Obesity attenuates inflammation, protein catabolism, dyslipidaemia, and muscle weakness during sepsis, independent of leptin

Abstract

Background Muscle weakness is a frequently occurring complication of sepsis, associated with increased morbidity and mortality. Interestingly, obesity attenuates sepsis‐induced muscle wasting and weakness. As the adipokine leptin is strongly elevated in obesity and has been shown to affect muscle homeostasis in non‐septic conditions, we aimed to investigate whether leptin mediates the protective effect of obesity on sepsis‐induced muscle weakness. Methods In a mouse model of sepsis, we investigated the effects of genetic leptin inactivation in obese mice (leptin‐deficient obese mice vs. diet‐induced obese mice) and of leptin supplementation in lean mice (n = 110). We assessed impact on survival, body weight and composition, markers of muscle wasting and weakness, inflammation, and lipid metabolism. In human lean and overweight/obese intensive care unit (ICU) patients, we assessed markers of protein catabolism (n = 1388) and serum leptin (n = 150). Results Sepsis mortality was highest in leptin‐deficient obese mice (53% vs. 23% in diet‐induced obese mice and 37% in lean mice, P = 0.03). Irrespective of leptin, after 5 days of sepsis, lean mice lost double the amount of lean body mass than obese mice (P < 0.0005). Also, irrespective of leptin, obese mice maintained specific muscle force up to healthy levels (P = 0.3) whereas lean mice suffered from reduced specific muscle force (72% of healthy controls, P < 0.0002). As compared with lean septic mice, both obese septic groups had less muscle atrophy, liver amino acid catabolism, and inflammation with a 50% lower plasma TNFα increase (P < 0.005). Conversely, again mainly irrespective of leptin, obese mice lost double amount of fat mass than lean mice after 5 days of sepsis (P < 0.0001), showed signs of increased lipolysis and ketogenesis, and had higher plasma HDL and LDL lipoprotein concentrations (P ≤ 0.01 for all). Muscle fibre type composition was not altered during sepsis, but a higher atrophy sensitivity of type IIb fibres compared with IIa and IIx fibres was observed, independent of obesity or leptin. After 5 days of critical illness, serum leptin was higher (P < 0.0001) and the net waste of nitrogen (P = 0.006) and plasma urea‐to‐creatinine ratio (P < 0.0001) was lower in overweight/obese compared with lean ICU human patients. Conclusions Leptin did not mediate the protective effect of obesity against sepsis‐induced muscle wasting and weakness in mice. Instead, obesity—independent of leptin—attenuated inflammation, protein catabolism, and dyslipidaemia, pathways that may play a role in the observed muscle protection.

Visceral adiposity and systemic inflammation in the obesity paradox in patients with unresectable or metastatic melanoma undergoing immune checkpoint inhibitor therapy: a retrospective cohort study

“… 9 Although the mechanism underlying the inverse correlation between VFI and SII remains unclear, suppressive pathways that counteract the chronic inflammatory status during obesity-associated inflammation could be a possible explanation. 8 Vankrunkelsven et al 45 also reported that obesity attenuates inflammation during sepsis, with a 50% decrease in plasma tumor necrosis factor-α increase in leptin-deficient and diet-induced mice with obesity compared with that in lean mice. However, the possibility of reverse causation still exists, given that our results are based on observational studies and cannot determine the true causal relationships between VFI and SII.…”

Early urea-to-creatinine ratio to predict ICU-acquired weakness in critically ill patients with sepsis

“…An early elevated UCR helped predict the development of ICUAW in patients with sepsis. The pronounced muscle wasting that contributed to the weakness of myogenic origin in sepsis patients was explained by the catabolic state of critical illness, with decreased anabolic effector hormones and increased catabolic hormones [21,22] , as well as the mechanical unloading brought on by immobilization or denervation. This metabolic disorder led to an increase in protein catabolism and a decrease in anabolism [5] .…”

Novel nutritional strategies to prevent muscle wasting

“…Other studies have suggested similar longitudinal profiles of urea and creatinine suggesting this is an effect observed nonpolytrauma critically ill patients [48]. Subsequent recent studies have echoed the utility of urea:creatinine ratio as a marker of muscle wasting [49]. The UCR have been used in a secondary analysis of multicentre trial data of ICU patients to assess the impact of novel nutritional strategies such as intermittent versus continuous feeding [50].…”