Biology subjects

Schweiger, M.

Publications and source records attributed to Schweiger, M..

9 recordsLinked to original sources

bioRxiv2026

Combined AMPK activation and ghrelin ameliorate cancer cachexia through complementary effects on energy homeostasis, inflammation, and wasting

BackgroundCancer-associated cachexia is characterized by progressive loss of skeletal muscle and adipose tissue driven by systemic inflammation and metabolic dysregulation. AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, but its role in cachexia and its therapeutic potential remains incompletely defined. We investigated AMPK signaling during cachexia and whether pharmacological AMPK activation alone or combined with ghrelin could ameliorate disease manifestations. MethodsCachexia was induced in male C57BL/6 mice by Lewis lung carcinoma (LLC) implantation. Additional models included fibrosarcoma (CHX and MN/MCA1) and chronic lymphocytic choriomeningitis virus (LCMV) infection. AMPK was activated using AICAR and BC1618 (AB), alone or combined with ghrelin (AB+G). Metabolic, inflammatory, and functional outcomes were assessed in hypothalamus, skeletal muscle, adipose tissue, and serum. ResultsLLC-bearing mice developed cachexia characterized by reduced body weight, lean and fat mass, hypophagia, and elevated circulating IL-6 and corticosterone. Cachectic LLC mice displayed increased Il6 and Il1{beta} expression in hypothalamus, skeletal muscle, and white adipose tissue (WAT). Furthermore, AMPK activation failed to increase in hypothalamus or peripheral tissues despite profound energy deficit. A similar defect in AMPK responsiveness was observed in CHX and LCMV models, indicating a conserved feature of cachexia. AB treatment in LLC mice reduced circulating IL-6 and corticosterone levels and decreased skeletal muscle atrogene expression and IL-6/STAT3 signaling, partially preserving muscle mass, fiber size, and grip strength. However, food intake remained low, and WAT was largely unresponsive, maintaining elevated Il6 expression and tissue loss. Ghrelin alone increased food intake in LLC mice but did not ameliorate the cachectic phenotype. In contrast, AB+G restored food intake and prevented loss of lean and fat mass. LLC AB+G mice exhibited reduced hypothalamic Il6 and serotonin transporter (Slc6a4) expression, normalized adipocyte morphology and serum leptin levels, decreased adipose Il6 and Atgl expression and reduced WAT sympathetic innervation. AB+G further lowered circulating corticosterone levels, and provided greater protection against muscle wasting, with increased Pgc1 expression and improved muscle function. Neither intervention affected tumor growth or tumor inflammatory gene expression. ConclusionsCancer cachexia is associated with a central and peripheral failure to appropriately activate AMPK signaling in response to the energetic stress imposed by cachexia. Combined AMPK activation and ghrelin administration exerted complementary effects on energy homeostasis, inflammation, and tissue wasting, resulting in greater protection against cachexia than either intervention alone. These findings support combined AMPK-ghrelin targeting as a promising therapeutic strategy for cancer cachexia.

cancer biology↗

bioRxiv2026

Fibroblast-derived thrombospondin-1 shapes macrophage polarization in advanced human co-culture models

BackgroundTumor-associated macrophages (TAMs) are key drivers of the immunosuppressive tumor microenvironment (TME), supporting tumor progression through diverse functions. However, mechanistic studies of TAM polarization remain limited by the lack of physiologically relevant human model systems that capture stromal-immune interactions and macrophage heterogeneity. MethodsWe established advanced human co-culture systems that integrate healthy donor-derived macrophages with patient-derived organoids and tumoroids (PDOs and PDTs), as well as matched normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs). These multicellular models enabled the investigation of interactions among stromal, epithelial, and immune cells within tumor and adjacent normal tissue environments. ResultsThe co-culture systems recapitulated distinct macrophage states associated with tumor and adjacent normal environments and identified fibroblasts as major regulators of macrophage phenotypes. CAFs promoted macrophage metabolic remodeling characterized by altered lipid handling and enrichment of TAM-like signatures. Mechanistically, we identified thrombospondin 1 (TSP1) as a CAF-secreted factor linked to metabolic priming. Recombinant TSP1 induced transient lipid accumulation followed by mitochondrial remodeling. In tumor co-culture conditions, CD36 inhibition reduced lipid accumulation in macrophages, supporting a role for TSP1-linked lipid crosstalk in stromal-immune interactions. ConclusionOur study establishes advanced patient-derived co-culture models as a platform to investigate human TAM biology and stromal-immune interactions in CRC. Using these systems, we identify a fibroblast-associated TSP1-lipid axis linked to macrophage metabolic remodeling and TAM-like polarization, highlighting stromal metabolic communication as a potential targetable feature of the CRC microenvironment. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=176 HEIGHT=200 SRC="FIGDIR/small/728363v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@11b8c9borg.highwire.dtl.DTLVardef@1ac3aa2org.highwire.dtl.DTLVardef@3da223org.highwire.dtl.DTLVardef@5fc3a7_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

