Somatostatin (somatotropin release inhibiting factor) is an abundant neuropeptide, which acts on five subtypes of somatostatin receptor (SST1-SST5; nomenclature as agreed by the NC-IUPHAR Subcommittee on Somatostatin Receptors [101]). Activation of these receptors produces a wide range of physiological effects throughout the body including the inhibition of secretion of many hormones. Endogenous ligands for these receptors are somatostatin-14 (SRIF-14) and somatostatin-28 (SRIF-28). cortistatin-14 has also been suggested to be an endogenous ligand for somatostatin receptors [62].

Resveratrol (RSV), a polyphenol with anti-aging properties affecting metabolism and energy balance, is considered as a mimetic candidate to calorie restriction (CR). However its potential effects on delaying the onset of age-related diseases and increasing longevity have not yet been demonstrated in non-obese models close to humans such as non-human primates. The longitudinal monitoring of cognitive and motor performances, occurrence of age-related pathologies, age-related brain atrophy and mortality was performed from adulthood to death in a cohort of male grey mouse lemurs (Microcebus murinus, N = 33), all receiving 105 kJ/day of food but with a subset of 18 animals receiving RSV (200 mg.kg-1 body weight.day-1). RSV supplementation improved cognitive and motor performance at middle age as compared to control (CTL) animals. Median-lifespan was greater in RSV-fed animals (7.9 years compared to 6.4 years for CTL) but long-term RSV supplementation did not significantly affect all-cause nor age-related mortality. Also, brain grey matter atrophy accelerated in the RSV group at old age as compared to the CTL group. Altogether, these results suggest that long-term RSV supplementation procures health benefits at middle-age in male mouse lemurs but has limited long-term effects on health and longevity and might even impair brain integrity at older ages. Long-term resveratrol supplementation procures health benefits at middle-age in a non-human primate but does not mimic the positive effects of calorie restriction on lifespan and might even impair brain integrity at older ages.

Hormones mediate long-range cell communication and play vital roles in physiology, metabolism, and health. Traditionally, endocrinologists have focused on one hormone or organ system at a time. Yet, hormone signaling by its very nature connects cells of different organs and involves crosstalk of different hormones. Here, we leverage the organism-wide single cell transcriptional atlas of a non-human primate, the mouse lemur ( Microcebus murinus ), to systematically map source and target cells for 84 classes of hormones. This work uncovers previously-uncharacterized sites of hormone regulation, and shows that the hormonal signaling network is densely connected, decentralized, and rich in feedback loops. Evolutionary comparisons of hormonal genes and their expression patterns show that mouse lemur better models human hormonal signaling than mouse, at both the genomic and transcriptomic levels, and reveal primate-specific rewiring of hormone-producing/target cells. This work complements the scale and resolution of classical endocrine studies and sheds light on primate hormone regulation.

Somatostatin (somatotropin release inhibiting factor) is an abundant neuropeptide, which acts on five subtypes of somatostatin receptor (SST1-SST5; nomenclature as agreed by the NC-IUPHAR Subcommittee on Somatostatin Receptors [98]). Activation of these receptors produces a wide range of physiological effects throughout the body including the inhibition of secretion of many hormones. Endogenous ligands for these receptors are somatostatin-14 (SRIF-14) and somatostatin-28 (SRIF-28). cortistatin-14 has also been suggested to be an endogenous ligand for somatostatin receptors [61].

