Astrocytes in the dorsal vagal complex are not activated by systemic glucoprivation and their chemogenetic activation does not elicit homeostatic glucoregulatory responses in mice

The dorsal vagal complex (DVC) is a brainstem site regulating diverse aspects of physiology including food intake and blood glucose homeostasis. Astrocytes are purported to play an active role in regulating DVC function and, by extension, physiological parameters. Previous work has demonstrated that DVC astrocytes directly sense hormones that regulate food intake and blood glucose and are critical for their effect. In addition, DVC astrocytes in ex vivo slices respond to low tissue glucose. The response of neurons, including catecholaminergic neurons, to low glucose is conditional on intact astrocyte signalling in slice preparations suggesting astrocytes are possibly the primary sensors of glucose deprivation (glucoprivation). Based on these findings we hypothesised that if DVC astrocytes act as glucoprivation sensors in vivo they would both show a response to systemic glucoprivation and drive physiological responses to restore blood glucose. We found that 2 hours of systemic glucoprivation induced neither FOS nor glial fibrillary acidic protein (GFAP)-immunoreactivity in DVC astrocytes, specifically those in the nucleus of the solitary tract (NTS). Furthermore, we found that while chemogenetic activation of DVC astrocytes suppressed food intake by reducing both meal size and meal number, this manipulation also suppressed food intake under conditions of glucoprivation. Chemogenetic activation of DVC astrocytes did not increase basal blood glucose nor protect against insulin-induced hypoglycaemia. In male mice chemogenetic DVC astrocyte activation did not alter glucose tolerance, in female mice the initial glucose excursion was reduced, suggesting enhanced glucose absorption. Taken together this suggests that as a whole-population DVC astrocytes do not function as glucoprivation sensors in vivo in mice. Instead, we propose that DVC astrocytes play an indispensable, homeostatic role to maintain the function of glucoregulatory neuronal circuitry.

The essential role of nesfatin-1 as a biological signal on the body systems

Nesfatin-1is first described in 2006 as an anorectic peptide and regulate food intake. In following years, the studies demonstrated the presence of nesfatin-1 in central and various peripheral tissues. Thus, nesfatin-1 popularity increasing widely in clinical medicine, especially in cardiology, neurology, reproduction, metabolic disorders, psychiatric disorders, gastrointestinal system. Today, the main point concerning nesfatin-1 action in body organ and systems is concentrate its biological signals effects. Thus the increasing knowledge in these area will be highlighted for future studies especially in serious health problem all over the world population.

Calcitonin gene related peptide α is dispensable for many danger-related motivational responses

Calcitonin gene related peptide (CGRP) expressing neurons in the parabrachial nucleus have been shown to encode danger. Through projections to the amygdala and other forebrain structures, they regulate food intake and trigger adaptive behaviors in response to threats like inflammation, intoxication, tumors and pain. Despite the fact that this danger-encoding neuronal population has been defined based on its CGRP expression, it is not clear if CGRP is critical for its function. It is also not clear if CGRP in other neuronal structures is involved in danger-encoding. To examine the role of CGRP in danger-related motivational responses, we used male and female mice lacking αCGRP, which is the main form of CGRP in the brain. These mice had no, or only very weak, CGRP expression. Despite this, they did not behave differently compared to wildtype mice when they were tested for a battery of danger-related responses known to be mediated by CGRP neurons in the parabrachial nucleus. Mice lacking αCGRP and wildtype mice showed similar inflammation-induced anorexia, conditioned taste aversion, aversion to thermal pain and pain-induced escape behavior, although it should be pointed out that the study was not powered to detect any possible differences that were minor or sex-specific. Collectively, our findings suggest that αCGRP is not necessary for many threat-related responses, including some that are known to be mediated by CGRP neurons in the parabrachial nucleus.

