Hypothalamic Regions Research Articles

AQP4-IgG NMOSD, MOGAD, and double-seronegative NMOSD: is it possible to depict the antibody subtype using magnetic resonance imaging?

There is clinical and radiological overlap among demyelinating diseases. However, their pathophysiological mechanisms are different and carry distinct prognoses and treatment demands. To investigate magnetic resonance imaging (MRI) features of patients with myelin-oligodendrocyte glycoprotein associated disease (MOGAD), antibody against aquaporin-4(AQP-4)-immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG NMOSD), and double-seronegative patients. A cross-sectional retrospective study was performed to analyze the topography and morphology of central nervous system (CNS) lesions. Two neuroradiologists consensually analyzed the brain, orbit, and spinal cord images. In total, 68 patients were enrolled in the study (25 with AQP4-IgG-positive NMOSD, 28 with MOGAD, and 15 double-seronegative patients). There were differences in clinical presentation among the groups. The MOGAD group had less brain involvement (39.2%) than the NMOSD group (p = 0.002), mostly in the subcortical/juxtacortical, the midbrain, the middle cerebellar peduncle, and the cerebellum. Double-seronegative patients had more brain involvement (80%) with larger and tumefactive lesion morphology. In addition, double-seronegative patients showed the longest optic neuritis (p = 0.006), which was more prevalent in the intracranial optic nerve compartment. AQP4-IgG-positive NMOSD optic neuritis had a predominant optic-chiasm location, and brain lesions mainly affected hypothalamic regions and the postrema area (MOGAD versus AQP4-IgG-positive NMOSD, p= 0 .013). Furthermore, this group had more spinal cord lesions (78.3%), and bright spotty lesions were a paramount finding to differentiate it from MOGAD (p = 0.003). The pooled analysis of lesion topography, morphology, and signal intensity provides critical information to help clinicians form a timely differential diagnosis.

Neuropeptides Modulate Feeding via the Dopamine Reward Pathway.

Dopamine (DA) is a catecholamine neurotransmitter widely distributed in the central nervous system. It participates in various physiological functions, such as feeding, anxiety, fear, sleeping and arousal. The regulation of feeding is exceptionally complex, involving energy homeostasis and reward motivation. The reward system comprises the ventral tegmental area (VTA), nucleus accumbens (NAc), hypothalamus, and limbic system. This paper illustrates the detailed mechanisms of eight typical orexigenic and anorexic neuropeptides that regulate food intake through the reward system. According to recent literature, neuropeptides released from the hypothalamus and other brain regions regulate reward feeding predominantly through dopaminergic neurons projecting from the VTA to the NAc. In addition, their effect on the dopaminergic system is mediated by the prefrontal cortex, paraventricular thalamus, laterodorsal tegmental area, amygdala, and complex neural circuits. Research on neuropeptides involved in reward feeding can help identify more targets to treat diseases with metabolic disorders, such as obesity.

Comparison of neuroimaging features of histiocytic neoplasms with central nervous system involvement: a retrospective study of 121 adult patients

