Electricity production from centralised and decentralised renewable energy resources in Europe is gaining significance, resulting in operational challenges in the electricity system. Although these ...challenges add to the locational and time dependency of the underlying cost of operating the system, this variability in time and location is not reflected in residential tariff schemes. Consequently, residential users are not incentivised to react to varying system conditions and to help the integration of renewable energy resources. Therefore, this paper provides a theoretical framework for designing a locational dynamic pricing scheme. This can be used to assess existing tariff structures for consumption and injection, and can serve as a theoretical background for developing new tariff schemes. Starting from the underlying costs, this paper shows that the potential for locational dynamic pricing depends on the locational and time dependency of its cost drivers. When converting costs into tariffs, the tariff design should be determined. This includes the advance notice of sending tariffs to users, and the length of price blocks and price patterns. This tariff design should find a balance between tariff principles related to costs, practicality and social acceptability on the one hand, and the resulting demand response incentive on the other.
•The integration of renewables affects the locational and time dependency of costs.•Locational dynamic pricing reflects cost variability and allows demand response.•A theoretical framework for designing and assessing tariff schemes is proposed.•Tariff variability depends on the locational & time dependency of its cost drivers.•The tariff design should consider the resulting demand response incentive.
Glucagon-like peptide 1 receptor (GLP-1R) agonists decrease body weight and improve glycemic control in obesity and diabetes. Patient compliance and maximal efficacy of GLP-1 therapeutics are limited ...by adverse side effects, including nausea and emesis. In three different species (i.e., mice, rats, and musk shrews), we show that glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling blocks emesis and attenuates illness behaviors elicited by GLP-1R activation, while maintaining reduced food intake, body weight loss, and improved glucose tolerance. The area postrema and nucleus tractus solitarius (AP/NTS) of the hindbrain are required for food intake and body weight suppression by GLP-1R ligands and processing of emetic stimuli. Using single-nuclei RNA sequencing, we identified the cellular phenotypes of AP/NTS cells expressing GIPR and GLP-1R on distinct populations of inhibitory and excitatory neurons, with the greatest expression of GIPR in γ-aminobutyric acid-ergic neurons. This work suggests that combinatorial pharmaceutical targeting of GLP-1R and GIPR will increase efficacy in treating obesity and diabetes by reducing nausea and vomiting.
Hunger and pain are two competing signals that individuals must resolve to ensure survival. However, the neural processes that prioritize conflicting survival needs are poorly understood. We ...discovered that hunger attenuates behavioral responses and affective properties of inflammatory pain without altering acute nociceptive responses. This effect is centrally controlled, as activity in hunger-sensitive agouti-related protein (AgRP)-expressing neurons abrogates inflammatory pain. Systematic analysis of AgRP projection subpopulations revealed that the neural processing of hunger and inflammatory pain converge in the hindbrain parabrachial nucleus (PBN). Strikingly, activity in AgRP → PBN neurons blocked the behavioral response to inflammatory pain as effectively as hunger or analgesics. The anti-nociceptive effect of hunger is mediated by neuropeptide Y (NPY) signaling in the PBN. By investigating the intersection between hunger and pain, we have identified a neural circuit that mediates competing survival needs and uncovered NPY Y1 receptor signaling in the PBN as a target for pain suppression.
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•Hunger attenuates inflammatory pain without influencing acute pain responses•Hunger-sensitive AgRP neurons projecting to the PBN suppress inflammatory pain•Neuropeptide Y signaling in the PBN attenuates inflammatory pain during hunger
Hunger suppresses responses to pain through an AgRP/NPY circuit.
Glucagon-like peptide-1 receptor (GLP-1R) activation within the nucleus tractus solitarius (NTS) suppresses food intake and body weight (BW), but the intracellular signals mediating these effects are ...unknown. Here, hindbrain (fourth i.c.v.) GLP-1R activation by Exendin-4 (Ex-4) increased PKA and MAPK activity and decreased phosphorylation of AMPK in NTS. PKA and MAPK signaling contribute to food intake and BW suppression by Ex-4, as inhibitors RpcAMP and U0126 (fourth i.c.v.), respectively, attenuated Ex-4's effects. Hindbrain GLP-1R activation inhibited feeding by reducing meal number, not meal size. This effect was attenuated with stimulation of AMPK activity by AICAR (fourth i.c.v.). The PKA, MAPK, and AMPK signaling responses by Ex-4 were present in immortalized GLP-1R-expressing neurons (GT1-7). In conclusion, hindbrain GLP-1R activation suppresses food intake and BW through coordinated PKA-mediated suppression of AMPK and activation of MAPK. Pharmacotherapies targeting these signaling pathways, which mediate intake-suppressive effects of CNS GLP-1R activation, may prove efficacious in treating obesity.