The growing interest concerning the role of metabolic sensors in various eating disorders requires the implementation of a strict methodology to collect, store and process blood samples in clinical studies. In particular, measurement of isoforms of the appetite-stimulating hormone, ghrelin, has been challenging in clinical settings. Indeed the acyl ghrelin (AG) isoform is rapidly degraded into desacyl ghrelin (DAG) by blood esterases, thus optimal conditions for the conservation of AG and accurate determination of AG/DAG ratio should be used. Here, we compared different protease inhibitors (Aprotinin, PHMB, AEBSF) during blood collection, increasing delays (0-180 min) before centrifugation, plasma supplementation with various HCl concentrations, storage durations of frozen plasma (8 and 447 days) and immunoenzyme-assay procedures (one-step versus sequential) in healthy subjects. Optimal conditions were obtained by collecting blood with aprotinin and supplementation of plasma with 0.1 N HCl with subsequent freezing for at least 8 days and using one-step assay. Under such conditions, different patterns of secretion of ghrelin isoforms were characterized in patients with restrictive-type anorexia nervosa (AN-R) before and after nutritional recovery. We illustrate the pulsatile variations of ghrelin isoforms according to the time around a meal and hunger rates in 3 patients with AN-R. This study offers a comprehensive comparison of various conditions using selective and specific immunoassays for both ghrelin isoforms in order to optimize assay sensitivity and consistency among procedures. These assay conditions could therefore be widely used to elucidate precisely the role of ghrelin isoforms on eating behavior in physiological and pathological situations.

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

Introduction: While the vast majority of research investigating the role of ghrelin or its receptor, GHS-R1a, in growth, feeding, and metabolism has been conducted in male rodents, very little is known about sex differences in this system. Furthermore, the role of GHS-R1a signaling in the control of pulsatile GH secretion and its link with growth or metabolic parameters has never been characterized. Methods: We assessed the sex-specific contribution of GHS-R1a signaling in the activity of the GH/IGF-1 axis, metabolic parameters, and feeding behavior in adolescent (5–6 weeks old) or adult (10–19 weeks old) GHS-R KO (Ghsr−/−) and WT (Ghsr+/+) male and female mice. Results: Adult Ghsr−/− male and female mice displayed deficits in weight and linear growth that were correlated with reduced GH pituitary contents in males only. GHS-R1a deletion was associated with reduced meal frequency and increased meal intervals, as well as reduced hypothalamic GHRH and NPY mRNA in males, not females. In adult, GH release from Ghsr−/− mice pituitary explants ex vivo was reduced independently of the sex. However, in vivo pulsatile GH secretion decreased in adult but not adolescent Ghsr−/− females, while in males, GHS-R1a deletion was associated with reduction in pulsatile GH secretion during adolescence exclusively. In males, linear growth did not correlate with pulsatile GH secretion, but rather with ApEn, a measure that reflects irregularity of the rhythmic secretion. Fat mass, plasma leptin concentrations, or ambulatory activity did not predict differences in GH secretion. Discussion/Conclusion: These results point to a sex-dependent dimorphic effect of GHS-R1a signaling to modulate pulsatile GH secretion and meal pattern in mice with different compensatory mechanisms occurring in the hypothalamus of adult males and females after GHS-R1a deletion. Altogether, we show that GHS-R1a signaling plays a more critical role in the regulation of pulsatile GH secretion during adolescence in males and adulthood in females.

OBJECTIVE:Predictive values of acute phase metabolic abnormalities of anorexia nervosa (AN) have seldom been studied. As early postrestoration weight loss is associated with poor outcome, discharge biologic parameters were assessed to detect an association with 2-month follow-up weight loss as a proxy to poor outcome.METHOD:Fasting plasma levels of leptin, acyl-ghrelin, obestatin, PYY, oxytocin and BDNF were measured in 26 inpatients, at inclusion, at discharge and 2 months later. A body mass index less than 18 2-month postdischarge was considered a poor outcome.RESULTS:Nineteen patients (73%) had a fair outcome and seven (27%) had a poor one with a mean loss of 0.69 versus 4.54 kg, respectively. Only discharge leptin levels were significantly higher in fair versus poor outcome patients (14.1 vs. 7.0 ng/ml, p = 0.006). The logistic regression model using discharge leptin, acyl-ghrelin, obestatin, oxytocin, PYY and BDNF levels as predictors of outcome disclosed a nearly significant effect of leptin (p < 0.10). Receiver operating characteristic analysis showed 11.9 ng/ml was the best value of threshold. Neither clinical variables differed according to outcome.CONCLUSION:Leptin level may be a biomarker of early weight relapse after acute inpatient treatment of AN. Its clinical usefulness in monitoring care in AN should further be determined.

