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.

Role of glucagon in protein catabolism.

PURPOSE OF REVIEW: Glucagon is known as a key hormone in the control of glucose and amino acid metabolism. Critical illness is hallmarked by a profound alteration in glucose and amino acid metabolism, accompanied by muscle wasting and hypoaminoacidemia. Here we review novel insights in glucagon (patho)physiology and discuss the recently discovered role of glucagon in controlling amino acid metabolism during critical illness. RECENT FINDINGS: The role of glucagon in glucose metabolism is much more complex than originally anticipated, and glucagon has shown to be a key player in amino acid metabolism. During critical illness, the contribution of glucagon in bringing about hyperglycemia appeared to be quite limited, whereas increased glucagon availability seems to contribute importantly to the typical hypoaminoacidemia via stimulating hepatic amino acid breakdown, without affecting muscle wasting. Providing amino acids further increases hepatic amino acid breakdown, mediated by a further increase in glucagon. SUMMARY: Glucagon plays a crucial role in amino acid metabolism during critical illness, with an apparent feedback loop between glucagon and circulating amino acids. Indeed, elevated glucagon may, to a large extent, be responsible for the hypoaminoacidemia in the critically ill and infusing amino acids increases glucagon-driven amino acid breakdown in the liver. These novel insights further question the rationale for amino acid administration during critical illness.

Amino acid supplements in critically ill patients.

Observational studies have associated a low amino acid intake with adverse outcome of critical illness. Although this finding could theoretically be explained by differences in feeding tolerance related to illness severity, guidelines have recommended to administer sufficient amounts of amino acids from early onwards in the disease course. Recently, however, several high quality randomized controlled trials have not shown benefit by early amino acid supplementation and some trials even found potential harm, thus questioning this recommendation. These negative results could be related to amino acid-induced suppression of autophagy, to the inability to suppress bulk catabolism by exogenous amino acids, or to the administration of an amino acid mixture with an inappropriate composition. Currently, there is no evidence supporting administration of individual amino acid supplements during critical illness and glutamine administration may be harmful. The optimal timing, dose and composition of the amino acid mixture for critically ill patients remain unclear.

The Role of Autophagy in Critical Illness-induced Liver Damage.

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress, which activates the unfolded protein response (UPR), mediate critical illness-induced organ failure, often affecting the liver. Autophagy is known to alleviate both and suppressed or insufficiently activated autophagy in prolonged illness has shown to associate with organ failure. Whether insufficient autophagy contributes to organ failure during critical illness by affecting these underlying mechanisms is incompletely understood. In this study, we investigated whether the inability to acutely activate hepatic autophagy during critical illness aggravates liver damage by increasing hepatic mitochondrial dysfunction and affecting the UPR. In a mouse model of critical illness, induced by surgery and sepsis, we investigated the impact of inactivating hepatic autophagy on markers of hepatic mitochondrial function, the UPR and liver damage in acute (1 day) and prolonged (3 days) critical illness. Hepatic autophagy inactivation during critical illness acutely worsened mitochondrial dysfunction and time-dependently modulated the hepatic UPR. Furthermore, autophagy inactivation aggravated markers of liver damage on both time points. In conclusion, the inability to acutely activate autophagy in liver during critical illness worsened hepatic mitochondrial damage and dysfunction, partially prohibited acute UPR activation and aggravated liver damage, indicating that autophagy is crucial in alleviating critical illness-induced organ failure.

Role of Glucagon in Catabolism and Muscle Wasting of Critical Illness and Modulation by Nutrition.

RATIONALE: Critical illness is hallmarked by muscle wasting and disturbances in glucose, lipid, and amino acid homeostasis. Circulating concentrations of glucagon, a catabolic hormone that affects these metabolic pathways, are elevated during critical illness. Insight in the nutritional regulation of glucagon and its metabolic role during critical illness is lacking. OBJECTIVES: To evaluate whether macronutrient infusion can suppress plasma glucagon during critical illness and study the role of illness-induced glucagon abundance in the disturbed glucose, lipid, and amino acid homeostasis and in muscle wasting during critical illness. METHODS: In human and mouse studies, we infused macronutrients and manipulated glucagon availability up and down to investigate its acute and chronic metabolic role during critical illness. MEASUREMENTS AND MAIN RESULTS: In critically ill patients, infusing glucose with insulin did not lower glucagon, whereas parenteral nutrition containing amino acids increased glucagon. In critically ill mice, infusion of amino acids increased glucagon and up-regulated markers of hepatic amino acid catabolism without affecting muscle wasting. Immunoneutralizing glucagon in critically ill mice only transiently affected glucose and lipid metabolism, did not affect muscle wasting, but drastically suppressed markers of hepatic amino acid catabolism and reversed the illness-induced hypoaminoacidemia. CONCLUSIONS: These data suggest that elevated glucagon availability during critical illness increases hepatic amino acid catabolism, explaining the illness-induced hypoaminoacidemia, without affecting muscle wasting and without a sustained impact on blood glucose. Furthermore, amino acid infusion likely results in a further breakdown of amino acids in the liver, mediated by increased glucagon, without preventing muscle wasting. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122).