Menstrual Disorders Related to Eating Disorders

: Eating disorders (ED) are associated with multiple physical complications that strongly affect the physical health of these young and fragile patients and can also cause significant mortality, the highest among psychiatric pathologies. Among the various organic complications, albeit still little known, the gynecological implications, up to infertility, are very widespread. Among adolescent and adult patients, gynecological symptoms can be very widespread and range from menstrual irregularities to amenorrhea, from vaginitis to ovarian polycystosis, up to complications during the gestational phase and postpartum, in addition to the possible consequences on the unborn child. Among the most frequent and significant gynecological disorders in women with ED, there are menstrual irregularities that may occur with oligomenorrhea or even amenorrhea. , Although no longer part of the DSM-5 diagnostic criteria for defining anorexia nervosa (AN), this symptom must be considered a very relevant event in the overall evaluation of young women and adolescents with eating disorders. Functional hypothalamic amenorrhea in ED patients is related to psychological distress, excessive exercise, disordered eating, or a combination of these factors, which results in suppression of the hypothalamic-pituitary-ovarian axis, and consequently, hypoestrogenism. This paper has the objective to summarize the causes and the mechanism underlying menstrual disorders and provide a better understanding of the correlation between the reproductive system and the mechanisms that regulate food intake and eating habits. In addition, early recognition of risk factors for eating disorders for gynecological implications can help put more accurate assessments of patients to prevent potentially fatal complications. The importance of the involvement of specialist gynecologists in the multidisciplinary team that has to follow patients with eating disorders is also discussed.

Dual origin and multiple neuropeptidergic trajectories of hypothalamic POMC progenitors revealed by developmental single-cell transcriptomics

Proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus are essential to regulate food intake and energy balance. However, the ontogenetic transcriptional programs that specify the identity and functioning of these neurons are poorly understood. Here, we use scRNAseq to define the transcriptomes characterizing POMC progenitors in the developing hypothalamus and their transition into mature neurons. Our data show that Pomc-expressing neurons originate from two independent developmental pathways expressing distinct combinations of transcription factors. The predominant cluster, featured by high levels of Pomc and Prdm12 transcripts represents the precursors of canonical arcuate POMC neurons. Additional clusters of progenitors expressing lower levels of Pomc mature into different neuronal phenotypes characterized by distinct combinations of transcription factors, neuropeptides, processing enzymes, cell surface and nuclear receptors. We conclude that the genetic programs specifying the identity and differentiation of arcuate POMC neurons are diverse and generate a heterogeneous repertoire of neuronal phenotypes early in development.

Serotonin as a Regulator of Leptin-Mediated Food Intake Control Within a Novel Neuronal Circuit Between the Hypothalamus and Raphe Nuclei

The onset and exacerbation of obesity involves the overproduction of the adipocyte-derived hormone leptin, a key mediator of homeostatic appetite regulation and a signal for satiety. Although leptin’s hypothalamic regulation of food intake has been extensively investigated, its role in tandem with the anorectic neurotransmitter serotonin (5-HT) has been less characterized. 5-HT is synthesized in the dorsal raphe nucleus (DRN) where anatomical projections to many hypothalamic nuclei have previously been identified. Preliminary studies in our lab have: (1) identified serotonergic neurons responsive to leptin in the DRN that project to the arcuate nucleus (ARC) of the hypothalamus and (2) demonstrated leptin injected into the DRN significantly decreases food intake. The objective of the current study was to identify the role of 5-HT in leptin’s regulation of food intake first within the DRN, then between the DRN and the ARC. Adult male Sprague Dawley rats underwent stereotaxic surgery for guide cannula implantation in the DRN. After recovery, animals were administered 100 µg of p-chlorophenylalanine (PCPA), an inhibitor of 5-HT synthesis, in the DRN each day for four days. On the fourth day, leptin was also administered in the DRN (5 µg/rat) and food intake was measured over a 24-hour time course. ANOVA analysis revealed a significant difference in 24-hour food intake [F (3, 18) = 3.972; P = 0.0246] and post-hoc analysis showed that animals treated with leptin significantly decreased food intake (17.2 ± 2.0 g) compared to control rats (25.4 ± 0.9 g), whereas PCPA-treated rats did not differ from the control rats, suggesting that depletion of 5-HT attenuated leptin’s ability to regulate food intake within the DRN. To examine the role of 5-HT on leptin’s hypothalamic action, a subsequent experiment was conducted by implanting an additional cannula into the ARC for the administration of leptin or vehicle on the fourth day of treatment. ANOVA analysis revealed a significant difference in 24-hour food intake [F (3, 16) = 5.998; P = 0.0061] and post-hoc analysis showed that only rats treated with leptin in the ARC significantly decreased food intake (14.0 ± 1.5 g) compared to controls (21.8 ± 0.5 g). 5-HT depletion was assessed post-mortem using immunohistochemistry and was later quantified. Collectively, these results demonstrate that leptin’s ability to regulate food intake is dependent on 5-HT, regardless of the area of regulation (i.e. DRN or the hypothalamus).