The hypothalamus has long been known to control food intake and energy metabolism through a complex network of primary and secondary neurons and glial cells. Anorexia nervosa being a complex disorder characterized by abnormal feeding behavior and food aversion, it is thus quite surprising that not much is known concerning potential hypothalamic modifications in this disorder. In this chapter, we review the recent advances in the fields of genetics, epigenetics, structural and functional imaging, and brain connectivity, as well as neuroendocrine findings and emerging animal models, which have begun to unravel the importance of hypothalamic adaptive processes to our understanding of the pathology of eating disorders.

Using preproghrelin-deficient mice ( Ghrl-/- ), we previously observed that preproghrelin modulates pulsatile growth hormone (GH) secretion in post-pubertal male mice. However, the role of ghrelin and its derived peptides in the regulation of growth parameters or feeding in females is unknown. We measured pulsatile GH secretion, growth, metabolic parameters and feeding behavior in adult Ghrl-/- and Ghrl+/+ male and female mice. We also assessed GH release from pituitary explants and hypothalamic growth hormone-releasing hormone (GHRH) expression and immunoreactivity. Body weight and body fat mass, linear growth, spontaneous food intake and food intake following a 48-h fast, GH pituitary contents and GH release from pituitary explants ex vivo , fasting glucose and glucose tolerance were not different among adult Ghrl-/- and Ghrl+/+ male or female mice. In vivo , pulsatile GH secretion was decreased, while approximate entropy, that quantified orderliness of secretion, was increased in adult Ghrl-/- females only, defining more irregular GH pattern. The number of neurons immunoreactive for GHRH visualized in the hypothalamic arcuate nucleus was increased in adult Ghrl-/- females, as compared to Ghrl+/+ females, whereas the expression of GHRH was not different amongst groups. Thus, these results point to sex-specific effects of preproghrelin gene deletion on pulsatile GH secretion, but not feeding, growth or metabolic parameters, in adult mice.

Abstract Background Constitutional thinness (CT), a non‐malnourished underweight state with no eating disorders, is characterized by weight gain resistance to high fat diet. Data issued from muscle biopsies suggested blunted anabolic mechanisms in free‐living state. Weight and metabolic responses to protein caloric supplementation has not been yet explored in CT. Methods A 2 week overfeeding (additional 600 kcal, 30 g protein, 72 g carbohydrate, and 21 g fat) was performed to compare two groups of CTs (12 women and 11 men) to normal‐weight controls (12 women and 10 men). Bodyweight, food intake, energy expenditure, body composition, nitrogen balance, appetite hormones profiles, and urine metabolome were monitored before and after overfeeding. Results Before overfeeding, positive energy gap was found in both CT genders (309 ± 370 kcal in CT‐F and 332 ± 709 kcal in CT‐M) associated with higher relative protein intake per kilo (1.74 ± 0.32 g/kg/day in CT‐F vs. 1.16 ± 0.23 in C‐F, P < 0.0001; 1.56 ± 0.36 in CT‐M vs. 1.22 ± 0.32 in C‐M, P = 0.03), lower nitrogen (7.26 ± 2.36 g/day in CT‐F vs. 11.41 ± 3.64 in C‐F, P = 0.003; 9.70 ± 3.85 in CT‐M vs. 14.14 ± 4.19 in C‐M, P = 0.02), but higher essential amino acids urinary excretion (CT/C fold change of 1.13 for leucine and 1.14 for arginine) in free‐living conditions. After overfeeding, CTs presented an accentuated positive energy gap, still higher than in controls (675 ± 540 in CTs vs. 379 ± 427 in C, P = 0.04). Increase in lean mass was induced in both controls genders but not in CTs (a trend was noticed in CT women), despite a similar nitrogen balance after overfeeding (5.06 ± 4.33 g/day in CTs vs. 4.28 ± 3.15 in controls, P = 0.49). Higher anorectic gut hormones' tone, glucagon‐like peptide 1 and peptide tyrosine tyrosine, during test meal and higher snacking frequency were noticed before and after overfeeding in CTs. Conclusions The blunted muscle energy mechanism, previously described in CTs in free‐living state, is associated with basal saturated protein turn over suggested by the concordance of positive nitrogen balance and an increased urine excretion of several essential amino acids. This saturation cannot be overpassed by increasing this spontaneous high‐protein intake suggesting a resistance to lean mass gain in CT phenotype.

