Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction during sleep. OSA leads to high cardiovascular morbidity and mortality. The pathogenesis of OSA has been linked to a defect in neuromuscular control of the pharynx. There is no effective pharmacotherapy for OSA. The objective of this study was to determine whether upper airway patency can be improved using chemogenetic approach by deploying designer receptors exclusively activated by designer drug (DREADD) in the hypoglossal motorneurons. DREADD (rAAV5-hSyn-hM3(Gq)-mCherry) and control virus (rAAV5-hSyn-EGFP) were stereotactically administered to the hypoglossal nucleus of C57BL/6J mice. In 6–8 weeks genioglossus EMG and dynamic MRI of the upper airway were performed before and after administration of the DREADD ligand clozapine-N-oxide (CNO) or vehicle (saline). In DREADD-treated mice, CNO activated the genioglossus muscle and markedly dilated the pharynx, whereas saline had no effect. Control virus treated mice showed no effect of CNO. Our results suggest that chemogenetic approach can be considered as a treatment option for OSA and other motorneuron disorders.

STUDY OBJECTIVES Obesity hypoventilation and obstructive sleep apnea are common complications of obesity linked to defects in respiratory pump and upper airway neural control. Leptin-deficient ob/ob mice have impaired ventilatory control and inspiratory flow limitation during sleep, which are both reversed with leptin. We aimed to localize central nervous system (CNS) site(s) of leptin action on respiratory and upper airway neuroventilatory control. METHODS We localized the effect of leptin to medulla versus hypothalamus by administering intracerbroventricular leptin (10 μg/2 μL) versus vehicle to the lateral (n = 14) versus fourth ventricle (n = 11) of ob/ob mice followed by polysomnographic recording. Analyses were stratified for effects on respiratory (nonflow-limited breaths) and upper airway (inspiratory flow limitation) functions. CNS loci were identified by (1) leptin-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation and (2) projections of respiratory and upper airway motoneurons with a retrograde transsynaptic tracer (pseudorabies virus). RESULTS Both routes of leptin administration increased minute ventilation during nonflow-limited breathing in sleep. Phrenic motoneurons were synaptically coupled to the nucleus of the solitary tract, which also showed STAT3 phosphorylation, but not to the hypothalamus. Inspiratory flow limitation and obstructive hypopneas were attenuated by leptin administration to the lateral but not to the fourth cerebral ventricle. Upper airway motoneurons were synaptically coupled with the dorsomedial hypothalamus, which exhibited STAT3 phosphorylation. CONCLUSIONS Leptin relieves upper airway obstruction in sleep apnea by activating the forebrain, possibly in the dorsomedial hypothalamus. In contrast, leptin upregulates ventilatory control through hindbrain sites of action, possibly in the nucleus of the solitary tract.

Multiple physiologic and neural systems contribute to the controls over what and how much we eat. These systems include signaling involved in the detection and signaling of nutrient availability, signals arising from consumed nutrients that provide feedback information during a meal to induce satiation, and signals related to the rewarding properties of eating. Each of these has a separate neural representation, but important interactions among these systems are critical to the overall controls of food intake.

The prevalence of obesity worldwide has nearly doubled since 1980 with current estimates of 2.1 billion in 2013. Overweight and obesity lead to numerous adverse conditions including type 2 diabetes, cardiovascular disease, stroke, and certain cancers. The worldwide spread of obesity and associated comorbidities not only threatens quality of life but also presents a significant economic burden. While bariatric surgery has proven to be a viable treatment option for the morbidly obese, there is clearly a need for less invasive alternatives. Recent research has suggested that long-acting analogs of the gut hormone, glucagon-like peptide 1 (GLP-1), may have potential as an antiobesity treatment. The GLP-1 receptor agonist, liraglutide (trade name Saxenda), was recently approved by the US Food and Drug Administration as an obesity treatment option and shown in clinical trials to be effective in reducing and sustaining body weight loss. This review presents the basis for GLP-1-based therapies with a specific focus on animal and human studies examining liraglutide's effects on food intake and body weight.

