Analysis of Functional Errors Produced by Long-Term Workload-Dependent BTI Degradation in Ultralow Power Processors

status: publishe

The Hepatic Glucocorticoid Receptor Is Crucial for Cortisol Homeostasis and Sepsis Survival in Humans and Male Mice

Sepsis is hallmarked by hypercortisolemia, a stress response essential for survival. This elevation in plasma cortisol is partially brought about by suppressed hepatic cortisol breakdown. We demonstrate that a controlled downregulation of the hepatic glucocorticoid receptor (hepatic GR) is crucial. In a mouse model of fluid-resuscitated, antibiotic-treated abdominal sepsis and in human intensive care unit patients, sepsis reduced hepatic GR expression and signaling but increased (free) plasma cortisol/corticosterone, explained by suppressed cortisol/corticosterone-binding proteins and A-ring reductases. However, further experimental inhibition of hepatic GR with short hairpin RNA (shRNA) in septic mice increased mortality fivefold. Acutely, this further hepatic GR suppression prevented the rise in total corticosterone but further reduced binding proteins, resulting in elevated free corticosterone. After 3 days of shRNA-GR inhibition in sepsis, both total and free corticosterone levels were elevated, now explained by an additional reduction in A-ring reductase expression. Hepatic GR inhibition blunted the hyperglycemic stress response without causing hypoglycemia but also markedly increased circulating and hepatic inflammation markers and caused liver destruction, the severity of which explained increased mortality. In human sepsis, glucocorticoid treatment further suppressed hepatic GR expression, which could directly predispose to worse outcomes. In conclusion, sepsis partially suppressed hepatic GR expression, which appeared crucial to upregulate free cortisol/corticosterone availability. However, further sustained hepatic GR suppression evoked lethal excessive liver and systemic inflammation, independent of systemic cortisol/corticosterone availability.status: publishe

Adipose tissue protects against sepsis-induced muscle weakness in mice: from lipolysis to ketones

BACKGROUND: ICU-acquired weakness is a debilitating consequence of prolonged critical illness that is associated with poor outcome. Recently, premorbid obesity has been shown to protect against such illness-induced muscle wasting and weakness. Here, we hypothesized that this protection was due to increased lipid and ketone availability. METHODS: In a centrally catheterized, fluid-resuscitated, antibiotic-treated mouse model of prolonged sepsis, we compared markers of lipolysis and fatty acid oxidation in lean and obese septic mice (n = 117). Next, we compared markers of muscle wasting and weakness in septic obese wild-type and adipose tissue-specific ATGL knockout (AAKO) mice (n = 73), in lean septic mice receiving either intravenous infusion of lipids or standard parenteral nutrition (PN) (n = 70), and in lean septic mice receiving standard PN supplemented with either the ketone body 3-hydroxybutyrate or isocaloric glucose (n = 49). RESULTS: Obese septic mice had more pronounced lipolysis (p ≤ 0.05), peripheral fatty acid oxidation (p ≤ 0.05), and ketogenesis (p ≤ 0.05) than lean mice. Blocking lipolysis in obese septic mice caused severely reduced muscle mass (32% loss vs. 15% in wild-type, p < 0.001) and specific maximal muscle force (59% loss vs. 0% in wild-type; p < 0.001). In contrast, intravenous infusion of lipids in lean septic mice maintained specific maximal muscle force up to healthy control levels (p = 0.6), whereas this was reduced with 28% in septic mice receiving standard PN (p = 0.006). Muscle mass was evenly reduced with 29% in both lean septic groups (p < 0.001). Lipid administration enhanced fatty acid oxidation (p ≤ 0.05) and ketogenesis (p < 0.001), but caused unfavorable liver steatosis (p = 0.01) and a deranged lipid profile (p ≤ 0.01). Supplementation of standard PN with 3-hydroxybutyrate also attenuated specific maximal muscle force up to healthy control levels (p = 0.1), but loss of muscle mass could not be prevented (25% loss in both septic groups; p < 0.001). Importantly, this intervention improved muscle regeneration markers (p ≤ 0.05) without the unfavorable side effects seen with lipid infusion. CONCLUSIONS: Obesity-induced muscle protection during sepsis is partly mediated by elevated mobilization and metabolism of endogenous fatty acids. Furthermore, increased availability of ketone bodies, either through ketogenesis or through parenteral infusion, appears to protect against sepsis-induced muscle weakness also in the lean.status: publishe