Interactions between Lateral Hypothalamic Orexin and Dorsal Raphe Circuitry in Energy Balance.

Orexin/hypocretin terminals innervate the dorsal raphe nucleus (DRN), which projects to motor control areas important for spontaneous physical activity (SPA) and energy expenditure (EE). Orexin receptors are expressed in the DRN, and obesity-resistant (OR) rats show higher expression of these receptors in the DRN and elevated SPA/EE. We hypothesized that orexin-A in the DRN enhances SPA/EE and that DRN-GABA modulates the effect of orexin-A on SPA/EE.

Obesogens and Obesity: State-of-the-Science and Future Directions Summary from a Healthy Environment and Endocrine Disruptors Strategies Workshop.

On September 7 and 8, 2022, Healthy Environment and Endocrine Disruptors Strategies, an Environmental Health Sciences program, convened a scientific workshop of relevant stakeholders involved in obesity, toxicology, or obesogen research to review the state of the science regarding the role of obesogenic chemicals that might be contributing to the obesity pandemic. The workshop's objectives were to examine the evidence supporting the hypothesis that obesogens contribute to the etiology of human obesity; to discuss opportunities for improved understanding, acceptance, and dissemination of obesogens as contributors to the obesity pandemic; and to consider the need for future research and potential mitigation strategies. This report details the discussions, key areas of agreement, and future opportunities to prevent obesity.

Changes in sensorimotor cortex oscillatory activity by orexin-A in the ventrolateral preoptic area of the hypothalamus reflect increased muscle tone.

Orexin-A (OXA) is a hypothalamic neuropeptide implicated in the regulation of wakefulness, appetite, reward processing, muscle tone, motor activity, and other physiological processes. The broad range of systems affected stems from the widespread projections of orexin neurons toward multiple brain regions regulating numerous physiological processes. Orexin neurons integrate nutritional, energetic, and behavioral cues and modulate the functions of target structures.

Behavioral plasticity: Role of neuropeptides in shaping feeding responses.

Behavioral plasticity refers to changes occurring due to external influences on an organism, including adaptation, learning, memory and enduring influences from early life experience. There are 2 types of behavioral plasticity: "developmental", which refers to gene/environment interactions affecting a phenotype, and "activational" which refers to innate physiology and can involve structural physiological changes of the body. In this review, we focus on feeding behavior, and studies involving neuropeptides that influence behavioral plasticity - primarily opioids, orexin, neuropeptide Y, and oxytocin.

Orexin enhances neuronal synchronization in adult rat hypothalamic culture: a model to study hypothalamic function.

The regulation of sleep/wake behavior and energy homeostasis is maintained in part by the hypothalamic neuropeptide orexin A (OXA, hypocretin). Reduction in orexin signaling is associated with sleep disorders and obesity, whereas higher lateral hypothalamic (LH) orexin signaling and sensitivity promotes obesity resistance. Similarly, dysregulation of hypothalamic neural networks is associated with onset of age-related diseases, including obesity and several neurological diseases.

Anatabine, Nornicotine, and Anabasine Reduce Weight Gain and Body Fat through Decreases in Food Intake and Increases in Physical Activity.

Obesity is a leading cause of preventable death in the United States. Currently approved pharmacotherapies for the treatment of obesity are associated with rebound weight gain, negative side effects, and the potential for abuse. There is a need for new treatments with fewer side effects.

Orexin, serotonin, and energy balance.

The lateral hypothalamus is critical for the control of ingestive behavior and spontaneous physical activity (SPA), as lesion or stimulation of this region alters these behaviors. Evidence points to lateral hypothalamic orexin neurons as modulators of feeding and SPA. These neurons affect a broad range of systems, and project to multiple brain regions such as the dorsal raphe nucleus, which contains serotoninergic neurons (DRN) important to energy homeostasis.

COVID-19 vaccines are effective in people with obesity: A position statement from The Obesity Society.