Anorexia nervosa (AN) is a severe metabopsychiatric disorder characterised by caloric intake restriction and often excessive physical exercise. Our aim is to assess in female AN patients and in a rodent model, the co-evolution of physical activity and potential dysregulation of acyl-(AG) and desacyl-(DAG) ghrelin plasma concentrations during denutrition and weight recovery. AN inpatients were evaluated at inclusion (T0, n = 29), half-(T1) and total (T2) weight recovery, and one month after discharge (T3, n = 13). C57/Bl6 mice with access to a running wheel, were fed ad libitum or submitted to short-(15 days) or long-(50 days) term quantitative food restriction, followed by refeeding (20 days). In AN patients, AG and DAG rapidly decreased during weight recovery (T0 to T2), AG increased significantly one-month post discharge (T3), but only DAG plasma concentrations at T3 correlated negatively with BMI and positively with physical activity. In mice, AG and DAG both increased during short- and long-term food restriction. After 20 days of ad libitum feeding, DAG was associated to persistence of exercise alteration. The positive association of DAG with physical activity during caloric restriction and after weight recovery questions its role in the adaptation mechanisms to energy deprivation that need to be considered in recovery process in AN.

[This corrects the article DOI: 10.3389/fnagi.2018.00297.].

Somatostatin (SOM) and somatostatin receptors (SSTR1-4) are present in all olfactory structures, including the olfactory bulb (OB), where SOM modulates physiological gamma rhythms and olfactory discrimination responses. In this work, histological, viral tracing and transgenic approaches were used to characterize SOM cellular targets in the murine OB. We demonstrate that SOM targets all levels of mitral dendritic processes in the OB with somatostatin receptor 2 (SSTR2) detected in the dendrites of previously uncharacterized mitral-like cells. We show that inhibitory interneurons of the glomerular layer (GL) express SSTR4 while SSTR3 is confined to the granule cell layer (GCL). Furthermore, SOM cells in the OB receive synaptic inputs from olfactory cortical afferents. Behavioral studies demonstrate that genetic deletion of SSTR4, SSTR2 or SOM differentially affects olfactory performance. SOM or SSTR4 deletion have no major effect on olfactory behavioral performances while SSTR2 deletion impacts olfactory detection and discrimination behaviors. Altogether, these results describe novel anatomical and behavioral contributions of SOM, SSTR2 and SSTR4 receptors in olfactory processing.

The neuroendocrine system (NES) plays a crucial role in synchronizing the physiology and behavior of the whole organism in response to environmental constraints. The NES consists of a hypothalamic-pituitary-target organ axis that acts in coordination to regulate growth, reproduction, stress and basal metabolism. The growth (or somatotropic), hypothalamic-pituitary-gonadal (HPG), hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes are therefore finely tuned by the hypothalamus through the successive release of hypothalamic and pituitary hormones to control the downstream physiological functions. These functions rely on a complex set of mechanisms requiring tight synchronization between peripheral organs and the hypothalamic-pituitary complex, whose functionality can be altered during aging. Here, we review the results of research on the effects of aging on the NES of nonhuman primate (NHP) species in wild and captive conditions. A focus on the age-related dysregulation of the master circadian pacemaker, which, in turn, alters the synchronization of the NES with the organism environment, is proposed. Finally, practical and ethical considerations of using NHP models to test the effects of nutrition-based or hormonal treatments to combat the deterioration of the NES are discussed.

