Inter-organ communication and metabolic regulators of adipose tissue and skeletal muscle

Inter-organ communication is essential for maintaining homeostasis, enabling different organ systems to coordinate and adapt to physiological demands. Disruptions in these communication networks can lead to metabolic dysfunction and disease. This thesis investigates the role of inter-organ communication in regulating metabolic processes, with a focus on adipose tissue and skeletal muscle. Additionally, we examine how specific signaling molecules-particularly those of the kynurenine pathway of tryptophan degradation-interact with these tissues to influence metabolic health and disease. We explore how these organs communicate in response to stressors and how this communication becomes disrupted in disease.

In Paper I, we investigate how changes in circulating kynurenine metabolites affect metabolism. We show that despite marked changes in circulating kynurenine metabolites, whole-body energy metabolism remains largely unaffected. Importantly, we highlight how the metabolic benefits of kynurenic acid depend on its intermittent increase in circulation, similar to transient exercise-induced signals that mediate improved metabolic health.

In Paper II, we identify the gene Zfp697/ZNF697 as a novel regulator of muscle regeneration, uncovering its crucial role in skeletal muscle recovery following injury.

In Paper III, we demonstrate that sensory neuron-derived alpha-calcitonin gene- related peptide (CGRPa) regulates key factors of adipose tissue, including adipogenesis, extracellular matrix remodeling, and adipocyte size distribution.

Together, these studies enhance our understanding of how inter-organ communication influences health and disease, offering exciting therapeutic opportunities for improving metabolic health.

List of scientific papers

I. Constitutive loss of kynurenine-3-monooxygenase changes circulating kynurenine metabolites without affecting systemic energy metabolism

Kyle D. Dumont, Paulo R. Jannig, Margareta Porsmyr-Palmertz, Jorge L. Ruas. Am J Physiol Endocrinol Metab. 2025 Feb 1;328(2):E274-E285. doi: 10.1152/ajpendo.00386.2024. Epub 2025 Jan 13. PMID: 39805032.
https://doi.org/10.1152/ajpendo.00386.2024

II. Zfp697 is an RNA-binding protein that regulates skeletal muscle inflammation and remodeling

Jorge C. Correia, Paulo R. Jannig, Maya L. Gosztyla, Igor Cervenka, Serge Ducommun, Stine M. Præstholm, José M. Dias, Kyle D. Dumont, Zhengye Liu, Qishan Liang, Daniel Edsgärd, Olof Emanuelsson, Paul Gregorevic, Håkan Westerblad, Tomas Venckunas, Marius Brazaitis, Sigitas Kamandulis, Johanna T. Lanner, Ana I. Teixeira, Gene W. Yeo, Jorge L. Ruas. Proc. Natl. Acad. Sci. U.S.A. 2024 Aug 20;121(34):e2319724121.
https://doi.org/10.1073/pnas.2319724121

III. Sensory neuron-derived a-calcitonin gene-related peptide controls adipogenesis Kyle D. Dumont, Saba Heydari Seradj, Yu Wang, Igor Cervenka, Paulo R. Jannig, Margareta Porsmyr-Palmertz, Carina Nihlen, José M. Dias, Simona S. Skiotyte, Shanshan Liu, Jon O Lundberg, Ana I. Teixeira, Jun Wu, Li Ye, Jorge L. Ruas. [Submitted]