CD8+ T cells regulate the bioenergetic reprogramming of lymphoid organs and the heart during viral infection

The activation of the immune system is a bioenergetically-costly process1. Yet, essential bodily functions require a continuous energy supply, imposing energy constraints and trade-offs between competing processes2. Our understanding of the underlying bioenergetic adaptations reconciling rapid immune activation with other vital processes remains scarce. 3-6 Here, by using experimental models of viral infections, we identified an unexpected CD8+ T cell-driven redistribution of energy substrates between lymphoid organs and the heart. Viral infection promoted systemic hypoglycaemia and ketogenesis, together with systemic reallocation of energy substrates. Across organs analysed, secondary lymphoid organs and the heart showed the most dramatic changes. The former increased glucose uptake and oxidation while the heart showed the opposite, switching to preferential fatty acid utilization. These bioenergetic adaptations were absent in infected mice lacking CD8+ T cells or with T cells lacking the glucose transporter GLUT1. Pharmacological inhibition of fatty acid oxidation forced a systemic switch to glucose oxidation. This was associated with metabolic decompensation, reduced cardiac energetics, left ventricular stress, and mortality in otherwise nonlethal viral infections. Our results reveal how the energetic cost of immune cell activation imposes bioenergetic adaptations on non-lymphoid organs, posing a major challenge for the heart by completely relying on fatty acids.

immunology↗

bioRxiv2024

Non-shivering thermogenesis is intact upon brown-adipocyte specific loss of ATGL and HSL due to white adipose tissue browning

Intracellular fatty acids (FAs) activate and fuel non-shivering thermogenesis (NST) via uncoupling protein 1 (UCP1). Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) control FA availability. Since mice lacking ATGL in brown adipose tissue (BAT) exhibit intact recruitable adrenergic thermogenesis, we hypothesized that HSL-mediated FA release is sufficient to activate UCP1-dependent NST. We demonstrate that mice with inducible brown adipocyte-specific loss of ATGL and HSL (iBDKO) exhibit normal recruitable adrenergic thermogenesis upon prolonged cold exposure. Mechanistically, we show that BAT thermogenic capacity is impaired in cold-adapted iBDKO mice due to diminished mitochondrial numbers. Increased browning of white adipose tissue (WAT) in iBDKO mice indicates a shift in thermogenesis from BAT to WAT. Consistently, the loss of ATGL and HSL in BAT and WAT disrupts thermogenesis in both depots, resulting in blunted UCP1-dependent NST. Our study highlights the metabolic adaptability of adipose tissue and the critical role of intracellular lipolysis in regulating thermogenesis.

physiology↗

bioRxiv2024

ATGL-mediated lipolysis is essential for myocellular mitochondrial function and augments PPARδ-induced improvements in mitochondrial respiration