The position statement is issued by The Obesity Society in response to published literature, as well as inquiries made to the Society by patients, providers, Society members, policy makers, and others regarding the efficacy of vaccines in persons with obesity against SARS-CoV-2, the virus that causes COVID-19. The Obesity Society has critically evaluated data from published peer-reviewed literature and briefing documents from Emergency Use Authorization applications submitted by Pfizer-BioNTech, Moderna, and Johnson & Johnson. We conclude that these vaccines are highly efficacious, and their efficacy is not significantly different in people with and without obesity, based on scientific evidence available at the time of publication.

Discovery of Arylsulfonamides as Dual Orexin Receptor Agonists.

Loss of orexin-producing neurons results in narcolepsy with cataplexy, and orexin agonists have been shown to increase wakefulness and alleviate narcolepsy symptoms in animal models. Several OX2R agonists have been reported but with little or no activity at OX1R. We conducted structure-activity relationship studies on the OX2R agonist YNT-185 () and discovered dual agonists such as RTOXA-43 () with EC's of 24 nM at both OX2R and OX1R.

Impact of Gut and Metabolic Hormones on Feeding Reward.

Ingestion of food activates a cascade of endocrine responses (thereby reflecting a contemporaneous feeding status) that include the release of hormones from the gastrointestinal (GI) tract, such as cholecystokinin (CCK), glucagonlike peptide YY (PYY), peptide PP, and oleoylethanolamide, as well as suppression of ghrelin secretion. The pancreas and adipose tissue, on the other hand, release hormones that serve as a measure of the current metabolic state or the long-term energy stores, that is, insulin, leptin, and adiponectin. It is well known and intuitively understandable that these hormones target either directly (by crossing the blood-brain barrier) or indirectly (e.

Inhibition of Orexin/Hypocretin Neurons Ameliorates Elevated Physical Activity and Energy Expenditure in the A53T Mouse Model of Parkinson's Disease.

Aside from the classical motor symptoms, Parkinson's disease also has various non-classical symptoms. Interestingly, orexin neurons, involved in the regulation of exploratory locomotion, spontaneous physical activity, and energy expenditure, are affected in Parkinson's. In this study, we hypothesized that Parkinson's-disease-associated pathology affects orexin neurons and therefore impairs functions they regulate.

Synchronous neuronal interactions in rat hypothalamic culture: a novel model for the study of network dynamics in metabolic disorders.

Synchronous neural activity is a feature of normal brain function, and altered synchronization is observed in several neurological diseases. Dysfunction in hypothalamic pathways leads to obesity, suggesting that hypothalamic neural synchrony is critical for energy homeostasis. The lateral hypothalamic orexin neurons are extensively interconnected with other brain structures and are important for energy balance.

Pharmacological and chemogenetic orexin/hypocretin intervention ameliorates Hipp-dependent memory impairment in the A53T mice model of Parkinson's disease.

Parkinson's disease (PD), classically defined as a progressive motor disorder accompanied with dopaminergic neuron loss and presence of Lewy bodies, is the second most common neurodegenerative disease. PD also has various non-classical symptoms, including cognitive impairments. In addition, inflammation and astrogliosis are recognized as an integral part of PD pathology.

Chemogenetic Modulation of Orexin Neurons Reverses Changes in Anxiety and Locomotor Activity in the A53T Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease. PD symptomology is recognized as heterogeneous and in addition to motor function decline includes cognitive, mood, sleep, and metabolic disorders. Previous studies showed early reductions in anxiety and locomotion in the A53T mice model of PD.

Obesity as a Disease: The Obesity Society 2018 Position Statement.

The emerging obesity epidemic and accompanying health consequences led The Obesity Society (TOS) in 2008 to publish a position paper defining obesity as a disease. Since then, new information has emerged on the underlying mechanisms leading to excess adiposity and the associated structural, cardiometabolic, and functional disturbances. This report presents the updated TOS 2018 position statement on obesity as a noncommunicable chronic disease.

Orexin/hypocretin treatment restores hippocampal-dependent memory in orexin-deficient mice.