ObjectivesTo compare neuroimaging characteristics of three types of histiocytoses, namely Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman disease (RDD), with central nervous system (CNS) involvement.MethodsA total of 121 adult patients with histiocytoses (77 LCH, 37 ECD, and 7 RDD) and CNS involvement were retrospectively included. Histiocytoses were diagnosed based on histopathological findings combined with suggestive clinical and imaging features. Brain and dedicated pituitary MRIs were systematically analyzed for tumorous, vascular, degenerative lesions, sinus, and orbital involvement and for hypothalamic pituitary axis involvement.ResultsEndocrine disorders, including diabetes insipidus and central hypogonadism, were more common in LCH patients than in ECD and RDD patients (p < 0.001). In LCH, tumorous lesions were mostly solitary (85.7%), located in the hypothalamic pituitary region (92.9%), and without peritumoral edema (92.9%), while in ECD and RDD, tumorous lesions were often multiple (ECD: 81.3%, RDD: 85.7%), their distribution was more widespread with meninges mostly involved (ECD: 75%, RDD: 71.4%), and they most likely presented with peritumoral edema (ECD: 50%, RDD: 57.1%; all p ≤ 0.020). Vascular involvement was an exclusive imaging characteristic of ECD (17.2%), which was not observed in LCH or RDD; this was also associated with a higher risk of death (p = 0.013, hazard ratio = 11.09).ConclusionThe typical characteristic of adult CNS-LCH was endocrine disorders with radiological findings limited to the hypothalamic pituitary axis. The pattern of multiple tumorous lesions with predominant involvement of meninges was the main manifestation of CNS-ECD and CNS-RDD, while vascular involvement was pathognomonic for ECD and associated with poor prognosis.Clinical relevance statementInvolvement of the hypothalamic-pituitary axis is the typical imaging characteristic of Langerhans cell histiocytosis. Multiple tumorous lesions, predominantly involving but not limited to meninges, occur in most Erdheim-Chester disease and Rosai-Dorfman disease patients. Vascular involvement occurs only in Erdheim-Chester disease patients.Key Points• The different distribution patterns of brain tumorous lesions can help differentiate among LCH, ECD, and RDD.• Vascular involvement was an exclusive imaging finding of ECD and was associated with high mortality.• Some cases with atypical imaging manifestations were reported to further expand the knowledge on these diseases.

Spectro-spatial features in distributed human intracranial activity proactively encode peripheral metabolic activity

Mounting evidence demonstrates that the central nervous system (CNS) orchestrates glucose homeostasis by sensing glucose and modulating peripheral metabolism. Glucose responsive neuronal populations have been identified in the hypothalamus and several corticolimbic regions. However, how these CNS gluco-regulatory regions modulate peripheral glucose levels is not well understood. To better understand this process, we simultaneously measured interstitial glucose concentrations and local field potentials in 3 human subjects from cortical and subcortical regions, including the hypothalamus in one subject. Correlations between high frequency activity (HFA, 70–170 Hz) and peripheral glucose levels are found across multiple brain regions, notably in the hypothalamus, with correlation magnitude modulated by sleep-wake cycles, circadian coupling, and hypothalamic connectivity. Correlations are further present between non-circadian (ultradian) HFA and glucose levels which are higher during awake periods. Spectro-spatial features of neural activity enable decoding of peripheral glucose levels both in the present and up to hours in the future. Our findings demonstrate proactive encoding of homeostatic glucose dynamics by the CNS.

Maternal high fat diets: impacts on offspring obesity and epigenetic hypothalamic programming.

Maternal high-fat diet (HFD) during pregnancy is associated with rapid weight gain and fetal fat mass increase at an early stage. Also, HFD during pregnancy can cause the activation of proinflammatory cytokines. Maternal insulin resistance and inflammation lead to increased adipose tissue lipolysis, and also increased free fatty acid (FFA) intake during pregnancy (˃35% of energy from fat) cause a significant increase in FFA levels in the fetus. However, both maternal insulin resistance and HFD have detrimental effects on adiposity in early life. As a result of these metabolic alterations, excess fetal lipid exposure may affect fetal growth and development. On the other hand, increase in blood lipids and inflammation can adversely affect the development of the liver, adipose tissue, brain, skeletal muscle, and pancreas in the fetus, increasing the risk for metabolic disorders. In addition, maternal HFD is associated with changes in the hypothalamic regulation of body weight and energy homeostasis by altering the expression of the leptin receptor, POMC, and neuropeptide Y in the offspring, as well as altering methylation and gene expression of dopamine and opioid-related genes which cause changes in eating behavior. All these maternal metabolic and epigenetic changes may contribute to the childhood obesity epidemic through fetal metabolic programming. Dietary interventions, such as limiting dietary fat intake <35% with appropriate fatty acid intake during the gestation period are the most effective type of intervention to improve the maternal metabolic environment during pregnancy. Appropriate nutritional intake during pregnancy should be the principal goal in reducing the risks of obesity and metabolic disorders.