Vesicular glutamate transporters (VGLUT1-3) mediate the uptake of glutamate into synaptic vesicles. VGLUTs are pivotal actors of excitatory transmission and of almost all brain functions. Their implication in various pathologies has been clearly documented. Despite their functional importance, the pharmacology of VGLUTs is limited to a few dyes such as Trypan Blue, Rose Bengal or Brilliant Yellow type. Here, we report the design and evaluation of new potent analogs based on Trypan Blue scaffold. Our best compound, named LSP5-2157, has an EC50 of 50 nM on glutamate vesicular uptake. Using a 3D homology model of VGLUT1 and docking experiments, we determined its putative binding subdomains within vesicular glutamate transporters and validated the structural requirement for VGLUT inhibition. To better estimate the specificity and potency of LSP5-2157, we also investigated its ability to block glutamatergic transmission in autaptic hippocampal cells. Neither glutamate receptors nor GABAergic transmission or transmission machinery were affected by LSP5-2157. Low doses of compound reversibly reduce glutamatergic neurotransmission in hippocampal autpases. LSP5-2157 had a low and depressing effect on synaptic efficacy in hippocampal slice. Furthermore, LSP5-2157 had no effect on NMDA-R- mediated fEPSP but reduce synaptic plasticity induced by 3 trains of 100 Hz. Finally, LSP5-2157 had the capacity to inhibit VGLUT3-dependent auditory synaptic transmission in the guinea pig cochlea. In this model, it abolished the compound action potential of auditory nerve at high concentration showing the limited permeation of LSP5-2157 in an in-vivo model. In summary, the new ligand LSP5-2157, has a high affinity and specificity for VGLUTs and shows some permeability in isolated neuron, tissue preparations or in vivo in the auditory system. These findings broaden the field of VGLUTs inhibitors and open the way to their use to assess glutamatergic functions in vitro and in vivo.

Recent data confirmed the efficiency of caloric restriction for promoting both healthspan and lifespan in primates, but also revealed potential adverse effects at the central level. This paper proposes perspectives and future directions to counterbalance potential adverse effects. Efforts should be made in combining nutrition-based clinical protocols with therapeutic and/or behavioral interventions to aim for synergetic effects, and therefore delay the onset of age-related diseases without adverse effects.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

To face the load of the prevalence of Alzheimer's disease in the aging population, there is an urgent need to develop more translatable animal models with similarities to humans in both the symptomatology and physiopathology of dementia. Due to their close evolutionary similarity to humans, non-human primates (NHPs) are of primary interest. Of the NHPs, to date, the gray mouse lemur (Microcebus murinus) has shown promising evidence of its translatability to humans. The present review reports the known advantages and limitations of using this species at all levels of investigation in the context of neuropsychiatric conditions. In this easily bred Malagasy primate with a relatively short life span (approximately 12 years), age-related cognitive decline, amyloid angiopathy, and risk factors (i.e., glucoregulatory imbalance) are congruent with those observed in humans. More specifically, analogous behavioral and psychological symptoms and neuropsychiatric symptoms of dementia (BPSD/NPS) to those in humans can be found in the aging mouse lemur. Aged mouse lemurs show typical age-related alterations of locomotor activity daily rhythms such as decreased rhythm amplitude, increased fragmentation, and increased activity during the resting-sleeping phase of the day and desynchronization with the light-dark cycle. In addition, sleep deprivation successfully induces cognitive deficits in adult mouse lemurs, and the effectiveness of approved cognitive enhancers such as acetylcholinesterase inhibitors or N-methyl-D-aspartate antagonists is demonstrated in sleep-deprived animals. This result supports the translational potential of this animal model, especially for unraveling the mechanisms underlying dementia and for developing novel therapeutics to prevent age-associated cognitive decline. In conclusion, actual knowledge of BPSD/NPS-like symptoms of age-related cognitive deficits in the gray mouse lemur and the recent demonstration of the similarity of these symptoms with those seen in humans offer promising new ways of investigating both the prevention and treatment of pathological aging.