► PKA activity mediates suppression of food intake by NTS GLP-1 receptor activation ► MAPK activity mediates suppression of food intake by NTS GLP-1 receptor activation ► AMPK activity mediates suppression of food intake by NTS GLP-1 receptor activation ► Suppression of food intake by NTS GLP-1R activation reduces body weight gain
Protein tyrosine phosphatase 1B (PTP1B) and SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) have been shown in mice to regulate metabolism via the central nervous system, but the specific ...neurons mediating these effects are unknown. Here, we have shown that proopiomelanocortin (POMC) neuron-specific deficiency in PTP1B or SHP2 in mice results in reciprocal effects on weight gain, adiposity, and energy balance induced by high-fat diet. Mice with POMC neuron-specific deletion of the gene encoding PTP1B (referred to herein as POMC-Ptp1b-/- mice) had reduced adiposity, improved leptin sensitivity, and increased energy expenditure compared with wild-type mice, whereas mice with POMC neuron-specific deletion of the gene encoding SHP2 (referred to herein as POMC-Shp2-/- mice) had elevated adiposity, decreased leptin sensitivity, and reduced energy expenditure. POMC-Ptp1b-/- mice showed substantially improved glucose homeostasis on a high-fat diet, and hyperinsulinemic-euglycemic clamp studies revealed that insulin sensitivity in these mice was improved on a standard chow diet in the absence of any weight difference. In contrast, POMC-Shp2-/- mice displayed impaired glucose tolerance only secondary to their increased weight gain. Interestingly, hypothalamic Pomc mRNA and alpha-melanocyte-stimulating hormone (alphaMSH) peptide levels were markedly reduced in POMC-Shp2-/- mice. These studies implicate PTP1B and SHP2 as important components of POMC neuron regulation of energy balance and point to what we believe to be a novel role for SHP2 in the normal function of the melanocortin system.
•Demand response (DR) provides an efficient means to integrate RES and avoid surplus.•DR decreases the loading and amount of start-ups of peak and mid-peak power plants.•DR leads to lower operational ...cost, higher reliability and lower emission level.•More uncontrollable capacity in a generation portfolio increases DR benefits.•Scheduling battery electric vehicles brings higher societal value than scheduling white goods.
The future power system is characterized by more renewable and uncontrollable capacity at the supply side and an electrification of energy at the demand side. Both evolutions increase the need for flexibility in the power system. Although this flexibility can be triggered at the supply and demand side, the latter is often overlooked. In this perspective, this paper assesses the impact of the use of flexibility at the demand side, also referred to as demand response, on power system operation. A two-stage modeling approach is used which combines a day-ahead deterministic unit commitment model and an hourly simulation in real-time. This approach is tested for two alternative Belgian generation technology mix scenarios including a detailed representation of residential demand response. Hereby, realistic cycling patterns of white goods and mobility patterns of battery electric vehicles serve as an input. This approach allows to quantify operational benefits of demand response and to assess a potential introduction of demand response in power system operation. Results show that in general demand response contributes to a lower cost, higher reliability, and lower emission level of power system operation. Moreover, a higher amount of uncontrollable capacity increases these benefits and therefore the societal value of demand response.