Neuropeptide Y regulates osteocyte phenotype and function through AHNAK-Smad signalling.

Neuropeptide Y (NPY) is a widespread hormone in the central and peripheral nervous systems that maintains body homeostasis. Central actions of hypothalamic NPY have been identified in bone metabolism. Osteocytes are the main source of NPY in bone tissue, indicating that osteocytic NPY could be a local alternative pathway for hypothalamic mediated regulation of bone and bone cells. Here, we show that osteocytic NPY induces cell viability and proliferation. Osteocyte-derived factors are also closely associated with changes in cellular NPY mRNA levels. Furthermore, osteoblast mineralization was significantly induced by conditioned medium collected from NPY-overexpressing osteocytes (P < 0.05). Importantly, the NPY-AHNAK interaction was identified for the first time by co-immunoprecipitation, and significant inactivation of p-Smad1/5/9 was found in osteocytes with NPY or AHNAK insufficiency (P < 0.05). The activation of p-Smad1/5/9 reversed NPY insufficiency-caused decreases in the expression of osteocytic proliferating cell nuclear antigen and osteoblast markers including osteocalcin and Runx2 (P < 0.05); these findings showed an additional molecular mechanism by which NPY acts on cells through AHNAK-mediated Smad1/5/9 signalling. Collectively, our findings provide novel insights into the function of NPY in regulating osteocyte phenotype and function and provide new insights for further investigation into osteocytic NPY-mediated therapy.

Sex-, strain and lateral differences in brain cytoarchitecture across a large mouse population.

The mouse brain is by far the most intensively studied among mammalian brains, yet basic measures of its cytoarchitecture remain obscure. For example, quantifying cell numbers, and the interplay of sex-, strain-, and individual variability in cell density and volume is out of reach for many regions. The Allen Mouse Brain Connectivity project produces high-resolution full brain images of hundreds of brains. Although these were created for a different purpose, they reveal details of neuroanatomy and cytoarchitecture. Here, we used this population to systematically characterize cell density and volume for each anatomical unit in the mouse brain. We developed a deep neural network-based segmentation pipeline that uses the auto-fluorescence intensities of images to segment cell nuclei even within the densest regions, such as the dentate gyrus. We applied our pipeline to 507 brains of males and females from C57BL/6J and FVB.CD1 strains. Globally, we found that increased overall brain volume does not result in uniform expansion across all regions. Moreover, region-specific density changes are often negatively correlated with the volume of the region, therefore cell count does not scale linearly with volume. Many regions, including layer 2/3 across several cortical areas, showed distinct lateral bias. We identified strain-specific or sex-specific differences. For example, males tended to have more cells in extended amygdala and hypothalamic regions (MEA, BST, BLA, BMA, and LPO, AHN) while females had more cells in the orbital cortex (ORB). Yet, inter-individual variability was always greater than the effect size of a single qualifier. We provide the results of this analysis as an accessible resource for the community.

β-asarone prolongs sleep via regulating the level of glutamate in the PVN

People of all ages could suffer from sleep disorders, which are increasingly recognized as common manifestations of neurologic disease. Acorus tatarinowii is a herb that has been used in traditional medicine to promote sleep. β-asarone, as the main component of volatile oil obtained from Acorus tatarinowii, may be the main contributor to the sleeping-promoting efficacy of Acorus tatarinowii. In the study, adult male C57BL/6 mice were administered β-asarone at 12.5 mg/kg, 25 mg/kg, and 50 mg/kg. Behavioral experiments showed that β-asarone at 25 mg/kg could significantly improve sleep duration. It was also observed that the proportion of NREM (Non-Rapid Eye Movement) sleep increased considerably after administration of β-asarone. In the PVN (paraventricular nucleus of hypothalamus) region of the hypothalamus, it was observed that the glutamate content decreased after β-asarone treatment. At the same time, the expression of VGLUT2 (vesicular glutamate transporters 2) decreased while the expression of GAD65 (glutamic acid decarboxylase 65) and GABARAP (GABA Type A Receptor-Associated Protein) increased in the hypothalamus, suggesting that β-asarone may suppress arousal by reducing glutamate and promoting transformation of glutamate to the inhibitory neurotransmitter GABA (γ-aminobutyric acid). This study is the first to focus on the association between β-asarone and sleep, shedding perspectives for pharmacological applications of β-asarone and providing a new direction for future research.

