Bezafibrate upregulates carnitine palmitoyltransferase II expression and promotes mitochondrial energy crisis dissipation in fibroblasts of patients with influenza-associated encephalopathy

Influenza-associated encephalopathy (IAE) is characterized by persistently high fever, febrile convulsions, severe brain edema and high mortality. We reported previously that a large proportion of patients with disabling or fatal IAE exhibit a thermolabile phenotype of compound variants for [1055T > G/F352C] and [1102G > A/V368I] of carnitine palmitoyltransferase II (CPT II) and mitochondrial energy crisis during high fever. In the present study, we studied the effect of bezafibrate, a hypolipidemic pan-agonist of peroxisome proliferator-activated receptor (PPAR), on CPT II expression and mitochondrial energy metabolism in fibroblasts of IAE patients and wild type (WT) fibroblasts from a healthy volunteer at 37 °C and 41 °C. Although heat stress markedly upregulated CPT II, CPT IA and PPAR-δ mRNA expression levels, CPT II activity, β-oxidation and ATP levels in WT and IAE fibroblasts at 41 °C were paradoxically downregulated probably due to the thermal instability of the corresponding enzymes. Bezafibrate significantly enhanced the expression levels of the above mRNAs and cellular functions of these enzymes in fibroblasts at 37 °C. Bezafibrate-induced increase in CPT II activity also tended to restore the downregulated ATP levels, though moderately, and improved mitochondrial membrane potential even at 41 °C to the levels at 37 °C in fibroblasts of IAE patients. L-carnitine, a substrate of CPT II, boosted the effects of bezafibrate on cellular ATP levels in WT and IAE fibroblasts, even in severe IAE fibroblasts with thermolabile compound variations of F352C + V368I at 37 °C and 41 °C. The results suggest the potential usefulness of bezafibrate for the treatment of IAE.     

Immunomodulatory actions of central ghrelin in diet-induced energy imbalance

We investigated the effects of centrally administered orexigenic hormone ghrelin on energy imbalance-induced inflammation. Rats were subjected for four weeks to three different dietary regimes: normal (standard food), high-fat (standard food with 30% lard) or food-restricted (70%, 50%, 40% and 40% of the expected food intake in 1st, 2nd, 3rd and 4th week, respectively). Compared to normal-weight controls, starved, but not obese rats had significantly higher levels of proinflammatory cytokines (TNF, IL-1β, IFN-γ) in the blood. When compared to normally fed animals, the hearts of starved and obese animals expressed higher levels of mRNAs encoding proinflammatory mediators (TNF, IL-1β, IL-6, IFN-γ, IL-17, IL-12, iNOS), while mRNA levels of the anti-inflammatory TGF-β remained unchanged. Intracerebroventricular (ICV) injection of ghrelin (1 μg/day) for five consecutive days significantly reduced TNF, IL-1β and IFN-γ levels in the blood of starved rats, as well as TNF, IL-17 and IL-12p40 mRNA expression in the hearts of obese rats. Conversely, ICV ghrelin increased the levels of IFN-γ, IL-17, IL-12p35 and IL-12p40 mRNA in the heart tissue of food-restricted animals. This was associated with an increase of immunosuppressive ACTH/corticosterone production in starved animals and a decrease of the immunostimulatory adipokine leptin both in food-restricted and high-fat groups. Ghrelin activated the energy sensor AMP-activated protein kinase (AMPK) in the hypothalamus and inhibited extracellular signal-regulated kinase (ERK) in the hearts of obese, but not starved rats. Therefore, central ghrelin may play a complex role in energy imbalance-induced inflammation by modulating HPA axis, leptin and AMPK/ERK signaling pathways.     

The lateral hypothalamus as integrator of metabolic and environmental needs: from electrical self-stimulation to opto-genetics

As one of the evolutionary oldest parts of the brain, the diencephalon evolved to harmonize changing environmental conditions with the internal state for survival of the individual and the species. The pioneering work of physiologists and psychologists around the middle of the last century clearly demonstrated that the hypothalamus is crucial for the display of motivated behaviors, culminating in the discovery of electrical self-stimulation behavior and providing the first neurological hint accounting for the concepts of reinforcement and reward. Here we review recent progress in understanding the role of the lateral hypothalamic area in the control of ingestive behavior and the regulation of energy balance. With its vast array of interoceptive and exteroceptive afferent inputs and its equally rich efferent connectivity, the lateral hypothalamic area is in an ideal position to integrate large amounts of information and orchestrate adaptive responses. Most important for energy homeostasis, it receives metabolic state information through both neural and humoral routes and can affect energy assimilation and energy expenditure through direct access to behavioral, autonomic, and endocrine effector pathways. The complex interplays of classical and peptide neurotransmitters such as orexin carrying out these integrative functions are just beginning to be understood. Exciting new techniques allowing selective stimulation or inhibition of specific neuronal phenotypes will greatly facilitate the functional mapping of both input and output pathways.     