Defects in ATGL-mediated myocellular LD lipolysis results in mitochondrial dysfunction of unknown origin, which can be rescued by PPAR agonists. Here we examine whether ATGL-mediated lipolysis is required to maintain mitochondrial network connectivity and function. Moreover, we explored if the functional implications of ATGL deficiency for mitochondrial network dynamics and function can be alleviated by promoting PPAR and/or PPAR{delta} transcriptional activity. To this end, we cultured human primary myotubes from patients with neutral lipid storage disease with myopathy (NLSDM), a rare metabolic disorder caused by a mutation in the PNPLA2 gene. These myotubes possess dysfunctional ATGL and compromised LD lipolysis. In addition, mitochondria-LD contacts, mitochondrial network dynamics, and TMRM intensity were abrogated. Using a humanized ATGL inhibitor in myotubes cultured form healthy donors, revealed similar results. Upon stimulating PPAR{delta} transcriptional activity, mitochondrial respiration improved by more than 50% in human primary myotubes from healthy lean individuals. This increase in respiration was dampened in myotubes with dysfunctional ATGL. Stimulation of PPAR{delta} transcriptional activity had no effect on mitochondria-LD contacts, mitochondrial network dynamics, and TMRM intensity. Our results demonstrate that dysfunctional ATGL results in compromised mitochondrial-LD contacts and mitochondrial dynamics, and that functional ATGL is required to improve mitochondrial respiratory capacity upon stimulation of PPAR{delta} transcriptional activity.

physiology↗

bioRxiv2024

Computational metabolic modeling unveils gut microbiomes role in metabolic shifts during murine cancer cachexia

Cancer cachexia is a multifactorial syndrome characterized by involuntary weight loss, muscle wasting, systemic inflammation, and metabolic alterations, affecting up to 87% of pancreatic and gastric cancer patients. Unlike simple starvation, cachexia is driven by metabolic disruption involving both host physiology and the gut microbiome. While microbiome changes in cachexia have been documented, a coherent understanding of how these changes translate into functional metabolic shifts remains elusive. In this study, we combined in vivo fecal and plasma metabolomic analyses with a novel computational microbiome simulation pipeline to identify cachexia-associated microbial metabolites. Using the murine MCA207 tumor line and its cachectic derivative CHX207, we differentiated microbiome changes driven by cachexia from those induced by tumor growth. Our computational tool, McMurGut, a murine-tailored extension of MICOM, enabled simulation of microbial metabolic interactions specific to the mouse microbiome, covering 91% of identified genera. We identified significant abundance changes in 35 microbial genera and corresponding shifts in metabolite production, including reductions in short-chain fatty acids (SCFAs) like acetate and butyrate, alongside increased production of galactose, formate, and propionate. Notably, decreases in SCFA production, particularly by genera such as Faecalibaculum and Dubosiella, correlated with exacerbated cachectic symptoms. Additionally, the elevated production of formate and galactose, primarily by Bacteroides and Lactobacillus, suggested altered fermentation pathways in cachexia, potentially linked to increased mucus degradation. Validation of our computational predictions via NMR metabolomics highlighted key congruencies between predicted and experimentally observed metabolites, supporting the role of microbiome-driven metabolic shifts in cachexia pathology. These findings provide crucial insights into the microbiomes involvement in cachexia and suggest future avenues for therapeutic interventions aimed at modulating microbial taxa and their metabolic outputs to improve patient outcomes.

microbiology↗

bioRxiv2023

An accurate probabilistic step finder for time-series analysis

Noisy time-series data is commonly collected from sources including Forster Resonance Energy Transfer experiments, patch clamp and force spectroscopy setups, among many others. Two of the most common paradigms for the detection of discrete transitions in such time-series data include: hidden Markov models (HMMs) and step-finding algorithms. HMMs, including their extensions to infinite state-spaces, inherently assume in analysis that holding times in discrete states visited are geometrically-or, loosely speaking in common language, exponentially-distributed. Thus the determination of step locations, especially in sparse and noisy data, is biased by HMMs toward identifying steps resulting in geometric holding times. In contrast, existing step-finding algorithms, while free of this restraint, often rely on ad hoc metrics to penalize steps recovered in time traces (by using various information criteria) and otherwise rely on approximate greedy algorithms to identify putative global optima. Here, instead, we devise a robust and general probabilistic (Bayesian) step-finding tool that neither relies on ad hoc metrics to penalize step numbers nor assumes geometric holding times in each state. As the number of steps themselves in a time-series are, a priori unknown, we treat these within a Bayesian nonparametric (BNP) paradigm. We find that the method developed, Bayesian Nonparametric Step (BNP-Step), accurately determines the number and location of transitions between discrete states without any assumed kinetic model and learns the emission distribution characteristic of each state. In doing so, we verify that BNP-Step can analyze sparser data sets containing higher noise and more closely-spaced states than otherwise resolved by current state-of-the-art methods. What is more, BNP-Step rigorously propagates measurement uncertainty into uncertainty over state transition locations, numbers, and emission levels as characterized by the posterior. We demonstrate the performance of BNP-Step on both synthetic data as well as data drawn from force spectroscopy experiments. SIGNIFICANCEMany time-series data sets exist which are challenging to analyze with current state-of-the-art methods, either because they contain excessive noise or because they violate one or more assumptions inherent to the chosen analysis method. To our knowledge, BNP-Step is the first time-series analysis algorithm which leverages Bayesian nonparametrics to learn the number and location of transitions between states and the emission levels associated to each state, while providing rigorous estimates of uncertainty for the learned quantities. We anticipate our algorithm will allow analysis of data sets at levels of noise or sparsity beyond what current state-of-the-art methods allow, and could potentially reveal previously unknown features in data sets analyzed using existing methods.