133 Anatomical evidence for kisspeptin and dopaminergic neuron interaction in the diestrous mare

Dopamine (DA), via dopaminergic neurons, modulates prolactin secretion from the pituitary by tonic inhibition of lactotropes. Previously, kisspeptin (Kp) attenuated the prolactin response to the DA antagonist, sulpiride, in diestrous mares and enhanced the prolactin response to sulpiride in estradiol-primed mares. Whether or not Kp can modulate prolactin by acting on DA neurons has yet to be described in horses; therefore, the objective of this study was to determine if Kp and kisspeptin receptor (Kiss1r) co-localize with DA neurons, thus providing evidence for a direct action of Kp on DA neurons. Hypothalami from 4 light-horse diestrous mares, aged 6 to 21, were obtained following euthanasia. Mares were determined to be diestrous based on presence of corpora lutea and progesterone concentrations. Immediately following euthanasia, the carotid artery was perfused with sodium nitrite and 4% paraformaldehyde before decapitation and dissection of hypothalami. Immunofluorescent double labeling of tyrosine hydroxylase (TH) and Kp, as well as TH and Kiss1r, was carried out on paraffin-embedded hypothalamic sections using validated antibodies. Whole slide scans were analyzed for double-labeled cells; percentage of DA neurons colocalized with Kp-ir cell bodies and fibers, as well as percentage of DA neurons colocalized with Kiss1r-ir cells, were calculated and averaged for multiple sectionsper horse from rostral to caudal throughout the hypothalamus. Similarly, percentage and number of Kp or Kiss1r-ir cell bodies co-colocalized with TH-ir cells were calculated for different hypothalamic regions: the arcuate nucleus (Arc), ventromedial nucleus (VMH), and dorsomedial nucleus (DMH), and compared using Kruskall Wallis with Dunn's multiple comparison test. DA neurons were observed lining the third ventricle and spread from the Arc to the DMH, with little to none present in the posterior nucleus. TH and Kp expressing cell bodies co-localized between 8 and 30%, with less in the caudal DMH (P ≤ 0.05) compared with the Arc. Kp fibers synapsed with TH-expressing cell bodies at a low percentage, between 0 and 16%, with less connections in the DMH (P ≤ 0.05) than in the ARC. TH and Kiss1r co-localized between 20 and 65%, with similar distribution throughout the Arc, VMH, and DMH in rostral sections. In caudal hypothalamic sections, co-localization was greater (P ≤ 0.05) in the Arc compared with other areas that express lower or no DA neurons. Co-localization of TH and Kiss1r as well as co-localization and synaptic attachment of Kp on TH positive cells suggests a direct effect of kisspeptin on DA neurons to modulate prolactin release.

Activation of mTOR signaling in the paraventricular nucleus of the hypothalamus (PVN) contributes to stress- and BDNF-induced hypertensive responses