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene. Disease pathogenesis derives, at least in part, from the long polyglutamine tract encoded by mutant HTT. Therefore, considerable effort has been dedicated to the development of therapeutic strategies that significantly reduce the expression of the mutant HTT protein. Antisense oligonucleotides (ASOs) targeted to the CAG repeat region of HTT transcripts have been of particular interest due to their potential capacity to discriminate between normal and mutant HTT transcripts. Here, we focus on phosphorodiamidate morpholino oligomers (PMOs), ASOs that are especially stable, highly soluble and non-toxic. We designed three PMOs to selectively target expanded CAG repeat tracts (CTG22, CTG25 and CTG28), and two PMOs to selectively target sequences flanking the HTT CAG repeat (HTTex1a and HTTex1b). In HD patient-derived fibroblasts with expanded alleles containing 44, 77 or 109 CAG repeats, HTTex1a and HTTex1b were effective in suppressing the expression of mutant and non-mutant transcripts. CTGn PMOs also suppressed HTT expression, with the extent of suppression and the specificity for mutant transcripts dependent on the length of the targeted CAG repeat and on the CTG repeat length and concentration of the PMO. PMO CTG25 reduced HTT-induced cytotoxicity in vitro and suppressed mutant HTT expression in vivo in the N171-82Q transgenic mouse model. Finally, CTG28 reduced mutant HTT expression and improved the phenotype of Hdh(Q7/Q150) knock-in HD mice. These data demonstrate the potential of PMOs as an approach to suppressing the expression of mutant HTT.

Purpose of review This review focuses on recent advances in understanding the multiple roles of gastrointestinal peptides in the control of food intake and body weight with specific emphasis on ghrelin, amylin and glucagon-like peptide 1. Recent findings Recent studies support a role for ghrelin, amylin and glucagon-like peptide 1 in short-term and long-term effects on food intake and body weight. Apart from contributing to energy homeostasis, ghrelin's participation in reward and sensory processing has been the focus of much recent work. New findings on amylin's effects on food intake and energy balance provide further support for its role in meal-related food intake and suggest that it may also function as an adiposity signal. New investigations on the role of central and peripheral glucagon-like peptide 1 receptors in mediating the anorexic effects of glucagon-like peptide 1 have suggested that they differentially contribute to short-term and long term effects on food intake. Summary Gastrointestinal peptides can influence food intake through mechanisms that involve short-term meal-related effects or through activation of central pathways involved in energy balance. An appreciation of the multiple actions of gastrointestinal peptides on food intake will aid in developing new strategies for weight management.

Signaling from energy stores provides feedback on overall nutrient availability to influence food intake. Beginning with seminal studies by Woods and colleagues identifying insulin as an adiposity signal, it has become clear that such factors affect food intake by modulating the efficacy of within meal feedback satiety signals. More recent work with leptin has revealed actions of the hormone in modulating the efficacy of multiple gut feedback signals, identified the dorsal hindbrain as a site of signal integration and suggested both local and descending hypothalamic to hindbrain actions in mediating these effects. The original work by Woods and colleagues provided the necessary experimental paradigms for these advances.

Endogenous cannabinoid signaling, mediated predominately by CB1 receptor activation, is involved in food intake control and body weight regulation. Despite advances in determining the role of the CB1 receptor in obesity, its involvement in the driven nature of eating pathologies has received little attention. The present study examined CB1 receptor alterations as a consequence of dietary-induced binge eating in female Sprague Dawley rats. Four control groups were used to control for calorie restriction and highly palatable food variables characterizing this behavioral model. All groups were kept on their respective feeding schedules for 6-weeks and were given a uniform 33% calorie restriction (~22 h food deprivation) prior to sacrifice. Our findings indicate that regional CB1 mRNA and density were influenced by dietary conditions, but were not specific to the dietary-induced binge eating paradigm used. An increase of approximately 50% (compared with naive controls) in CB1 receptor mRNA levels in the nucleus of the solitary tract as measured by in situ hybridization was found in animals receiving continuous access to a highly palatable food (i.e., vegetable shortening with 10% sucrose). This group also had a significant increase in body weight and adiposity. An approximate 20% reduction in CB1 mRNA was observed in the cingulate cortex (areas 1 and 2) in animals exposed to an intermittent schedule of feeding, compared with groups that had ad libitum feeding schedules (i.e., continuous access and naive controls). Receptor density as measured by [(3)H]CP55,940 autoradiography, was reduced by approximately 30% in the nucleus accumbens shell region in groups receiving repeated access to the highly palatable food. Taken together, these findings indicate that dietary conditions can differentially influence CB1 receptors in forebrain and hindbrain regions.