Orexin A is produced in neurons of the lateral, perifornical and dorsomedial regions of the lateral hypothalamic area, which then project widely throughout the central nervous system to regulate arousal state, sleep-wake architecture, energy homeostasis and cognitive processes. Disruption of orexin signaling leads to sleep disturbances and increased body mass index, but recent studies also indicate that orexin neuron activation improves learning and memory. We hypothesized that hippocampal orexin receptor activation improves memory.

Spontaneous Physical Activity Defends Against Obesity.

Purpose Of Review: Spontaneous physical activity (SPA) is a physical activity not motivated by a rewarding goal, such as that associated with food-seeking or wheel-running behavior. SPA is often thought of as only "fidgeting," but that is a mischaracterization, since fidgety behavior can be linked to stereotypies in neurodegenerative disease and other movement disorders. Instead, SPA should be thought of as all physical activity behavior that emanates from an unconscious drive for movement.

Orexin signaling in rostral lateral hypothalamus and nucleus accumbens shell in the control of spontaneous physical activity in high- and low-activity rats.

Spontaneous physical activity (SPA) describes activity outside of formal exercise and shows large interindividual variability. The hypothalamic orexin/hypocretin peptides are key regulators of SPA. Orexins drive SPA within multiple brain sites, including rostral lateral hypothalamus (LH) and nucleus accumbens shell (NAcSh).

Effect of Housing Types on Growth, Feeding, Physical Activity, and Anxiety-Like Behavior in Male Sprague-Dawley Rats.

Background: Animal welfare and accurate data collection are equally important in rodent research. Housing influences study outcomes and can challenge studies that monitor feeding, so housing choice needs to be evidence-based. The goal of these studies was to (1) compare established measures of well-being between rodents housed in wire grid-bottom floors with a resting platform compared to solid-bottom floors with bedding and (2) determine whether presence of a chewable device (Nylabone) affects orexin-A-induced hyperphagia.

Comparative analysis of growth characteristics of Sprague Dawley rats obtained from different sources.

Genetic background in animal models is an intrinsic research variable in biomedical research. Although inbred strains offer genetic uniformity, the outbred stocks, known for genetic variability are often used to develop animal models of human disease. The genetic variability is considered to be even higher when outbred stocks are obtained from different sources.

Role of orexin A signaling in dietary palmitic acid-activated microglial cells.

Excess dietary saturated fatty acids such as palmitic acid (PA) induce peripheral and hypothalamic inflammation. Hypothalamic inflammation, mediated in part by microglial activation, contributes to metabolic dysregulation. In rodents, high fat diet-induced microglial activation results in nuclear translocation of nuclear factor-kappa B (NFκB), and increased central pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6).

Promotion of Wakefulness and Energy Expenditure by Orexin-A in the Ventrolateral Preoptic Area.

Study Objectives: The ventrolateral preoptic area (VLPO) and the orexin/hypocretin neuronal system are key regulators of sleep onset, transitions between vigilance states, and energy homeostasis. Reciprocal projections exist between the VLPO and orexin/hypocretin neurons. Although the importance of the VLPO to sleep regulation is clear, it is unknown whether VLPO neurons are involved in energy balance.

Sleep disorders, obesity, and aging: the role of orexin.

The hypothalamic neuropeptides orexin A and B (hypocretin 1 and 2) are important homeostatic mediators of central control of energy metabolism and maintenance of sleep/wake states. Dysregulation or loss of orexin signaling has been linked to narcolepsy, obesity, and age-related disorders. In this review, we present an overview of our current understanding of orexin function, focusing on sleep disorders, energy balance, and aging, in both rodents and humans.

The orexin neuropeptide system: physical activity and hypothalamic function throughout the aging process.

There is a rising medical need for novel therapeutic targets of physical activity. Physical activity spans from spontaneous, low intensity movements to voluntary, high-intensity exercise. Regulation of spontaneous and voluntary movement is distributed over many brain areas and neural substrates, but the specific cellular and molecular mechanisms responsible for mediating overall activity levels are not well understood.