A Comparison of Gastric and Jejunal Feeding in Hypercatabolism Associated With Hypothalamic AMPK-Autophagy-POMC in Endotoxemic Rats.

BACKGROUND: Hypercatabolism is associated with increased infectious rates and mortality in critically ill patients. Enteral nutrition (EN) is usually used to counteract hypercatabolism. However, the impact of different routes of EN on hypercatabolism remains unknown. Here, we compared the impact of gastric feeding (GF) and jejunal feeding (JF) on gastrointestinal hormones and hypercatabolism, which is associated with hypothalamic adenosine 5'-monophosphate-activated protein kinase (AMPK)-autophagy-proopiomelanocortin (POMC). METHODS: Sixty adult male Sprague-Dawley rats were divided into 5 groups: Sham and lipopolysaccharide (LPS) groups fed a standard chow diet, a pair-fed group that was a subset of saline-treated rats pair-fed with the LPS group, and LPS + JF and LPS + GF groups (received EN via jejunal and gastric tube, respectively, for 3 days [100 kcal/kg/d]). Hypercatabolism was measured by insulin resistance, muscle protein synthesis, and atrophy. Serum gastrointestinal hormones, hypothalamic ghrelin, growth hormone secretagogue receptor-1α (GHS-R1α), and AMPK-autophagy-POMC markers were also detected. RESULTS: GF increased serum total, acylated, desacylated, and hypothalamic ghrelin and decreased glucagon-like peptide-1 (GLP-1). But no effect on pancreatic polypeptide (PYY) and hypothalamic GHS-R1α was observed. JF showed no effect on hypothalamic ghrelin, GHS-R1α, and serum total, acylated, and desacylated ghrelin and even further aggravated GLP-1 and PYY. GF could effectively augment hypothalamic AMPK-autophagy-POMC and hypercatabolism. However, JF showed no effect on hypothalamic AMPK-autophagy-POMC and hypercatabolism. CONCLUSIONS: GF could activate hypothalamic AMPK-autophagy and suppress POMC expression via gastrointestinal hormones to ameliorate hypercatabolism compared with JF, which suggested that GF may be the preferred route of EN in endotoxemic rats.

Hypothalamic AMPK-induced autophagy ameliorates hypercatabolism in septic rats by regulating POMC expression.

Hypercatabolism plays a critical role in the pathogenesis of post-critical care debility in critical patients. Central nervous system may exerte a critical role in the regulation of hypercatabolism. However, little is known about the exact mechanisms of the central role. Here, we reported that actived hypothalamic AMP-activated protein kinase (AMPK)-induced autophagy modulated the expression of POMC to ameliorate hypercatabolism in septic rats. Firstly, rats were i.c.v. injected with the lentiviral vector containing shRNA against POMC. Two weeks after injections, rats were intraperitoneally injected with LPS or saline. Twenty-four hours later, blood, skeletal muscle and hypothalamus tissues were obtained. Hypercatabolism markers and neuropeptides expression were detected. Then, rats were injected with AICAR or saline into third ventricle and promptly intraperitoneally injected with LPS or saline. Twenty-four hours after infection, blood, skeletal muscle and hypothalamus tissues were obtained. Hypercatabolism, hypothalamic AMPK-induced autophagy markers and neuropeptides expression were also detected. Results showed that sepsis would decrease the level of hypothalamic autophagy accompany with the alterations of POMC expression and hypercatabolism. Knocking out hypothalamus POMC expression could significantly ameliorate hypercatabolism. Moreover, Central activation of AMPK-induced autophagy pathway via third ventricle injection of AICAR, an AMPK activator, could efficiently ameliorate hypercatabolism as well as attenuate the elevated POMC expression rather than other neuropeptides. Taken together, these results suggested that hypothalamic AMPK-autophagy pathway as a regulatory pathway for POMC expression was essential for hypercatabolism during sepsis. And hypothalamic AMPK-autophagy activation could attenuate the POMC expression to ameliorate hypercatabolism. Pharmaceuticals with the ability of activating hypothalamic AMPK-autophagy pathway may be a therapeutic potential for hypercatabolism in septic patients.