The paraventricular nucleus of the hypothalamus (PVN) integrates afferent inputs from limbic, medullary and hypothalamic regions to orchestrate cardiovascular stress responses via its medullary and spinal projections. Brain-derived neurotrophic factor (BDNF) is an important pro-hypertensive regulator in the PVN upregulated during stress that transforms the PVN neurocircuitry to facilitate responsiveness to hypertensive stimuli by shifting the balance of excitatory/inhibitory synaptic mechanisms. Mechanistic target of rapamycin (mTOR), as part of mTOR complex-1 (mTORC1), is stimulated by trophic factors, such as BDNF, in other brain regions to induce changes in neuronal morphology and increases in neuronal excitability. We tested the hypothesis that activation of mTORC1 in the PVN by BDNF and acute stress plays a key role in stimulating hypertensive responses. Male Sprague Dawley (SD) rats (n=4/group) received bilateral PVN injections of AAV2 viral vectors expressing myc-tagged BDNF (BDNFmyc), shRNA against TSC1 (a repressor of mTORC1) to stimulate mTORC1, shRNA against Raptor (a key component of the mTORC1) to inhibit mTORC1 or GFP for control. Blood pressure and heart rate were monitored by telemetry for 4 wks, and cardiovascular responses to restraint (60min) and water stress (15 minutes, 1-cm deep, 25°C water) were recorded 4-5 wks after vector injections. Vector injections were confirmed and neuronal morphology as well as pS6 levels (a marker of mTOR activity) were analyzed with immunofluorescence. Activation mTORC1 with TSC1 knock-down significantly increased resting blood pressure compared with control, but inhibition of mTORC1 with Raptor knock-down had no effect. BDNF overexpression significantly elevated blood pressure, as we have shown previously, and these increases were completely abolished by Raptor knock-down (daytime mean arterial pressure: shTSC1: 108.0±1.4*; BDNFmyc: 131.4±2.5*; shRaptor: 101.8±0.9; BDNF+shRaptor: 102.7±2.8#, GFP: 96.5±1.8 mmHg at week 4, *p&lt;0.05 vs GFP; #p&lt;0.05 vs. BDNFmyc). In addition, mTORC1 inhibition with Raptor knock-down also significantly diminished stress-induced hypertensive responses. Maximum blood pressure increase in shRaptor rats was 30.3±1.3 mmHg during restraint and 26.0±3.4 mmHg during water stress vs 43.8±2.2 and 37.4±2.5 mmHg in control rats (p&lt;0.05). Immunofluorescence of pS6, an indicator of mTOR activity, and neuronal soma size were significantly elevated by both TSC1 knock-down and BDNF overexpression in the PVN, whereas Raptor knock-down reduced pS6 intensity and soma size and completely abolished the effects of BDNF. In summary, we demonstrated that mTOR activation in the PVN significantly increased blood pressure both during baseline conditions and during acute stress, and mediated hypertensive responses and neuronal morphological changes elicited by BDNF. Supported by R01 HL133211. R01 HL133211 (BE), R03 AG072016 (BE) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Essential roles of the hypothalamic A11 region and the medullary raphe nuclei in regulation of colorectal motility in rats.

The supraspinal brain regions controlling defecation reflex remain to be elucidated. The purpose of this study was to determine the roles of the hypothalamic A11 region and the medullary raphe nuclei in regulation of defecation. For chemogenetic manipulation of specific neurons, we used the double virus vector infection method in rats. hM3Dq or hM4Di was expressed in neurons of the A11 region and/or the raphe nuclei that send output to the lumbosacral defecation center. Immunohistological and functional experiments revealed that both the A11 region and the raphe nuclei directly connected with the lumbosacral spinal cord through descending pathways composed of stimulatory monoaminergic neurons. Stimulation of the hM3Dq-expressing neurons in the A11 region or the raphe nuclei enhanced colorectal motility only when GABAergic transmission in the lumbosacral spinal cord was blocked by bicuculline. Experiments using inhibitory hM4Di-expressing rats revealed that enhancement of colorectal motility caused by noxious stimuli in the colon is mediated by both the A11 region and the raphe nuclei. Furthermore, suppression of the A11 region and/or the raphe nuclei significantly inhibited water avoidance stress-induced defecation. These findings demonstrate that the A11 region and the raphe nuclei play an essential role in regulation of colorectal motility. This is important because brain regions that mediate both intracolonic noxious stimuli-induced defecation and stress-induced defecation have been clarified for the first time.

