@article {70365,
	title = {Lipid mobilization establishes metabolic tolerance and prevents autonomic collapse in infection},
	journal = {bioRxiv},
	year = {2026},
	month = {2026 Apr 21},
	abstract = {<p>Survival during infection depends on both pathogen clearance and the ability to tolerate infection-induced physiological changes. Metabolic adaptations are a central component of this tolerance, but the mechanisms underlying these responses remain incompletely defined. Here, we identify white adipose tissue (WAT) lipolysis as a central regulator of metabolic tolerance to infection. In patients with sepsis, higher circulating non-esterified fatty acid (NEFA) levels were associated with reduced mortality. In mouse models of polymicrobial sepsis, infection induced robust adipose lipolysis and increased circulating NEFAs. Genetic ablation of adipose triglyceride lipase (ATGL) in adipose tissue impaired lipolysis, leading to hypothermia, bradycardia, and increased mortality without altering immune cell populations or pathogen burden, consistent with a defect in tolerance rather than resistance. Mechanistically, lipolysis-derived NEFAs, but not glycerol, were required for protection, as restoring circulating NEFAs rescued autonomic stability and survival in adipose tissue ATGL-deficient mice. Infection-induced lipolysis was redundantly regulated and did not depend on any single upstream signaling pathway. Both pharmacologic activation of lipolysis using a β3-adrenergic agonist and exogenous fatty acid supplementation increased circulating NEFAs, improved survival, and promoted tolerance in mice. Consistent with these findings, analysis of real-world electronic health record data demonstrated that septic patients receiving FDA-approved β3-adrenergic agonists had reduced mortality or hospice discharge in a propensity-matched cohort. Together, these results identify WAT lipolysis and circulating fatty acids as key mediators of tolerance to infection and support a therapeutic strategy based on repurposing clinically available β3-adrenergic agonists to improve outcomes in sepsis.</p>
},
	doi = {10.64898/2026.04.16.717052},
	url = {https://www.biorxiv.org/content/early/2026/04/21/2026.04.16.717052},
	author = {Sarkar, Ankita and Xie, Shangkui and Rizvi, Syed Muhammad Musa Ali and Gwatiringa, Tadiwanashe and Heston, Sophie and Piaker, Samuel and Alipanah-Lechner, Narges and YIN, JIANYI and Gautron, Laurent and Kamath, Soumya and Alex, Neethu and Shukla, Ashutosh and Jia, Lin and Shiao, Rani and Kemp, Lauren and Thomas, David G and Tatara, Alexander and Chen, Catherine and Basit, Mujeeb and Kong, Xiaofei and Nomellini, Vanessa and Ilanges, Anoj and Heaselgrave, Samuel and Elmquist, Joel and Stout-Delgado, Heather W and Schenck, Edward J. and Rogers, Angela J. and Calfee, Carolyn and Matthay, Michael and Rong, Shunxing and Horton, Jay D and Rajagopalan, Kartik and Patel, Suraj J}
}