Efficacy and safety of pectin-supplemented enteral nutrition in intensive care: a randomized controlled trial.

BACKGROUND AND OBJECTIVES: Enteral nutrition (EN) can improve clinical outcomes as an important treatment in critically ill patients. However, when patients suffer from gastrointestinal function disorders, intestinal intolerance occurs and EN administration may be delayed and even fails to perform. Pectin, a structural heteropolysaccharide, could protect gastrointestinal function from disorders in many gastrointestianl diseases. The present study aimed to determine whether pectin-supplemented EN was safe and improved clinical outcomes in intensive care unit (ICU) patients. METHODS AND STUDY DESIGN: Patients enrolled in ICU from August 2014 to January 2015 were randomized to EN group and pectin-supplemented EN group (PEC/EN group). Both group received isonitrogenous, isocaloric EN support within 36 hours after ICU admission, and last for 6 days. The primary endpoints were 30-day mortality and gastrointestinal intolerance. RESULTS: There were 125 patients included in this study (63 in EN group, and 62 in PEC/EN group). The results showed that the 30-day mortality was 4.8% in EN group and 1.61% in PEC/EN group (p=0.317). PEC/EN group had a smaller gastrointestinal intolerance rate than EN group (41.3% vs 27.4%, p=0.04). Furthermore, there were shorter times to reach full EN (13.0±5.12 vs 9.99±1.91, p=0.05), length of ICU stay (17.9±9.72 vs 13.8±8.59, p<0.001), and length of hospital stay (32.9±19.0 vs 23.4±13.2, p<0.001) in EN group than those in PEC/EN group. CONCLUSIONS: These results revealed that pectin- supplemented EN was safe, and could improve clinical outcomes in ICU patients.

Mild hypothermia ameliorates muscle wasting in septic rats associated with hypothalamic AMPK-induced autophagy and neuropeptides.

Sepsis, always developing muscle wasting, contributes to serious complications and mortality. Mild hypothermia has been reported to have protective effects on the prognosis of septic patients. However, the underlying mechanisms remain unclear. We therefore hypothesized that mild hypothermia could ameliorate muscle wasting during sepsis and whether it was associated with hypothalamus AMPK-induced autophagy and neuropeptides. Adult male Sprague-Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) (5 mg/kg) or saline. Mild hypothermia was instantly induced at 33 °C for 3h after LPS injected. Meanwhile, the control and sepsis groups were simultaneously placed on the thermal mattress to maintain the a normal temperature in control group whatever the changes induced by anesthesia. Twenty-four hours after injection, skeletal muscle and hypothalamus tissues were obtained. Muscle wasting was measured by the mRNA expression of two muscle atrophic genes, muscle ring finger 1 (MuRF-1) and muscle atrophy F-box (MAFbx), as well as 3-methylhistidine (3-MH) and tyrosine release. Hypothalamic AMPK-induced autophagy markers and neuropeptides expression were also detected. Results showed that LPS administration significantly decreased hypothalamic AMPK-induced autophagy together with muscle wasting. Also, increased hypothalamic neuropeptides, proopiomelanocortin (POMC), cocaine and amphetamine-related transcript (CART) and neuro-peptides Y (NPY) and decreased agouti-related protein (AgRP) were observed. Mild hypothermia significantly increased hypothalamic AMPK-induced autophagy and ameliorated LPS-induced muscle wasting, and attenuated the alteration of neuropeptides, POMC, CART and NPY. In conclusion, mild hypothermia could alleviate muscle wasting by LPS injection, which was associated with reversing the level of hypothalamic AMPK-induced autophagy and the alteration of neuropeptides. These results suggested that mild hypothermia could be a potential treatment concept and a novel mechanism in management of muscle wasting in critically ill patients.

Dexmedetomidine ameliorates muscle wasting and attenuates the alteration of hypothalamic neuropeptides and inflammation in endotoxemic rats.