Circulating Prokineticin 2 Levels Are Increased in Children with Obesity and Correlated with Insulin Resistance

Objective. Prokineticin 2 (PK2) has been shown to regulate food intake, fat production, and the inflammation process, which play vital roles in the pathogenesis of obesity. The first aim of this study was to investigate serum PK2 levels in children with obesity and normal-weight children. The second aim was to compare the levels of PK2 between children with obesity, with and without nonalcoholic fatty liver disease (NAFLD). Methods. Seventy normal-weight children and 91 children with obesity (22 with NAFLD) were recruited. Circulating PK2, IL-6, and TNF-α were measured by enzyme-linked immunosorbent assays. Anthropometric and biochemical measurements related to adiposity, lipid profile, and insulin resistance were examined for all participants. Results. Serum PK2 was significantly higher in children with obesity than in the normal-weight controls. Circulating PK2 levels were not different between the patients with and without NAFLD. Circulating PK2 was positively correlated with BMI, BMI z-score, insulin, glucose, HOMA-IR, total cholesterol, low-density lipoprotein cholesterol, alanine aminotransferase, and gamma-glutamyl transpeptidase. Binary logistic regression revealed that the odds ratios for obesity were significantly elevated with increasing PK2. Conclusions. PK2 was strongly associated with obesity, and it may also be related to metabolic disorders and insulin resistance. This trial is registered with ChiCTR2000038838.

Calcitonin Gene Related Peptide Α Is Dispensable for Many Danger-related Motivational Responses

Calcitonin gene related peptide (CGRP) expressing neurons in the parabrachial nucleus have been shown to encode danger. Through projections to the amygdala and other forebrain structures, they regulate food intake and trigger adaptive behaviors in response to threats like inflammation, intoxication, tumors and pain. Despite the fact that this danger-encoding neuronal population has been defined based on its CGRP expression, it is not clear if CGRP is critical for its function. To examine the role of CGRP in danger-related motivational responses, we used male and female mice lacking αCGRP, which is the main form of CGRP in the brain. These mice had no, or only very weak, CGRP expression in the parabrachial nucleus and its projections to the amygdala. Despite this, they displayed normal danger-related responses such as inflammation-induced anorexia and conditioned taste aversion. Further, mice lacking αCGRP showed normal nociceptive responses, intact aversion to thermal pain and close to normal pain-induced escape behavior. Collectively, our findings suggest that αCGRP is not necessary for short term danger-encoding and threat-related responses but that the parabrachial CGRP expressing neurons use other transmitters for these functions.

The metabolic impact of small intestinal nutrient sensing

The gastrointestinal tract maintains energy and glucose homeostasis, in part through nutrient-sensing and subsequent signaling to the brain and other tissues. In this review, we highlight the role of small intestinal nutrient-sensing in metabolic homeostasis, and link high-fat feeding, obesity, and diabetes with perturbations in these gut-brain signaling pathways. We identify how lipids, carbohydrates, and proteins, initiate gut peptide release from the enteroendocrine cells through small intestinal sensing pathways, and how these peptides regulate food intake, glucose tolerance, and hepatic glucose production. Lastly, we highlight how the gut microbiota impact small intestinal nutrient-sensing in normal physiology, and in disease, pharmacological and surgical settings. Emerging evidence indicates that the molecular mechanisms of small intestinal nutrient sensing in metabolic homeostasis have physiological and pathological impact as well as therapeutic potential in obesity and diabetes.

Discrete TrkB-expressing neurons of the dorsomedial hypothalamus regulate feeding and thermogenesis

Mutations in the TrkB neurotrophin receptor lead to profound obesity in humans, and expression of TrkB in the dorsomedial hypothalamus (DMH) is critical for maintaining energy homeostasis. However, the functional implications of TrkB-fexpressing neurons in the DMH (DMHTrkB) on energy expenditure are unclear. Additionally, the neurocircuitry underlying the effect of DMHTrkB neurons on energy homeostasis has not been explored. In this study, we show that activation of DMHTrkB neurons leads to a robust increase in adaptive thermogenesis and energy expenditure without altering heart rate or blood pressure, while silencing DMHTrkB neurons impairs thermogenesis. Furthermore, we reveal neuroanatomically and functionally distinct populations of DMHTrkB neurons that regulate food intake or thermogenesis. Activation of DMHTrkB neurons projecting to the raphe pallidus (RPa) stimulates thermogenesis and increased energy expenditure, whereas DMHTrkB neurons that send collaterals to the paraventricular hypothalamus (PVH) and preoptic area (POA) inhibit feeding. Together, our findings provide evidence that DMHTrkB neuronal activity plays an important role in regulating energy expenditure and delineate distinct neurocircuits that underly the separate effects of DMHTrkB neuronal activity on food intake and thermogenesis.