Intensive exercise: a remedy for childhood obesity?

Background

Acute exercise can affect the energy intake regulation, which is of major interest in terms of obesity intervention and weight loss.

Objective

To test the hypothesis that intensive exercise can affect the subsequent energy intake and balance in obese adolescents.

Design

The study was conducted in 2009 and enrolled 12 obese pubertal adolescents ages 14.4 ± 1.5 years old. Two exercise and one sedentary sessions were completed. The first exercise (EX₁) and sedentary session (SED) were randomly conducted 1 week apart. The second exercise session (EX₂) was conducted following 6 weeks of diet modification and physical activity (3 × 90 min/week) to produce weight loss. Energy intake was recorded, subjective appetite sensation was evaluated using Visual Analogue Scales and energy expenditure was measured using ActiHerats during EX₁, EX₂ and SED.

Results

Total energy intake over the awakened period was significantly reduced by 31% and 18% during the EX₁ and EX₂ sessions compared with the SED session, respectively (p < 0.01). Energy balance over the awakened period was negative during EX₁, neutral during EX₂ and positive during SED. There was no significant difference in terms of subjective appetite rates between sessions during the awakened hours.

Conclusions

Intensive exercise favors a negative energy balance by dually affecting energy expenditure and energy intake without changes in appetite sensations, suggesting that adolescents are not at risk of food frustration.     

阻塞性睡眠呼吸暂停低通气综合征患者体脂分布及脂代谢的临床研究

目的运用双能X射线吸收法（DXA）测定阻塞性睡眠呼吸暂停低通气综合征（OSAHS）患者脂肪分布特点,探讨OSAHS与肥胖的关系。方法对49例肥胖者行多导睡眠监测（PSG）,根据呼吸暂停低通气指数（AHI）分为OSAHS组及非OSAHS组,分别测量体质量、身高、颈围、腰围、腹围、臀围,计算腰臀比（WHR）、体质量指数（BMr）;检测血脂;运用DXA测量腹部脂肪比、躯干脂肪比及全身脂肪比。结果两组间腰围、臀围、WHR、BMI、全身脂肪比、躯干脂肪比及腹部脂肪比均无差异（P〉0．05）,而OSAHS组颈围明显增大,差异有统计学意义（P〈0．01）。OSAHS患者血总胆固醇（TC）、三酰甘油（TG）增高,差异有统计学意义（P〈0．05）,高密度脂蛋白胆固醇（HDL—C）显著低于非OSAHS患者（P〈0．01）。OSAHS患者夜间平均血氧饱和度（MSa02）低于非OSAHS组,差异有统计学意义（P〈0．05、而最低血氧饱和度（LSa02）两组间无差异（P〉0．05）。结论OSAHS患者体内脂肪分布失衡,颈部脂肪堆积明显过多。OSAHS常合并脂代谢紊乱,且病情越重脂代谢紊乱更加明显。     

Alcohol mixed with energy drinks: Are there associated negative consequences beyond hazardous drinking in college students?

Objective

The consumption of alcohol mixed with energy drinks (AmED) is prevalent among college students as is hazardous drinking, a drinking pattern that places one at risk for alcohol-related harm. The present study, therefore, examined associations between AmED use, hazardous drinking, and alcohol-related consequences in college students.

Methods

Based on a probability sample conducted in 2010, participants were 606 undergraduate students aged 18–25. AmED consumption included lifetime and past year use. Hazardous drinking and alcohol-related consequences were measured during the past year. Point prevalence was used to estimate rates of AmED use, and chi-square, ANOVA, and logistic regression were used to examine associations between AmED use, hazardous drinking, and alcohol-related consequences.

Results

Lifetime and past year AmED use prevalence rates were 75.2% and 64.7%, respectively. Hazardous drinkers who engaged in AmED use were significantly more likely than past year hazardous drinkers who did not engage in AmED use to have had unprotected sex (OR = 2.35, CI 1.27–4.32).