Intraoperative Central Diabetes Insipidus during Aneurysmal Clipping Surgery: An Unusual Phenomenon

AbstractCentral diabetes insipidus (DI) is a known complication associated with pituitary surgeries occurring in postoperative period. However, development of DI following aneurysmal subarachnoid hemorrhage (SAH) is rarely reported. We describe here a case of intraoperative DI in a patient undergoing aneurysmal clipping surgery that posed a challenge for both diagnosis and management. Intraoperative development of central DI was attributed to the evolving ischemic injury to the hypothalamus at the time of rebleeding that was not apparent in the preoperative scan. DI resolved postoperatively after 18 hours of medical management. A careful observation of preoperative scans and vigilant monitoring may help in early diagnosis and management of such complication in the perioperative period.

Distribution of the transcription factor islet-1 in the central nervous system of nonteleost actinopterygian fish: Relationship with cholinergic and catecholaminergic systems.

Islet-1 (Isl1) is one of the most conserved transcription factors in the evolution of vertebrates, due to its continuing involvement in such important functions as the differentiation of motoneurons, among other essential roles in cell fate in the forebrain. Although its functions are thought to be similar in all vertebrates, the knowledge about the conservation of its expression pattern in the central nervous system goes as far as teleosts, leaving the basal groups of actinopterygian fishes overlooked, despite their important phylogenetic position. In order to assess the extent of its conservation among vertebrates, we studied its expression pattern in the central nervous system of selected nonteleost actinopterygian fishes. By means of immunohistochemical techniques, we analyzed the Isl1 expression in the brain, spinal cord, and sensory ganglia of the cranial nerves of young adult specimens of the cladistian species Polypterus senegalus and Erpetoichthys calabaricus, the chondrostean Acipenser ruthenus, and the holostean Lepisosteus oculatus. We also detected the presence of the transcription factor Orthopedia and the enzymes tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT) to better locate all the immunoreactive structures in the different brain areas and to reveal the possible coexpression with Isl1. Numerous conserved features in the expression pattern of Isl1 were observed in these groups of fishes, such as populations of cells in the subpallial nuclei, preoptic area, subparaventricular and tuberal hypothalamic regions, prethalamus, epiphysis, cranial motor nuclei and sensory ganglia of the cranial nerves, and the ventral horn of the spinal cord. Double labeling of TH and Isl1 was observed in cells of the preoptic area, the subparaventricular and tuberal hypothalamic regions, and the prethalamus, while virtually all motoneurons in the hindbrain and the spinal cord coexpressed ChAT and Isl1. Altogether, these results show the high degree of conservation of the expression pattern of the transcription factor Isl1, not only among fish, but in the subsequent evolution of vertebrates.

New discoveries on the interaction between testosterone and oxytocin in male rats ― Testosterone-mediated effects of oxytocin in the prevention of obesity

Sex steroid hormones are important for the maintenance of metabolism in both sexes. Oxytocin (OT) is a neuropeptide that is synthesized in hypothalamic regions, secreted from the posterior lobe of the pituitary gland, and is involved in the control of appetite, body weight, and metabolism. Estrogen and OT both play a role in the metabolism of nutrients, and OT has potential in the prevention of obesity. However, the relationship between testosterone and OT remains unclear. Therefore, the present study investigated the relationship between testosterone and OT in hypogonadal male rats and male rats receiving testosterone replacement therapy. The results obtained showed that testosterone increased serum OT levels and promoted the secretion of adiponectin from visceral fat, and reduced body fat directly and/or indirectly through OT and adiponectin. Testosterone also increased the expression of OT receptors in the hypothalamus to increase sensitivity to OT, and perhaps because of this, OT administration had the effect of reducing food intake and body weight gain in both normal and castrated rats, and this effect was stronger in normal rats. In other words, the preventative effects of OT on obesity may be synergistic with testosterone. Collectively, the present results indicate that testosterone exerts indirect effects to prevent obesity and atherosclerosis through OT and adiponectin. In conclusion, testosterone replacement therapy is useful for preventing obesity caused by hypogonadism, and OT has potential in supportive medicine to prevent obesity and adult diseases.