Fusion proteins made up of glucagon-like peptide 1 (GLP-1) and exendin-4 (EX-4) fused to a nonglycosylated form of human transferrin (GLP-1-Tf or EX-4-Tf) were produced and characterized. GLP-1-Tf activated the GLP-1 receptor, was resistant to inactivation by peptidases, and had a half-life of approximately 2 days, compared with 1 to 2 min for native GLP-1. GLP-1-Tf retained the acute, glucose-dependent insulin-secretory properties of native GLP-1 in diabetic animals and had a profound effect on proliferation of pancreatic beta-cells. In addition, Tf and the fusion proteins did not cross the blood-brain-barrier but still reduced food intake after peripheral administration. EX-4-Tf proved to be as effective as EX-4 but had longer lived effects on blood glucose and food intake. This novel transferrin fusion technology could improve the pharmacology of various peptides.

In the early 1970s, the screening of over 500 amphibian species led to the discovery by two independent investigators of several structurally related peptides from amphibian skin now referred to as the bombesin (BN) family of peptides. These peptides were classified into three subfamilies (bombesin, ranatensin and litorin) based on their carboxy terminal amino acid sequences. Subsequently, two mammalian peptides were identified that showed remarkable sequence homology with other members of this family. Neuromedin B (NMB), a decapeptide originally isolated from porcine spinal cord, bears close structural homology with ranatensin whereas gastrin-releasing peptide (GRP) isolated from porcine stomach shares the same carboxy terminal heptapeptide sequence with BN and similar biological activity. In mammals, this family of peptides is composed of three known subtypes of closely related G-protein-coupled receptors. Two subtypes, neuromedin B receptor (NMB-R or BB1) and gastrin-releasing peptide receptor (GRP-R or BB2), were initially identified and characterized in the periphery and brain by pharmacological methods. GRP-R was shown to have a greater than 50-fold higher affinity for GRP than NMB, while NMB-R had a 100-fold higher affinity for NMB than GRP. Subsequently, these receptors were cloned, and an additional mammalian BN receptor subtype, BN receptor subtype-3 (BRS-3 or BB3) was identified through homology screening and found to share approximately 50% identity with GRP-R and NMB-R; however, the natural ligand for this receptor has not been identified. These peptides have distinct distributions throughout the periphery and central nervous system and possess a wide spectrum of biological activity. Many of the actions of NMB are similar to those of BN or GRP but are frequently less potent in stimulating these actions. In the periphery, NMB has been shown to contract rat uterus and gastrointestinal smooth muscle and stimulate the release of several gastrointestinal and pancreatic peptides. Relevant to this discussion, exogenous administration of BN-like peptides suppresses food intake after either peripheral or central administration with the rank order of inhibition being BN > GRP > NMB. The development of specific BN receptor antagonists was instrumental in demonstrating that NMB acted independently of GRP to suppress food intake. However, the lack of a robust effect on food intake made it the ‘underdog’ of bombesin-like peptides and consequently it received very limited attention as a satiety peptide. Because of complications in interpreting much of the pharmacological data, Ohki-Hamazaki and colleagues developed mice with specific deletions of the three mammalian BN receptor subtypes to help elucidate their physiological roles (Ohki-Hamazaki et al. 2005). It was found that deletions of BRS-3 resulted in an obese phenotype with deficits in energy regulation and an increased preference for sweet taste. Mice lacking GRP-R exhibited deficits in meal-related satiety signalling and developed late onset obesity. Despite an apparent role for NMB in food intake, the phenotype of mice with a targeted deletion of NMB-R could only be characterized as unremarkable. Mice deficient in NMB-R exhibited normal body weight and chow intake, and showed no differences in taste preference for palatable foods compared to wild-type mice. However, a variety of behavioural tests in NMB-R knockout (KO) mice have suggested that NMB plays a role in anxiety and stress-related behaviours. In this issue of The Journal