Conclusions

AmED use appears to be highly prevalent among college students, and AmED use may confer additional risk for unprotected sex beyond hazardous drinking. Unprotected sex has implications for public health, and students who drink hazardously and consume AmED may be at greater risk.     

Measuring key parameters of intense pulsed light (IPL) devices

Background: Unlike medical lasers, intense pulsed light (IPL) devices are largely unregulated and unclassified as to degree of safety hazard. With the exception of most of the USA, the United Kingdom and parts of Europe, the Far East and Australia, the sale of IPLs is generally unrestricted, with the majority being sold into the beauty therapy and spa markets. Standards are only imposed on manufacturers for technical performance data and operating tolerances determined by CE‐compliance under electrical safety standards or the EU Medical Device Directive. Currently, there is no requirement for measurement of key IPL performance characteristics. Objective: To identify the key IPL parameters, emphasize their importance in terms of safe and effective treatment and provide examples of preliminary measurement methods. These measurements can highlight changes in an IPL device's performance, improving patient safety and treatment efficacy. Methods: Five key parameters were identified as having an important role to play in the way light interacts with the skin, and therefore an important role in patient safety and effective treatment. Simple methods were devised to measure the parameters, which include fluence, pulse duration, pulse profile, spectral output and time‐resolved spectral output. Results: The measurement methods permitted consistent and comparable measurements to be made by two of the authors at working clinic locations on 18 popular IPL devices and allowed assessment of output variations. Results showed discrepancies between the measured IPL device outputs and those values displayed on the system or claimed by the manufacturers. The importance of these discrepancies and their impact is discussed. Conclusions: This study, of 18 popular devices in regular daily use in England and Wales, provides example methods for measuring key IPL device parameters and highlights the need for regular measurement of at least those five key parameters measured in this study. These methods can help service technicians to check performance and eliminate device malfunction.     

Hypermetabolism in a triple-transgenic mouse model of Alzheimer's disease

A common feature of Alzheimer's disease (AD) is weight loss, even though there is often an increase in food intake in AD patients. The reasons for this weight loss are unknown, but may be due to increased energy expenditure (metabolic rate) or a reduction in energy intake. This was investigated in the present study, using a triple-transgenic (3xTgAD) mouse model of AD. Two-month-old 3xTgAD mice displayed greater food intake (17%) and body weight (34%) but no difference in metabolic rate, as compared with nontransgenic controls (non-Tg). At 12 months of age, 3xTgAD mice still consumed more food (30%), but their body weight was significantly lower (15%) than non-Tg controls. This reduction in body weight was accompanied by a significant rise in metabolic rate, indicated by greater oxygen consumption (24%) and carbon dioxide production (29%); the effects were also observed in 18-month-old 3xTgAD mice. These data demonstrate for the first time the existence of a hypermetabolic state in an experimental model of AD, but whether this can explain the weight loss observed in AD patients remains to be determined.     

Ultrastructural evidence of mitochondrial abnormalities in postresuscitation myocardial dysfunction

Objectives

Though there is evidence to implicate that the mitochondrion may play an important role in the development of postresuscitation myocardial dysfunction, limited data are available regarding the ultrastructural alterations of the mitochondria, mitochondrial energy-producing ability, and their relationship to postresuscitation myocardial dysfunction. This study was designed to determine whether mitochondrial abnormalities contribute to the development of postresuscitation myocardial dysfunction.

Methods

Fifteen anesthetized male Sprague-Dawley rats were randomized to: (1) global myocardial ischemia/reperfusion, in which 8 min of ventricular fibrillation was induced and successful defibrillation was achieved after 6 min of cardiopulmonary resuscitation (CPR); (2) global myocardial ischemia, in which ventricular fibrillation and CPR were performed without defibrillation attempt; and (3) sham control.

Results

Myocardial function was significantly impaired after resuscitation. Mitochondria were massively swollen in global ischemic hearts and mildly swollen in the resuscitated hearts. Concomitantly, ATP levels abruptly declined during global ischemia and partially recovered after resuscitation. Furthermore, mitochondrial abnormalities were supported by the incapability of utilizing energy substrates manifested by the accumulations of intramyocellular lipid droplets and glycogen deposits.

Conclusions

In this model of cardiac arrest and CPR, the presence of ultrastructural mitochondrial abnormalities, further evidenced by the incapability of utilizing energy substrates and impairment of energy-production, might, in part, contribute to the development of postresuscitation myocardial dysfunction.