Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine.

Brown adipose tissue (BAT) dissipates energy1,2 and promotes cardiometabolic health3. Loss of BAT during obesity and ageing is a principal hurdle for BAT-centred obesity therapies, but not much is known about BAT apoptosis. Here, untargeted metabolomics demonstrated that apoptotic brown adipocytes release a specific pattern of metabolites with purine metabolites being highly enriched. This apoptotic secretome enhances expression of the thermogenic programme in healthy adipocytes. This effect is mediated by the purine inosine that stimulates energy expenditure in brown adipocytes by the cyclic adenosine monophosphate-protein kinase A signalling pathway. Treatment of mice with inosine increased BAT-dependent energy expenditure and induced 'browning' of white adipose tissue. Mechanistically, the equilibrative nucleoside transporter 1 (ENT1, SLC29A1) regulates inosine levels in BAT: ENT1-deficiency increases extracellular inosine levels and consequently enhances thermogenic adipocyte differentiation. In mice, pharmacological inhibition of ENT1 as well as global and adipose-specific ablation enhanced BAT activity and counteracted diet-induced obesity, respectively. In human brown adipocytes, knockdown or blockade of ENT1 increased extracellular inosine, which enhanced thermogenic capacity. Conversely, high ENT1 levels correlated with lower expression of the thermogenic marker UCP1 in human adipose tissues. Finally, the Ile216Thr loss of function mutation in human ENT1 was associated with significantly lower body mass index and 59% lower odds of obesity for individuals carrying the Thr variant. Our data identify inosine as a metabolite released during apoptosis with a 'replace me' signalling function that regulates thermogenic fat and counteracts obesity.

Role of Micro-RNA for Pain After Surgery: Narrative Review of Animal and Human Studies.

One of the most prevalent symptoms after major surgery is pain. When postoperative pain treatment is unsatisfactory, it can lead to poor surgical recovery, decreased quality of life, and increased health care costs. Current analgesics, single or in combination, have limited efficacy due to low potency, limited duration of action, toxicities, and risk of addiction. The lack of nonaddictive strong analgesics along with the over prescription of opioids has led to an opioid epidemic in the United States. Therefore, there is an urgent need for the development of newer analgesics. Microribonucleic acids (miRNAs) are small noncoding RNA molecules that modulate protein synthesis in neurons and supporting cells (glia, leukocytes, and Schwann cells). The literature indicates that miRNA regulation is important in nociception. Here, we summarize the current evidence on the role of miRNAs on mechanisms involved in incisional, inflammatory, neuropathic, and cancer pain. We also discuss the role of modulating miRNA functions as potential therapeutic targets for analgesic use and opioid tolerance. Finally, we propose how the delivery of analog miRNAs (mimic-miRNAs or antago-miRNAs) could be introduced into clinical practice to provide analgesia in the perioperative period.

Assessment of a multimodal analgesia protocol to allow the implementation of enhanced recovery after cardiac surgery: Retrospective analysis of patient outcomes.

STUDY OBJECTIVE: To investigate the impact of utilizing a multimodal analgesia protocol to allow the implementation of Enhanced Recovery after Cardiac Surgery (ERACS) in patients requiring cardio-pulmonary bypass. DESIGN: Retrospective analysis of patients treated with the proposed ERACS bundle in comparison to matched controls. SETTING: Single-center study. PATIENTS: A total of 50 patients undergoing elective cardiac surgery limited to on pump coronary artery bypass graft. MEASUREMENTS: Perioperative outcomes of 25 patients that underwent ERACS protocol and 25 controls were measured. In-operating room (OR) extubation, total intubation time, total intra-OP fentanyl given, total post-OP morphine equivalent given, intensive care unit (ICU) length of stay (LOS), hospital LOS and post-OP complications were examined. MAIN RESULTS: The ERACS group and control group were equivalent with regards to age, gender, comorbidities, ASA classification and type of surgery. Mean cardiac bypass time and mean aortic clamp time were similar. Extubation in the OR was achieved for 12 patients in the ERACS group compared to 1 in the control group. Post-operative opioid consumption was lower in ERACS group (27.3 vs. 51.7 morphine equivalents, p = 0.006). Although ICU LOS and hospital LOS were shorter in the ERACS group, this did not reach significance. CONCLUSIONS: The ERACS group showed a significant decrease in opioid use and increased incidence of successful in OR extubation.