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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.

SUBMITTER: Raje V

PROVIDER: S-EPMC7584576 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Adipocyte lipolysis drives acute stress-induced insulin resistance.

Raje Vidisha V Ahern Katelyn W KW Martinez Brittany A BA Howell Nancy L NL Oenarto Vici V Granade Mitchell E ME Kim Jae Woo JW Tundup Smanla S Bottermann Katharina K Gödecke Axel A Keller Susanna R SR Kadl Alexandra A Bland Michelle L ML Harris Thurl E TE

Scientific reports 20201023 1

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 ...[more]

PMID: 33097799

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Project description:BACKGROUND:CEACAM1 regulates insulin sensitivity by promoting insulin clearance. Accordingly, global C57BL/6J.Cc1-/- null mice display hyperinsulinemia due to impaired insulin clearance at 2?months of age, followed by insulin resistance, steatohepatitis, visceral obesity and leptin resistance at 6?months. The study aimed at investigating the primary role of hepatic CEACAM1 in insulin and lipid homeostasis independently of its metabolic effect in extra-hepatic tissues. METHODS:Liver-specific C57BL/6J.AlbCre+Cc1fl/fl mice were generated and their metabolic phenotype was characterized by comparison to that of their littermate controls at 2-9?months of age, using hyperinsulinemic-euglycemic clamp analysis and indirect calorimetry. The effect of hyperphagia on insulin resistance was assessed by pair-feeding experiments. RESULTS:Liver-specific AlbCre+Cc1fl/fl mutants exhibited impaired insulin clearance and hyperinsulinemia at 2?months, followed by hepatic insulin resistance (assessed by hyperinsulinemic-euglycemic clamp analysis) and steatohepatitis at ~ 7?months of age, at which point visceral obesity and hyperphagia developed, in parallel to hyperleptinemia and blunted hypothalamic STAT3 phosphorylation in response to an intraperitoneal injection of leptin. Hyperinsulinemia caused hypothalamic insulin resistance, followed by increased fatty acid synthase activity, which together with defective hypothalamic leptin signaling contributed to hyperphagia and reduced physical activity. Pair-feeding experiment showed that hyperphagia caused systemic insulin resistance, including blunted insulin signaling in white adipose tissue and lipolysis, at 8-9?months of age. CONCLUSION:AlbCre+Cc1fl/fl mutants provide an in vivo demonstration of the key role of impaired hepatic insulin clearance and hyperinsulinemia in the pathogenesis of secondary hepatic insulin resistance independently of lipolysis. They also reveal an important role for the liver-hypothalamic axis in the regulation of energy balance and subsequently, systemic insulin sensitivity.

Dataset Information

Adipocyte lipolysis drives acute stress-induced insulin resistance.

Publications

Adipocyte lipolysis drives acute stress-induced insulin resistance.

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