Biology subjects

Persson, K. W.

Publications and source records attributed to Persson, K. W..

3 recordsLinked to original sources

bioRxiv2026

Decreased food intake contributes to elevated insulin-responsiveness in pre-clinical cancer cachexia

PurposeCancer cachexia is a life-threatening complication of advanced malignancies, driven by anorexia and profound systemic metabolic reprogramming. Insulin action in skeletal muscle is markedly impaired in patients with cancer and may contribute directly to cachexia pathogenesis. However, the interplay between reduced nutrient intake and cancer-associated metabolic rewiring in cachexia remains poorly defined. Clarifying this relationship is essential for identifying the fundamental drivers of cachexia and for developing effective therapeutic strategies. MethodsWe assessed metabolic rewiring by glucose tolerance test and isotopic tracers to determine muscle insulin-stimulated glucose uptake in male cachectic and non-cachectic C26- and KPC-tumor-bearing, as well as mice towards C26 cachectic mice. ResultsCachectic C26-tumor-bearing mice displayed reduced body weight, lean, and fat mass, and food intake (-20%, -15%, -75%, -40%, respectively). Cachectic C26- and KPC-tumor mice showed improved glucose tolerance compared to non-cachectic mice, correlating inversely with tumor size. Ex vivo insulin-stimulated glucose uptake was elevated in soleus (+78%) and extensor digitorum longus (+35%) muscle from cachectic C26-cancer mice compared to non-cachectic and control mice. This increase was associated with enhanced AKT signaling. This was phenocopied in pair-fed non-tumor-bearing mice to match the food intake of cachectic mice, where glucose tolerance, insulin-stimulated glucose uptake ex vivo, and AKT signaling were all enhanced by food restriction. ConclusionsOur findings suggest that enhanced skeletal muscle insulin responsiveness in cachectic tumor-bearing mice is due to anorexia-induced adaptations, highlighting AKT signaling as a key node connecting nutrient status to muscle glucose metabolism in cancer cachexia. HighlightsO_LIC26 and KPC cancer-induced weight loss (cachexia) increases glucose tolerance in mice C_LIO_LIInsulin responsiveness is increased in cachectic, but not in non-cachectic, tumor-bearing mice. C_LIO_LILowered food intake drives elevated muscle insulin responsiveness in cachectic mice C_LI

molecular biology↗

bioRxiv2025

The metabolic and molecular mechanisms underlying running-induced energy compensation

Exercise not only regulates energy expenditure but also appetite, yet the underpinnings remain unclear. We describe that increased energy intake is a defense against energy loss that depends on initial running distance and operates independently of diet and age. Running caused a rapid circadian-dependent fat remodeling leading to a decline in circulating leptin accompanied by the activation of hypothalamic neurons. We discovered that the activation of the {beta}3-adrenergic receptor drives running-induced fat loss and the lower leptin triggers energy compensation by upregulating Neuropeptide Y. Once energy compensation is achieved, running is associated with molecular changes in hypothalamic signaling related to appetite and functional adaptations, such as enhanced sensitivity to hunger and satiety signals and increased responsiveness to appetite suppression induced by -Melanocyte-Stimulating Hormone. The increased food intake persisted without fat rebound beyond running in both lean and obese young mice, uncovering a new homeostatic balance in young mice.

physiology↗

bioRxiv2022

Microtubule-mediated GLUT4 trafficking is disrupted in insulin resistant skeletal muscle

Microtubules serve as tracks for long-range intracellular trafficking of glucose transporter 4 (GLUT4), but the role of this process in skeletal muscle and insulin resistance is unclear. Here, we used fixed and live-cell imaging to study microtubule-based GLUT4 trafficking in human and mouse muscle fibers and L6 rat muscle cells. We found GLUT4 localized along and on the microtubules in mouse and human muscle fibers. Pharmacological microtubule disruption using Nocodazole (Noco) prevented long-range GLUT4 trafficking and depleted GLUT4-enriched structures at microtubule nucleation sites in a fully reversible manner. Using a perfused muscle-on-a-chip system to enable real-time glucose uptake measurements in isolated mouse skeletal muscle fibers, we observed that Noco maximally disrupted the microtubule network after 5 min without affecting insulin-stimulated glucose uptake. In contrast, a 2h Noco treatment markedly decreased insulin responsiveness of glucose uptake. Insulin resistance in mouse muscle fibers induced either in vitro by C2 ceramides or in vivo by diet-induced obesity, impaired microtubule-based GLUT4 trafficking. In L6 muscle cells, pharmacological activation of the microtubule motor protein kinesin-1 increased basal and insulin-stimulated GLUT4 translocation, whereas shRNA-mediated knockdown of the kinesin-1 protein encoding gene Kif5B reduced insulin-stimulated GLUT4 translocation. Thus, in adult skeletal muscle fibers, the microtubule network is essential for intramyocellular GLUT4 movement, likely functioning to maintain an insulin-responsive cell-surface recruitable GLUT4 pool via kinesin-1 mediated trafficking.

cell biology↗