The FDA-approved glucagon-like-peptide-1 receptor (GLP-1R) agonists exendin-4 and liraglutide reduce food intake and body weight. Nausea is the most common adverse side effect reported with these ...GLP-1R agonists. Whether food intake suppression by exendin-4 and liraglutide occurs independently of nausea is unknown. Further, the neurophysiological mechanisms mediating the nausea associated with peripheral GLP-1R agonist use are poorly understood. Using two established rodent models of nausea conditioned taste avoidance (CTA) and pica (ingestion of nonnutritive substances), results show that all peripheral doses of exendin-4 that suppress food intake also produce CTA, whereas one dose of liraglutide suppresses intake without producing CTA. Chronic (12 days) daily peripheral administration of exendin-4 produces a progressive increase in pica coupled with stable, sustained food intake and body weight suppression, whereas the pica response and food intake reduction by daily liraglutide are more transient. Results demonstrate that the nausea response accompanying peripheral exendin-4 occurs via a vagal-independent pathway involving GLP-1R activation in the brain as the exendin-4-induced pica response is attenuated with CNS co-administration of the GLP-1R antagonist exendin-(9–39), but not by vagotomy. Direct administration of exendin-4 to the medial subnucleus of the nucleus tractus solitarius (mNTS), but not to the central nucleus of the amygdala, reduced food intake and produced a pica response, establishing the mNTS as a potential GLP-1R-expressing site mediating nausea responses associated with GLP-1R agonists.
► Peripheral exendin-4 produces conditioned taste avoidance at all doses that suppress food intake. ► One dose of liraglutide reduced food intake without conditioned taste avoidance. ► Chronic peripheral exendin-4 produced pica via vagal-independent direct CNS action. ► Chronic peripheral liraglutide produced transient food intake suppression and pica. ► NTS but not CeA exendin-4 injection produced pica and food intake suppression.
The anorectic and weight-suppressive effects of growth differentiation factor-15 (GDF15) are attracting considerable attention for treating obesity. Current experiments in rats investigate whether ...GDF15 induces an aversive visceral malaise-based state that mediates its acute anorectic effect and, through aversion conditioning, exerts longer-term anorexia. Visceral malaise, conditioned affective food responses (taste reactivity), gastric emptying (GE), food intake, and body weight are evaluated after acute and chronic systemic dosing of GDF15 or long-acting Fc-GDF15. Pica, a marker of visceral malaise, is present at all anorectic GDF15 doses. Moreover, malaise induced by GDF15 does not decline over time, suggesting the lack of an improved tolerance after prolonged exposure. One association between GDF15 and novel food conditions a disgust/aversive response that persists beyond GDF15 acute action. Delayed GE is not a requirement for GDF15-induced anorexia. Clinical studies are required to evaluate whether GDF15’s aversive-state-based anorexia will be contraindicated as an obesity treatment.
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•Acute GDF15 systemic delivery induces visceral malaise, anorexia, and body weight loss•Chronic GDF15 exposure triggers visceral malaise that does not decline over time•GDF15 conditions food-aversive responses persisting beyond its acute anorectic action•GDF15’s visceral malaise and anorectic effects do not require slowed gastric emptying
Borner et al. show that the visceral malaise (i.e., pica) that accompanies GDF15-induced anorexia persists after prolonged exposure, denoting the lack of improved tolerance. Further, the food-GDF15 pairing conditions a disgust/aversive response that contributes to anorexia and lasts beyond GDF15’s acute action. Reduced gastric emptying is not required for GDF15-induced anorexia/malaise.
Unexpected crystal structures: The noble‐metal pernitrides OsN2 and IrN2 are found to adopt structure types never before observed in nitrides (see picture; Os/Ir blue, N green). Furthermore, the ...crystal structures of RuN2 and RhN2, which have yet to be synthesized, are predicted. A pressure‐induced displacive phase transition and a semiconductor–metal transition are predicted for IrN2.
Abstract The peripheral and central glucagon-like-peptide-1 (GLP-1) systems play an essential role in glycemic and energy balance regulation. Thus, pharmacological targeting of peripheral and/or ...central GLP-1 receptors (GLP-1R) may represent a potential long-term treatment option for both obesity and type-II diabetes mellitus (T2DM). Uncovering and understanding the neural pathways, physiological mechanisms, specific GLP-1R populations, and intracellular signaling cascades that mediate the food intake inhibitory and incretin effects produced by GLP-1R activation are vital to the development of these potential successful therapeutics. Particular focus will be given to the essential role of the nucleus tractus solitarius (NTS) in the caudal brainstem, as well as the gut-to-brain communication by vagal afferent fibers in mediating the physiological and behavioral responses following GLP-1R activation. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior SSIB Annual Meeting in Portland, July 2009.
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