Adipocyte lipolysis drives acute stress-induced insulin resistance

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.

Adipose‐specific ATGL ablation reduces burn injury‐induced metabolic derangements in mice

“…2,3 This increase in REE (>110% of predicted REE) perpetuates a catabolic state characterized by supraphysiological nutritional requirements, weight loss, muscle atrophy, and the breakdown of adipose depots. 1,4 Systemically, these changes culminate in organ dysfunction and failure, as demon-…”

Feeding desensitizes A1 adenosine receptors in adipose through FOXO1-mediated transcriptional regulation

“…Adenosine levels are known to rise during stress, and adenosine signaling provides numerous protective benefits during stress responses (16,23,28). Stress-induced adrenergic stimulation activates lipolysis within adipose tissue, and exposure to high levels of NEFA during stress is associated with insulin resistance and lipotoxicity (18,19). We hypothesized that adenosine provides a protective limit on lipolysis in adipose tissue and that the loss of adipose A1R would result in a stronger lipolytic response to adrenergic stimulation and higher serum NEFA levels.…”

“…In adipocytes, the degradation of adenosine with exogenous adenosine deaminase or inhibition with an A1R antagonist enhances the stimulation of lipolysis by adrenergic signals such as norepinephrine or the β-adrenergic receptor agonist isoproterenol (13–15,17). This suggests that A1R activation may serve as a protective response since high levels of NEFA resulting from stress-induced lipolysis can have deleterious effects such as insulin resistance and lipotoxicity (18,19). However, the effects of A1R signaling in adipocytes in response to endogenous adenosine and subsequent impacts to circulating NEFA during stress have not been investigated.…”

Diminished ketone interconversion, hepatic TCA cycle flux, and glucose production in D-β-hydroxybutyrate dehydrogenase hepatocyte-deficient mice

“…At 15 min post injection, both AcAc and D-βOHB injected mice exhibited sharp increases in circulating TKB with minimal change in vehicle-injected mice ( Figure 1 A). Vehicle-injected mice exhibited a minimal increase in TKB at 60 min that dissipated by 120 min (note graph inset, left panel of Figure 1 A), perhaps attributable to modest stress-induced lipolysis [ 28 ].

Figure 1 Effects of boluses of exogenous AcAc and D-βOHB on circulating ketones and liver redox.

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