Controlling hypothalamic DNA methylation at the Pomc promoter does not regulate weight gain during the development of obesity.

Obesity is a complex medical condition that is linked to various health complications such as infertility, stroke, and osteoarthritis. Understanding the neurobiology of obesity is crucial for responding to the etiology of this disease. The hypothalamus coordinates many integral activities such as hormone regulation and feed intake and numerous studies have observed altered hypothalamic gene regulation in obesity models. Previously, it was reported that the promoter region of the satiety gene, Pomc, has increased DNA methylation in the hypothalamus following short-term exposure to a high fat diet, suggesting that epigenetic-mediated repression of hypothalamic Pomc might contribute to the development of obesity. However, due to technical limitations, this has never been directly tested. Here, we used the CRISPR-dCas9-TET1 and dCas9-DNMT3a systems to test the role of Pomc DNA methylation in the hypothalamus in abnormal weight gain following acute exposure to a high fat diet in male rats. We found that exposure to a high fat diet increases Pomc DNA methylation and reduces gene expression in the hypothalamus. Despite this, we found that CRISPR-dCas9-TET1-mediated demethylation of Pomc was not sufficient to prevent abnormal weight gain following exposure to a high fat diet. Furthermore, CRISPR-dCas9-DNMT3a-mediated methylation of Pomc did not alter weight gain following exposure to standard or high fat diets. Collectively, these results suggest that high fat diet induced changes in Pomc DNA methylation are a consequence of, but do not directly contribute to, abnormal weight gain during the development of obesity.

In silico approach to identify non-synonymous missense variants in human obesity-related genes: Comprehensive analyses in variants reported in Brazilian databases

In recent years, the search for understanding the pathophysiology of obesity has been intense, especially in understanding satiety signs in the hypothalamus and brain regions associated with hormonal signaling in orexigenic and anorexigenic neurons. Such signs are quite complex and often associated with regulating energy expenditure and sensations of hunger and satiety in mammals. However, different phenotypes result from mutations (allelic variants) in the genes encoding these proteins, especially peptide receptors. In this sense, searching for allelic variants and identifying central genes related to obesity that can explain the different phenotypes of thinness or overweight/obesity can help understand the various proteins involved in these processes and define new strategies for early laboratory diagnosing patients. Initially, mining was conducted on the ClinVar database retrieving 468 reports. After manually discharging unrelated variants and selecting only mutations classified as pathogenic, we selected 20 mutations in 7 different genes for further analysis. After being submitted to in silico prediction tools, 16 potential pathogenic variants were searched in Brazilian databases, and 4 were found: L72M and R51Q on gene GHRL, R70W on gene UCP3, and T150I on MC4R gene.

Dual Behavior Regulation: Tether-Free Deep-Brain Stimulation by Photothermal and Upconversion Hybrid Nanoparticles.

Optogenetics has been plagued by invasive brain implants and thermal effects during photo-modulation. Here, two upconversion hybrid nanoparticles modified with photothermal agents, named PT-UCNP-B/G, which can modulate neuronal activities via photostimulation and thermo-stimulation under near-infrared laser irradiation at 980nm and 808nm, respectively, are demonstrated. PT-UCNP-B/G emits visible light (410-500nm or 500-570nm) through the upconversion process at 980nm, while they exhibit efficient photothermal effect at 808nm with no visible emission and tissue damage. Intriguingly, PT-UCNP-B significantly activates extracellular sodium currents in neuro2a cells expressing light-gated channelrhodopsin-2 (ChR2) ion channels under 980-nm irradiation, and inhibits potassium currents in human embryonic kidney 293 cells expressing the voltage-gated potassium channels (KCNQ1) under 808-nm irradiation in vitro. Furthermore, deep-brain bidirectional modulation of feeding behavior is achieved under tether-free 980 or 808-nm illumination (0.8W cm-2 ) in mice stereotactically injected with PT-UCNP-B in the ChR2-expressing lateral hypothalamus region. Thus, PT-UCNP-B/G creates new possibility of utilizing both light and heat to modulate neural activities and provides a viable strategy to overcome the limits of optogenetics.

