Adipocyte lipolysis drives acute stress-induced insulin resistance

Vidisha Raje,Brittany A Martinez,Mitchell E Granade,Jae Woo Kim,Alexandra Kadl,Smanla Tundup,Susanna R Keller,Axel Gödecke,Michelle L Bland,Vici Oenarto,Nancy L Howell,Thurl E Harris,Katelyn W Ahern,Katharina Bottermann

doi:10.1038/s41598-020-75321-0

Vidisha Raje, Brittany A Martinez + Show 12 more

Open Access

https://doi.org/10.1038/s41598-020-75321-0

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Abstract

Stress hyperglycemia and insulin resistance are evolutionarily conserved metabolic adaptations to severe injury including major trauma, burns, or hemorrhagic shock (HS). In response to injury, the neuroendocrine system increases secretion of counterregulatory hormones that promote rapid mobilization of nutrient stores, impair insulin action, and ultimately cause hyperglycemia, a condition known to impair recovery from injury in the clinical setting. We investigated the contributions of adipocyte lipolysis to the metabolic response to acute stress. Both surgical injury with HS and counterregulatory hormone (epinephrine) infusion profoundly stimulated adipocyte lipolysis and simultaneously triggered insulin resistance and hyperglycemia. When lipolysis was inhibited, the stress-induced insulin resistance and hyperglycemia were largely abolished demonstrating an essential requirement for adipocyte lipolysis in promoting stress-induced insulin resistance. Interestingly, circulating non-esterified fatty acid levels did not increase with lipolysis or correlate with insulin resistance during acute stress. Instead, we show that impaired insulin sensitivity correlated with circulating levels of the adipokine resistin in a lipolysis-dependent manner. Our findings demonstrate the central importance of adipocyte lipolysis in the metabolic response to injury. This insight suggests new approaches to prevent insulin resistance and stress hyperglycemia in trauma and surgery patients and thereby improve outcomes.

Highlights

Stress hyperglycemia and insulin resistance are evolutionarily conserved metabolic adaptations to severe injury including major trauma, burns, or hemorrhagic shock (HS)
Understanding the early metabolic changes leading to insulin resistance and impaired glucose metabolism during severe trauma or surgical injury is key to finding better therapeutic approaches and improving outcomes
Both serum glycerol and non-esterified fatty acids (NEFA) were observed to increase in WT mice, but this increase was prevented by genetic deletion of adipocyte ATGL in FATA−/− mice (Supplementary Fig. S2b,c,g)

Summary

Introduction

Stress hyperglycemia and insulin resistance are evolutionarily conserved metabolic adaptations to severe injury including major trauma, burns, or hemorrhagic shock (HS). Our findings demonstrate the central importance of adipocyte lipolysis in the metabolic response to injury This insight suggests new approaches to prevent insulin resistance and stress hyperglycemia in trauma and surgery patients and thereby improve outcomes. While stress-induced mobilization of fuel is an evolutionary adaptation that was necessary to feed tissues in critical need, in the current clinical environment, stress hyperglycemia and insulin resistance are maladaptive. They are associated with adverse outcomes such as increased risk of infection, delayed wound healing, episodes of cardiovascular dysfunction, and increased mortality[3,4]. Our data suggests adipocyte lipolysis may be a possible therapeutic target for reducing the maladaptive acute stress response

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