The Study On Insulin Ameliorating Sepsis-induced Hypercatabolism Via Hypothalamic IKKβ/NF-κB- POMC Pathway

Objective:Sepsis-induced muscle wasting was considered to be an important contributor to complications and mortality in critical patients. Previous work mainly focus on the peripheral molecular mechanism of muscle degradation, little evidence exist for the role of central nervous system in the lethal process.In the present study, we characterized the relationship between muscle wasting and central neuropeptide changes in a septic model.Methods:Thirty-six adult male Sprague-Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) or saline. Twelve,24 and 48 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 the release of 3-methl-histidine (3-MH) and tyrosine. Hypothalamic neuropeptides and inflammatory marker expression were also measured in 3 time points.Results:Sepsis group shown a reduction of body weight, muscle-body weight ratio. 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. Importantly, the expression of POMC, AgRP and NPY were well correlated with muscle atrophy gene, MuRF-1,expression.Conclusion:Endotoxin-induced muscle wasting is paralleled with neuropeptides change, with an increase of POMC and CART expression and reduced ARGP expression. The hypothalamic inflammation may be the mediator of central neuropeptide alteration.Objective:Acute skeletal muscle wasting is a key factor affecting nutritional support and prognosis in septic patients. Since Little was known about the central role, We tested the hypothesis whether central inflammatory pathway and neuropeptides were involved in the process.Methods:After intraperitoneal lipopolysaccharide (LPS) injection, third ventricle cannulated male rats received central infusion of NF-κB inhibitor (PS 1145)or vehicle. Twenty four hours later, the hypothalamus and skeletal muscle were harvested for the measurement of central neuropeptides and inflammation, and muscle wasting. In a second set of rats, the ARC of hypothalamus was injected with lentiviral vector containing shRNA against neuropeptide proopiomelanocortin (POMC), or vehicle. Two weeks later, they received intraperitoneal LPS or saline administration. At 24 hours after treatment, the hypothalamus and skeletal muscle were collected for measurement.Results:Ini LPS-treated rats, hypothalamic NF-κB pathway and inflammation were highly activated, which was accompanied with severe muscle wasting. Central inhibition of NF-κB pathway activation can efficiently reduce muscle wasting as well as attenuate hypothalamic neuropeptides alteration. Furthermore, knockdown the expression of anorexigenic neuropeptide POMC expression can significantly alleviate LPS-induced muscle wasting, whereas hypothalamic inflammation or NF-κB pathway was barely affected.Conclusion:Activation of hypothalamic NF-κB pathway was 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.Objective: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.Methods:Thirty-two adult male Sprague-Dawley rats were in intraperitoneally injected with lipopolysaccharide (LPS) (10mg/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 of 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 endotoxemia-induced muscle wasting and hypothalamic inflammation, and attenuated the alteration of neuropeptides, POMC, CART and NPY.Conclusion:Hypothalamic inflammation and neuropeptides are involved in the endotoxemia-induced muscle wasting. Insulin treatment can reduce muscle wasting, which is associated with reduced hypothalamic inflammation and alteration of hypothalamic neuropeptides.