Dexmedetomidine is generally used for sedaton in critically ill, it could shorten duration of mechanical ventilation, ICU stay and lower basic metabolism. However, the exact mechanism of these positive effects remains unkown. Here we investigated the hypothesis that dexmedetomidine could ameliorate muscle wasting in endotoxemic rats and whether it was related to hypothalamic neuropeptides alteration and inflammation. Fourty-eight adult male Sprague-Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) (5 mg/kg) or saline, followed by 50 µg/kg dexmedetomidine or saline administration via the femoral vein catheter (infusion at 5 µg·kg-1·hr-1). Twenty-four hours after injection, hypothalamus tissues and skeletal muscle were obtained. Muscle wasting was measured by the mRNA expression of two E3 ubiquitin ligases, muscle atrophy F-box (MAFbx) and muscle ring finger 1 (MuRF-1) as well as 3-methylhistidine (3-MH) and tyrosine release. Hypothalamic inflammatory markers and neuropeptides expression were also detected in all four groups. Results showed that LPS administration led to significant increase in hypothalamic inflammation together with muscle wasting. Increased hypothalamic neuropeptides, proopiomelanocortin (POMC), cocaine and amphetamine-related transcript (CART) and neuropeptides Y (NPY) and decreased agouti-related protein (AgRP) were also observed. Meanwhile dexmedetomidine administration ameliorated muscle wasting, hypothalamic inflammation and modulated the alteration of neuropeptides, POMC, CART and AgRP, in endotoxemic rats. In conclusion, dexmedetomidine could alleviate muscle wasting in endotoxemic rats, and it could also attenuate the alteration of hypothalamic neuropeptides and reduce hypothalamic inflammation.

Estrogen Maintains Skeletal Muscle in Septic Rats Associated with Altering Hypothalamic Inflammation and Neuropeptides.

Muscle wasting is one of the main contributors to the worse outcomes in sepsis. Whether estrogen could alleviate muscle wasting induced by sepsis remains unclear. This study was designed to test the effect of estrogen on muscle wasting and its relationship with central alteration in sepsis. Thirty Sprague-Dawley rats were divided into 3 groups: control group, sepsis group, and estrogen treated sepsis group. Animals were intraperitoneally injected with lipopolysaccharide (10 mg/kg) or saline, followed by subcutaneous injection of 17ß-estradiol (1 mg/kg) or saline. Twenty-four hours later, all animals were killed and their hypothalamus and skeletal muscles were harvested for analysis. Muscle wasting markers, hypothalamic neuropeptides, and hypothalamic inflammatory markers were measured. As a result, lipopolysaccharide administration caused a significant increase in muscle wasting, hypothalamic inflammation, and anorexigenic neuropeptides (POMC and CART) gene expression, and a significant decrease in orexigenic neuropeptides (AgRP and NPY) gene expression. Administration of estrogen signifcantl attenuated lipopolysaccharide-induced muscle wasting (body weight and extensor digitorum longus loss [52 and 62 %], tyrosine and 3-methylhistidine release [17 and 22 %], muscle ring fnger 1 [MuRF-1; 65 %], and muscle atrophy F-box [MAFbx] gene expression), hypothalamic inflammation (Tumor necrosis factor-α and interlukin-1ß [69 and 70%]) as well as alteration of POMC, CART and AgRP (61, 37, and 1008 %) expression.In conclusion, estrogen could alleviate sepsis-induced muscle wasting and it was associated with reducing hypothalamic inflammation and alteration of hypothalamic neuropeptides.

Hypothalamic activation is essential for endotoxemia-induced acute muscle wasting.

Growing evidence suggests acute skeletal muscle wasting is a key factor affecting nutritional support and prognosis in critical patients. Previously, plenty of studies of muscle wasting focused on the peripheral pathway, little was known about the central role. We tested the hypothesis whether central inflammatory pathway and neuropeptides were involved in the process. In lipopolysaccharide (LPS) treated rats, hypothalamic NF-κB pathway and inflammation were highly activated, which was accompanied with severe muscle wasting. Central inhibition of nuclear factor kappa-B (NF-κB) pathway activation by infusion of an inhibitor (PS1145) can efficiently reduce muscle wasting as well as attenuate hypothalamic neuropeptides alteration. Furthermore, knockdown the expression of anorexigenic neuropeptide proopiomelanocortin (POMC) expression with a lentiviral vector containing shRNA can significantly alleviate LPS-induced muscle wasting, whereas hypothalamic inflammation or NF-κB pathway was barely affected. Taken together, these results suggest activation of hypothalamic POMC is pivotal for acute muscle wasting caused by endotoxemia. Neuropeptide POMC expression may have mediated the contribution of hypothalamic inflammation to peripheral muscle wasting. Pharmaceuticals with the ability of inhibiting hypothalamic NF-κB pathway or POMC activation may have a therapeutic potential for acute muscle wasting and nutritional therapy in septic patients.

