Hypothalamic AMP-activated protein kinase (AMPK) is a canonical regulator of energy balance and metabolism at the whole-body level. This makes this enzyme an attractive target for treating energy ...balance-related diseases. However, targeting AMPK within the hypothalamus presents a challenge related to the specific cellular biodistribution of the enzyme and the need to use clinically safe methods of administration. Current evidence has shown that targeting based on small extracellular vesicles (sEVs) might offer a realistic approach for regulating hypothalamic AMPK. This would allow modulation of both sides of the energy-balance equation, namely food intake and energy expenditure, and therefore of overall metabolism. Moreover, this strategy could provide treatment options not only for obesity but also for catabolic/wasting diseases such as hyperthyroidism, rheumatoid arthritis, and even cancer cachexia.
Hypothalamic AMP-activated protein kinase (AMPK) is a canonical regulator of energy balance that regulates food intake (both homeostatic and hedonic), brown adipose tissue thermogenesis, and peripheral glucose and lipid metabolism.Genetic evidence, using conditional mouse models and virogenetic approaches, shows that nucleus- and/or neuron-specific targeting of hypothalamic AMPK can be a useful strategy for targeting both positive (e.g., obesity) and negative (e.g., hyperthyroidism and rheumatoid arthritis) energy balance-related diseases.Targeting hypothalamic AMPK faces three major challenges: (i) cell-specificity, (ii) the need to cross the blood–brain barrier, and (iii) delivery via a clinically safe mode of administration.Targeting hypothalamic AMPK in steroidogenic factor 1 (SF1) neurons with small extracellular vesicles (sEVs) is an effective strategy for treating obesity in preclinical rodent models.
Hypothalamic AMPK and energy balance López, Miguel
European journal of clinical investigation,
September 2018, Letnik:
48, Številka:
9
Journal Article
Recenzirano
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AMP‐activated protein kinase (AMPK) is the main cellular energy sensor. Activated following a depletion of cellular energy stores, AMPK will restore the energy homoeostasis by increasing energy ...production and limiting energy waste. At a central level, the AMPK pathway will integrate peripheral signals (mostly hormones and metabolites) through neuronal networks. Hypothalamic AMPK is directly implicated in feeding behaviour, brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT). It also participates in other metabolic functions: glucose and muscle metabolisms, as well as hepatic function. Numerous anti‐obesity and/or antidiabetic agents, such as nicotine, metformin and liraglutide, are known to induce their effects through a modulation of AMPK pathway, either at central or at peripheral levels. Moreover, the weight‐gaining side effects of antipsychotic drugs, such as olanzapine, are also mediated by hypothalamic AMPK. Therefore, considering hypothalamic AMPK as a therapeutic target in metabolic diseases appears as an interesting strategy due to its implication in feeding and energy expenditure, the two sides of the energy balance equation.
Obesity, a major risk factor for the development of diabetes mellitus, cardiovascular diseases and certain types of cancer, arises from a chronic positive energy balance that is often due to ...unlimited access to food and an increasingly sedentary lifestyle on the background of a genetic and epigenetic vulnerability. Our understanding of the humoral and neuronal systems that mediate the control of energy homeostasis has improved dramatically in the past few decades. However, our ability to develop effective strategies to slow the current epidemic of obesity has been hampered, largely owing to the limited knowledge of the mechanisms underlying resistance to the action of metabolic hormones such as leptin and ghrelin. The development of resistance to leptin and ghrelin, hormones that are crucial for the neuroendocrine control of energy homeostasis, is a hallmark of obesity. Intensive research over the past several years has yielded tremendous progress in our understanding of the cellular pathways that disrupt the action of leptin and ghrelin. In this Review, we discuss the molecular mechanisms underpinning resistance to leptin and ghrelin and how they can be exploited as targets for pharmacological management of obesity.
The mechanisms by which estrogens modulate physical activity remain unclear. A recent article published in Nature by Krause et al. (2021) demonstrates that estradiol increases the expression of ...melanocortin receptor 4 in a particular subset of neurons in the ventromedial nucleus of the hypothalamus, leading to increased physical activity.
Daylight Saving Time (DST) policies have been in use since early in the 20th century. However, their energy saving effect is under review. The generalization of LED lighting has reduced the impact of ...lighting energy on the total energy consumption and, therefore, the effect of DST has been reduced. Nevertheless, in order to design an effective new policy in this aspect, it is necessary to understand how total electricity consumption would be affected by it but also how the load daily profile would change. This paper proposes an hourly load model that quantifies the effect of daylight on electricity consumption and simulates the effect of different DST policies. The model is applied to the inland Spanish electricity system and the three scenarios more likely to be implemented if current DST policy is changed: year round winter time (UTC+1), year round summer time (UTC+2) and keep DST but change clock 1 h back (GMT). The results show how changes in sunrise and sunset times affect daily load profiles. They provide overall, monthly and hourly energy savings for each scenario that are necessary for a well-informed DST policy design and implementation.
•Daylight Saving Time's effect as energy saver is under review.•Electricity demand has a non-linear (sigmoid) relation to available daylight.•Quantifying the effect of daylight allows to simulate different DST policies.•DST policies not only affect overall demand but also peak loads.•Adopting UTC+2 all-year round would save 0.14% overall electric energy in Spain.
Test whether high dose corticosteroid pulse therapy (HDCPT) with either methylprednisolone or dexamethasone is associated with increased survival in COVID-19 patients at risk of hyper-inflammatory ...response. Provide some initial diagnostic criteria using laboratory markers to stratify these patients.