biophysics↗

bioRxiv2020

Adipose Triglyceride Lipase is needed for homeostatic control of Sterol Element-Binding Protein-1c driven hepatic lipogenesis

Sterol Regulatory Element-Binding Protein-1c (SREBP-1c) is translated as an inactive precursor-protein that is proteolytically activated to promote fatty-acid (FA) biosynthesis, when unsaturated (u)FAs are scarce. During fasting, however, lipogenesis is low, and adipose-tissue lipolysis supplies the organism with FAs. Adipose TriGlyceride Lipase (ATGL) is the rate-limiting enzyme for lipolysis, and it preferentially hydrolyzes uFAs. Therefore, we hypothesized that ATGL-derived FAs may suppress the proteolytic activation of SREBP-1c in the liver. Here we show that (i) SREBP-1c is inactive during fasting but active after refeeding, (ii) uFA species liberated by ATGL suppress SREBP-1c activation in vitro, (iii) SREBP-1c is hyper-activated in livers of mice lacking ATGL, and (iv) pharmacological inhibition of ATGL selectively activates SREBP-1c in hepatocytes. Our findings highlight an ATGL/SREBP-1c axis, instrumental to coordinate lipogenesis and lipolysis, whose homeostatic regulation is crucial to avoid severe diseases including diabetes, cardiomyopathy, and even cancer.

biochemistry↗

bioRxiv2018

Genome-wide scan and fine-mapping of rare nonsynonymous associations implicates intracellular lipolysis genes in fat distribution and cardio-metabolic risk

Difficulties in identifying causal variants and genes underlying genetic associations have limited the translational potential of genetic studies of body fat distribution, an important, partly-heritable risk factor for cardio-metabolic disease. Rare variant associations facilitate fine-mapping of causal alleles, but their contribution to fat distribution is understudied. We performed a genome-wide scan of rare nonsynonymous variants for body mass index-adjusted waist-to-hip-ratio (BMI-adjusted WHR; a widely-used measure of fat distribution) in 450,562 European ancestry individuals, followed by systematic Bayesian fine-mapping at six genome-wide (p<5x10-08; main-analysis) and two subthreshold signals (significant at a Bonferroni-corrected p<1.3x10-06). We found strong statistical evidence of causal association for nonsynonymous alleles in CALCRL (p.L87P, pconditional=5.9x10-12; posterior-probability of association [PPA]=52%), PLIN1 (p.L90P, pconditional=5.5x10-13; PPA>99%), PDE3B (p.R783X, pconditional=6.2x10-15; PPA>99%), ACVR1C (p.I195T; pconditional=5.4x10-12; PPA>99%), and FGF1 (p.G21E, pconditional=1.6x10-07; PPA=98%). Alleles at the four likely-causal main-analysis genes affected fat distribution primarily via larger hip-rather than smaller waist-circumference and six of nine conditionally-independent WHR-lowering index-variants were associated with protection from cardiovascular or metabolic disease. All four genes are expressed in adipose tissue and have been linked with the regulation of intracellular lipolysis, which controls fat retention in mature cells. Targeted follow-up analyses of key intracellular-lipolysis genes revealed associations for a variant in the initiator of intracellular lipolysis PNPLA2 (p.N252K) with higher BMI-adjusted-WHR and higher cardio-metabolic risk. This study provides human genetic evidence of a link between intracellular lipolysis, fat-distribution and its cardio-metabolic complications in the general population.

genetics↗