Insulin ameliorating endotoxaemia-induced muscle wasting is associated with the alteration of hypothalamic neuropeptides and inflammation in rats.

OBJECTIVES: Septic patients always develop muscle wasting, which delays the rehabilitation and contributes to the increased complications and mortality. Previous studies have implied the crucial role of central inflammation and neuropeptides in the energy balance and muscle metabolism. Insulin has been confirmed to attenuate muscle degradation and inhibit inflammation. We tested the hypothesis whether insulin ameliorating muscle wasting was associated with modulating hypothalamic inflammation and neuropeptides. DESIGN AND SUBJECTS: Thirty-two adult male Sprague-Dawley rats were in intraperitoneally injected with lipopolysaccharide (LPS) (5 mg/kg) or saline, followed by subcutaneous injection of insulin (5 IU/kg) or saline. Twenty-four hours after injection, skeletal muscle and hypothalamus tissues were harvested. Muscle wasting was measured by the mRNA expression of two E3 ubiquitin ligases, muscle ring finger 1 (MuRF-1) and muscle atrophy F-box (MAFbx), as well as 3-methylhistidine (3-MH) and tyrosine release. Hypothalamic inflammatory markers and neuropeptides expression were also measured in four groups. RESULTS: LPS injection led to significant increase in hypothalamic inflammation as well as muscle wasting. Also, increased hypothalamic neuropeptides, proopiomelanocortin (POMC), cocaine and amphetamine-related transcript (CART) and neuropeptides Y (NPY) and decreased agouti-related protein (AgRP) were observed. Insulin treatment ameliorated endotoxaemia-induced muscle wasting and hypothalamic inflammation, and attenuated the alteration of neuropeptides, POMC, CART and AgRP. CONCLUSION: Hypothalamic inflammation and neuropeptides are involved in the endotoxaemia-induced muscle wasting. Insulin treatment can reduce muscle wasting, which is associated with reduced hypothalamic inflammation and alteration of hypothalamic neuropeptides.

Endotoxemia-induced muscle wasting is associated with the change of hypothalamic neuropeptides in rats.

In critical patients, sepsis-induced muscle wasting is considered to be an important contributor to complications and mortality. Previous work mainly focuses on the peripheral molecular mechanism of muscle degradation, however little evidence exists for the role of central nervous system in the process. In the present study, we, for the first time, characterized the relationship between muscle wasting and central neuropeptide changes in a septic model. Thirty-six adult male Sprague-Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) or saline. Twelve, 24 and 48 hrs after injection, skeletal muscle and hypothalamus tissues were harvested. Muscle wasting was measured by the mRNA expression of two E3 ubiquitin ligases, muscle ring finger 1 (MuRF-1) and muscle atrophy F-box (MAFbx), as well as 3-methyl-histidine (3-MH) and tyrosine release. Hypothalamic neuropeptides and inflammatory marker expressions were also measured in three time points. LPS injection caused an increase expression of MuRF-1 and MAFbx, and a significant higher release of 3-MH and tyrosine. Hypothalamic neuropeptides, proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), agouti-related protein (AgRP) and neuropeptide Y (NPY) presented a dynamic change after LPS injection. Also, hypothalamic inflammatory markers, interleukin-1 ß (IL-1ß) and tumor necrosis factor α (TNF-α) increased substantially after LPS administration. Importantly, the expressions of POMC, AgRP and CART were well correlated with muscle atrophy gene, MuRF-1 expression. These findings suggest hypothalamic peptides and inflammation may participate in the sepsis-induced muscle wasting, but the exact mechanism needs further study.