Metabolic trade‐off and adipose tissue role in Neonatal Sepsis
Authors: Alves Michele J. , Torres Juliet J. , de Araujo Fernandes Silvio , Dias Ana , Fadda Paolo , Baer Lisa , Stanford Kristin , Czeisler Catherine , Otero Jose 
Published: May 2022

Background

Neonatal sepsis contributes substantially to neonatal morbidity and mortality. The activation of an inflammatory response by the host triggers a significant metabolic challenge in which mobilization of stored energy is redistributed. Metabolic costs of immunity are high and physiological trade‐offs that neonates suffering from sepsis undergoes can determine the disease tolerance. Adipose tissue (AT) is a highly dynamic endocrine organ that partakes inter‐organs communication and regulates metabolism. In this study, we investigated whether immunity activation due to distinct TLRs ligands in neonatal sepsis promoted an energetic trade‐off and if the AT depots promoted tissue tolerance.

Methods

Postnatal day 5 (PD5) CD1 mice were I.P. treated either with saline (Control), LPS, or Pam3CSK4 (PAM). Body weight and temperature were accessed prior treatments and after 3 hours. Oxygen and CO2 consumption was assessed through Comprehensive Lab Animal Monitoring System (CLAMS). Following euthanasia, blood was collected and subcutaneous white AT (WAT) and brown AT (BAT) depots were dissected out and submitted to microarray analysis utilizing Clariom™ S Assay mouse and the Affymetrix GeneChip Mouse Gene ST 2.0 arrays. Blood glucose was assessed using a glucometer.

Results

The activation of inflammation promoted either by LPS or PAM resulted in significantly reduced total body weight due to the treatment only after 3 hours. We asked if this effect was due to the growth or nutritional status, we found the control pups kept with the mom increased body weight, whereas the pups fasting did not, as expected. However, these changes were not observed in the TLR4 and TLR1/2 ligands treated pups, in which, the bodyweight was decreased independently of them being fasted or not. The cutaneous temperature remained similar in the control group, while LPS induced a loss of ‐1.5°C degrees post‐treatment, and only ‐0.5°C variation was observed in the PAM treated pups. A reduction in VO2 and VCO2 consumption was stronger in LPS than in PAM treated pups, in which they started to increase these levels after 90 minutes, indicating that TLR4 induced energy conservation also in neonates. LPS and PAM induced diminished blood glucose levels compared to control in fasting pups, and only in LPS in fed pups. Next, we evaluated the contribution of AT to lower metabolic rate and promote energy conservation. Microarray analysis showed LPS induced a total of 103 up‐regulated genes, and 238 due to PAM in BAT. Enrichment analysis of this depot was related to Collagen‐containing extracellular matrix, and Inflammatory response in LPS treated pups, while mRNA metabolic process was highlighted in pups treated with PAM. Moreover, in the WAT, LPS promoted enrichment of inflammatory responses along with lipid storage, fatty acid‐binding and lipid metabolism, whereas PAM induced several pathways related to lipid storage, catabolism, and temperature homeostasis.

Conclusions

Collectively, these data highlight the physiological trade‐offs occurring between immunity and energy suggesting that the hypometabolic‐hypothermic state is inducing energy conservation. AT depots are promoting fatty acid oxidation and perhaps mediating this energetic trade‐off. Thus, these physiological outcomes demonstrate the importance of AT regulation over the course of neonatal sepsis.