This is a prospective observational study, 318 met the inclusion criteria. 64 patients (20.1%) were treated with HDCPT by using at least 1.5mg/kg/24h of methylprednisolone or dexamethasone equivalent. A multivariate Cox regression (controlling for co-morbidities and other therapies) was carried out to determine whether HDCPT (among other interventions) was associated with decreased mortality. We also carried out a 30-day time course analysis of laboratory markers between survivors and non-survivors, to identify potential markers for patient stratification.
HDCPT showed a statistically significant decrease in mortality (HR = 0.087 95% CI 0.021-0.36; P < 0.001). 30-day time course analysis of laboratory marker tests showed marked differences in pro-inflammatory markers between survivors and non-survivors. As diagnostic criteria to define the patients at risk of developing a COVID-19 hyper-inflammatory response, we propose the following parameters (IL-6 > = 40 pg/ml, and/or two of the following: C-reactive protein > = 100 mg/L, D-dimer > = 1000 ng/ml, ferritin > = 500 ng/ml and lactate dehydrogenase > = 300 U/L).
HDCPT can be an effective intervention to increase COVID-19 survival rates in patients at risk of developing a COVID-19 hyper-inflammatory response, laboratory marker tests can be used to stratify these patients who should be given HDCPT. This study is not a randomized clinical trial (RCT). Future RCTs should be carried out to confirm the efficacy of HDCPT to increase the survival rates of COVID-19.
The motion of self-propelled tubular micro- and nanojets has so far been achieved by bubble propulsion, e.g., O2 bubbles formed by catalytic decomposition of H2O2, which renders future biomedical ...applications inviable. An alternative self-propulsion mechanism for tubular engines on the nanometer scale is still missing. Here, we report the fabrication and characterization of bubble-free propelled tubular nanojets (as small as 220 nm diameter), powered by an enzyme-triggered biocatalytic reaction using urea as fuel. We studied the translational and rotational dynamics of the nanojets as functions of the length and location of the enzymes. Introducing tracer nanoparticles into the system, we demonstrated the presence of an internal flow that extends into the external fluid via the cavity opening, leading to the self-propulsion. One-dimensional nanosize, longitudinal self-propulsion, and biocompatibility make the tubular nanojets promising for future biomedical applications.
The use of enzyme catalysis to power micro- and nanomachines offers unique features such as biocompatibility, versatility, and fuel bioavailability. Yet, the key parameters underlying the motion ...behavior of enzyme-powered motors are not completely understood. Here, we investigate the role of enzyme distribution and quantity on the generation of active motion. Two different micromotor architectures based on either polystyrene (PS) or polystyrene coated with a rough silicon dioxide shell (PS@SiO2) were explored. A directional propulsion with higher speed was observed for PS@SiO2 motors when compared to their PS counterparts. We made use of stochastically optical reconstruction microscopy (STORM) to precisely detect single urease molecules conjugated to the micromotors surface with a high spatial resolution. An asymmetric distribution of enzymes around the micromotor surface was observed for both PS and PS@SiO2 architectures, indicating that the enzyme distribution was not the only parameter affecting the motion behavior. We quantified the number of enzymes present on the micromotor surface and observed a 10-fold increase in the number of urease molecules for PS@SiO2 motors compared to PS-based micromotors. To further investigate the number of enzymes required to generate a self-propulsion, PS@SiO2 particles were functionalized with varying amounts of urease molecules and the resulting speed and propulsive force were measured by optical tracking and optical tweezers, respectively. Surprisingly, both speed and force depended in a nonlinear fashion on the enzyme coverage. To break symmetry for active propulsion, we found that a certain threshold number of enzymes molecules per micromotor was necessary, indicating that activity may be due to a critical phenomenon. Taken together, these results provide new insights into the design features of micro/nanomotors to ensure an efficient development.
Estrogenic actions in the brain prevent obesity. Better understanding of the underlying mechanisms may facilitate development of new obesity therapies.
This review focuses on the critical brain ...regions that mediate effects of estrogens on food intake and/or energy expenditure, the molecular signals that are involved, and the functional interactions between brain estrogens and other signals modulating metabolism. Body weight regulation by estrogens in male brains will also be discussed.
17β-estradiol acts in the brain to regulate energy homeostasis in both sexes. It can inhibit feeding and stimulate brown adipose tissue thermogenesis. A better understanding of the central actions of 17β-estradiol on energy balance would provide new insight for the development of therapies against obesity in both sexes.
Many patients previously using darunavir/ritonavir (DRV/r) (800/100mg) have switched to darunavir/cobicistat (DRV/C) (800/150 mg) either as part of triple therapy (ART) or as monotherapy with DRV ...(mDRV). The latter approach continues to be used in some countries for patients receiving long-term treatment. However, to date, the behaviour of DRV/C in the seminal compartment has not been analysed. This study explores how the combination behaves in monotherapy, with respect to the control of viral load and seminal quality. To this end, we studied 20 patients who were treated with mDRV/C after previous treatment with mDRV/r for at least 24 weeks. A viral load control in seminal plasma similar to that published in the literature was observed after 24 weeks of treatment with mDRV/C (viral load positivity in 20% of patients). Similarly, semen quality was confirmed (70% normozoospermic) in patients treated with this formulation, as has previously been reported for ART and mDRV/r. The DRV levels measured in seminal plasma were above EC50, regardless of whether the seminal viral load was positive or negative. We conclude that this mDRV/C co-formulation behaves like mDRV/r in seminal plasma in terms of viral load control and semen quality.
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