Hypopituitarism in Adults: Rational Approaches to Diagnosis and Treatment

AbstractPituitary hormones are responsible for the regulation of growth, development, metabolism, reproduction, and homeostasis. Hypopituitarism is a condition that is defined as partial or complete insufficiency of anterior pituitary hormone secretion, and rarely, posterior pituitary hormone secretion. This condition can result from diseases of the pituitary gland or the hypothalamus. The annual incidence of hypopituitarism has been estimated to be 4.2 per 100,000 yearly, and the prevalence has been estimated at 45.5 per 100,000. The symptoms of hypopituitarism vary. The onset is insidious and depends on the number of hormone deficiencies and their degree of severity. Pituitary hormone deficiency can result in substantial clinical changes that increase the risk of morbidity and mortality. People commonly report persistent symptoms and a decline in their quality of life, both of which can be explained, at least in part, by the inherent shortcomings of hormone replacement strategies in their ability to imitate the normal hormone secretion processes. The diagnosis of hypopituitarism can be straightforward by measuring the lowered basal hormone levels. In cases where the basal hormone levels are uncertain or partial hormone deficiencies have been identified, it may be necessary to perform provocative testing of the hypothalamic–pituitary axis. The hypothalamus and pituitary region can be imaged using magnetic resonance imaging, which provides useful anatomical information. When necessary, genetic studies may be added to the diagnostic approach. The treatment consists of physiological replacement of the individual end-organ hormone deficiencies, and careful monitoring is required throughout the patient's entire life. Individualized hormone replacement therapy that considers potential interactions is recommended. This article provides an overview of the pathophysiology, clinical presentation, general diagnostic guidelines, and treatment options of hypopituitarism.

Obesity increases blood-brain barrier permeability and aggravates the mouse model of multiple sclerosis.

Obesity-induced insulin resistance (OIR) has been associated with an increased prevalence of neurodegenerative disorders such as multiple sclerosis. Obesity results in increased blood-brain barrier (BBB) permeability, specifically in the hypothalamic regions associated with the control of caloric intake. In obesity, the chronic state of low-grade inflammation has been implicated in several chronic autoimmune inflammatory disorders. However, the mechanisms that connect the inflammatory profile of obesity with the severity of experimental autoimmune encephalomyelitis (EAE) are poorly defined. In this study, we show that obese mice are more susceptible to EAE, presenting a worse clinical score with more severe pathological changes in the spinal cord when compared with control mice. Analysis of immune infiltrates at the peak of the disease shows that high-fat diet (HFD)- and control (chow)-fed groups do not present any difference in innate or adaptive immune cell compartments, indicating the increased severity occurs prior to disease onset. In the setting of worsening EAE in HFD-fed mice, we observed spinal cord lesions in myelinated regions and (blood brain barrier) BBB disruption. We also found higher levels of pro-inflammatory monocytes, macrophages, and IFN-γ+CD4+ T cells in the HFD-fed group compared to chow-fed animals. Altogether, our results indicate that OIR promotes BBB disruption, allowing the infiltration of monocytes/macrophages and activation of resident microglia, ultimately promoting CNS inflammation and exacerbation of EAE.

Medications for the treatment of obesity.

After several years with no real therapeutic alternatives, the management of obesity is entering a new era with the development of new surgical and endoscopic bariatric techniques, digital therapeutics and the arrival of new classes of drugs. New medication treatments aim to reduce food intake, targeting the hypothalamic regulation of food intake and satiety. The mechanism of their action remains poorly understood but, combines weight reduction and amelioration of cardiometabolic risk factors with a favorable benefit-risk balance and known side effects, mainly digestive. The future will tell us how these drugs will find their place in the management of this chronic disease that is obesity.