Mitochondrial and endoplasmic reticulum dysfunction and related defense mechanisms in critical illness-induced multiple organ failure.

Patients with critical illness-induced multiple organ failure suffer from a very high morbidity and mortality, despite major progress in intensive care. The pathogenesis of this condition is complex and incompletely understood. Inadequate tissue perfusion and an overwhelming inflammatory response with pronounced cellular damage have been suggested to play an important role, but interventions targeting these disturbances largely failed to improve patient outcome. Hence, new therapeutic perspectives are urgently needed. Cellular dysfunction, hallmarked by mitochondrial dysfunction and endoplasmic reticulum stress, is increasingly recognized as an important contributor to the development of organ failure in critical illness. Several cellular defense mechanisms are normally activated when the cell is in distress, but may fail or respond insufficiently to critical illness. This insight may open new therapeutic options by stimulating these cellular defense mechanisms. This review summarizes the current understanding of the role of mitochondrial dysfunction and endoplasmic reticulum stress in critical illness-induced multiple organ failure and gives an overview of the corresponding cellular defense mechanisms. Therapeutic perspectives based on these cellular defense mechanisms are discussed. This article is part of a Special Issue entitled: Immune and Metabolic Alterations in Trauma and Sepsis edited by Dr. Raghavan Raju.

Premorbid obesity, but not nutrition, prevents critical illness-induced muscle wasting and weakness.

BACKGROUND: The 'obesity paradox' of critical illness refers to better survival with a higher body mass index. We hypothesized that fat mobilized from excess adipose tissue during critical illness provides energy more efficiently than exogenous macronutrients and could prevent lean tissue wasting. METHODS: In lean and premorbidly obese mice, the effect of 5 days of sepsis-induced critical illness on body weight and composition, muscle wasting, and weakness was assessed, each with fasting and parenteral feeding. Also, in lean and overweight/obese prolonged critically ill patients, markers of muscle wasting and weakness were compared. RESULTS: In mice, sepsis reduced body weight similarly in the lean and obese, but in the obese with more fat loss and less loss of muscle mass, better preservation of myofibre size and muscle force, and less loss of ectopic lipids, irrespective of administered feeding. These differences between lean and obese septic mice coincided with signs of more effective hepatic fatty acid and glycerol metabolism, and ketogenesis in the obese. Also in humans, better preservation of myofibre size and muscle strength was observed in overweight/obese compared with lean prolonged critically ill patients. CONCLUSIONS: During critical illness premorbid obesity, but not nutrition, optimized utilization of stored lipids and attenuated muscle wasting and weakness.

FGF21 Response to Critical Illness: Effect of Blood Glucose Control and Relation With Cellular Stress and Survival.

CONTEXT: Critical illness is hallmarked by mitochondrial damage, which is attenuated by targeting normoglycemia. Mitochondrial dysfunction induces fibroblast growth factor-21 (FGF21) via the integrated stress response (ISR). OBJECTIVE: We evaluated whether critical illness elevates serum FGF21 concentrations and whether targeting normoglycemia (80-110 mg/dL) with insulin vs tolerating hyperglycemia may lower serum FGF21 by attenuating mitochondrial dysfunction and the ISR. SETTING/DESIGN: We quantified serum FGF21 concentrations in critically ill patients. To allow tissue analyses, including hepatic fgf21 expression in relation with mitochondrial function and ISR markers, we studied critically ill rabbits. Patients and rabbits were randomized to hyper- or normoglycemia. Patients/Other Participants: We studied 405 fed critically ill patients vs 20 matched non-critically ill control subjects as well as 26 critically ill rabbits vs 13 healthy rabbits. INTERVENTIONS: Insulin was infused to control blood glucose. MAIN OUTCOME MEASURES AND RESULTS: Serum FGF21 concentrations upon intensive care unit admission were 8-fold higher than in control subjects (P < .0001), decreased with time, but always remained higher in nonsurvivors than survivors (P ≤ .006). Maintaining normoglycemia lowered serum FGF21 (P = .01), statistically explaining at least part of its mortality benefit. In ill rabbits, hepatic fgf21 expression was substantially increased (P < .0001) and was tightly correlated with mitochondrial dysfunction (all R(2) ≥ 0.49; all P ≤ .0006 for complex I and V) and ISR markers on day 3 (R(2) ≥ 0.73; P ≤ .0001), all lowered by targeting normoglycemia. CONCLUSION: Critical illness is a potent inducer of serum FGF21 and of liver fgf21 expression, possibly driven at least in part by mitochondrial damage and the ISR, which were all attenuated by targeting normoglycemia.