhances insulin secretion and improves insulin sensitivity in adipose tissue, thereby preventing sugar-induced hyperglycemia. Inhibition of Bursicon-LGR signaling in adipose tissue exacerbates sugar-induced insulin resistance, and we discovered that this condition could be alleviated by suppressing NF-{kappa}B signaling. Our findings identify a muscle-neuronal-fat tissue axis that drives metabolic adaptation to high-sugar conditions by modulating insulin secretion and adipocyte insulin sensitivity, highlighting mechanisms that may be exploited for the development of strategies for the treatment and reversal of insulin resistance.

physiology↗

bioRxiv2021

Insulin signaling couples growth and early maturation to cholesterol intake

Nutrition is one of the most important influences on growth and the timing of developmental maturation transitions including mammalian puberty and insect metamorphosis. Childhood obesity is associated with precocious puberty, but the assessment mechanism that links body fat to early maturation is unknown. During development, intake of nutrients promotes signaling through insulin-like systems that govern the growth of cells and tissues and also regulates the timely production of the steroid hormones that initiate the juvenile-adult transition. We show here that the dietary lipid cholesterol, required as a component of cell membranes and as a substrate for steroid biosynthesis, also governs body growth and maturation in Drosophila via promoting the expression and release of insulin-like peptides. This nutritional input acts via the Niemann-Pick-type-C (Npc) cholesterol sensors/transporters in the glia of the blood-brain barrier and cells of the adipose tissue to remotely drive systemic insulin signaling and body growth. Furthermore, increasing intracellular cholesterol levels in the steroid-producing prothoracic gland strongly promotes endoreduplication, leading to accelerated attainment of a nutritional checkpoint that ensures that animals do not initiate maturation prematurely. These findings couple sensing of the lipid cholesterol to growth control and maturational timing, which may help explain both the link between cholesterol and cancer as well as the critical connection between body fat (obesity) and early puberty. HIGHLIGHTSO_LIDietary cholesterol promotes developmental growth and leads to early maturation C_LIO_LIInsulin signaling couples cholesterol intake with systemic growth C_LIO_LICholesterol promotes insulin signaling and growth via glial and fat-tissue relays C_LIO_LICholesterol sensing affects a nutritional checkpoint that prevents early maturation C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/447368v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@14e786borg.highwire.dtl.DTLVardef@c3eab5org.highwire.dtl.DTLVardef@6645c8org.highwire.dtl.DTLVardef@6f729a_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG

cell biology↗

bioRxiv2020

The gut hormone Allatostatin C regulates food intake and metabolic homeostasis under nutrient stress

The intestine is a central regulator of metabolic homeostasis. Dietary inputs are absorbed through the gut, which senses their nutritional value and relays hormonal information to other organs to coordinate systemic energy balance. However, the specific gut hormones that communicate energy availability to target organs to induce appropriate metabolic and behavioral responses are poorly defined. Here we show that the enteroendocrine cells (EECs) of the Drosophila gut sense nutrient stress via the intracellular TOR pathway, and in response secrete the peptide hormone allatostatin C (AstC). Gut-derived AstC induces secretion of glucagon-like adipokinetic hormone (AKH) via its receptor AstC-R2, a homolog of mammalian somatostatin receptors, to coordinate food intake and energy mobilization. Loss of gut AstC or its receptor in the AKH-producing cells impairs lipid and sugar mobilization during fasting, leading to hypoglycemia. Our findings illustrate a nutrient-responsive endocrine mechanism that maintains energy homeostasis under nutrient-stress conditions, a function that is essential to health and whose failure can lead to metabolic disorders.

physiology↗