of Physiology, Paula et al. (2010) have conducted experiments in female NMB-R-deficient mice that reveal a previously undetected phenotype with important implications in food intake and energy balance. As reported previously, when female NMB-R KO mice were fed a standard chow diet their food intake and body weight did not differ from wild-type (WT) mice. However, when challenged with a high-fat diet NMB-R KO mice were partially resistant to the obesogenic effects of the high fat diet. Remarkably, NMB-R KO mice consumed the same number of calories as WT mice but failed to gain significant body weight. Consistent with this, the authors demonstrate that high-fat-fed NMB-R KO mice exhibited less adipose tissue hypertrophy and adipose tissue mass than similarly fed WT mice. Because no differences in adipose tissue mass were demonstrated between NMB-R KO and WT mice fed a normolipid diet, the authors suggest that NMB-R KO mice must increase their energy expenditure in response to high-fat feeding. Unlike high-fat-fed WT mice, NMB-R KO mice did not exhibit impairments in glucose tolerance. Since NMB-KO mice were consuming the same amount of food as WT mice, this suggests that diet composition alone was not contributing to impaired glucose tolerance but that the latter was probably dependent upon increased body weight. The results of this study highlight a renewed interest in NMB as an important component in energy balance regulation. Recent studies have shown NMB and NMB-R to be significant regulators of the hypothalamic-pituitary-adrenal axis through modulation of thyrotropin secretion (Oliveira et al. 2007). Studies by Hoggard et al. (2007) have demonstrated that NMB mRNA is present in human and rodent adipose tissue and that expression levels can be altered by changes in energy balance and leptin signalling. Moreover, electrophysiological studies have shown a robust excitatory effect of NMB on neuropeptide Y neurons in the arcuate nucleus, a brain region that is critical to energy homeostasis (von den Pol et al. 2009). In humans, NMB has been suggested as a strong candidate gene linking eating behaviours to the susceptibility to obesity (Bouchard et al. 2004). The Quebec Family Study, a large prospective study designed to identify the genetics of obesity and related diseases, found that a missense mutation within exon 2 of the NMB gene was significantly associated with eating behaviours and obesity. This mutation resulted in twice as much body fat gain over a 6 year period compared to those without the mutation. How these data mesh with the results from the present study remains to be determined; however, they do suggest that NMB/NMB-R pathways may play a critical role in adipose tissue deposition or metabolism and provide a potential target for therapeutic intervention in the control of body weight.

Gastrin-releasing peptide (GRP) is a bombesin-like peptide widely distributed in the gastrointestinal tract and central nervous system. In the brain, GRP mRNA is located in the hypothalamic paraventricular nucleus (PVN), a region that receives neural input from the arcuate nucleus and plays a critical role in food intake and energy balance. Because GRP neurons are localized in the vicinity of projection sites in the PVN for peptides that participate in energy homeostasis, we investigated whether GRP mRNA expression in the PVN may be sensitive to challenges imposed by either 38 h food deprivation or stimulation of the melanocortin system by the melanocortin 3/4 receptor agonist, melanotan II (MTII). We found that food deprivation significantly decreased GRP mRNA expression, whereas lateral ventricular MTII administration increased GRP mRNA expression in ad libitum-fed rats 4 h after administration. Furthermore, administration of MTII at a dose that reduces 24 h food intake and body weight prevented the decrease in GRP mRNA expression observed in animals that were pair fed to the amount of food consumed by those injected with MTII. These results demonstrate that food deprivation and stimulation of the melanocortin system produce opposing changes in GRP gene expression in the PVN, suggesting that GRP-containing neurons in the PVN may be part of the hypothalamic signaling pathway controlling food intake and energy balance.

As quantum computing moves closer to real-world application, engineers are considering how to meet the challenge of transmitting quantum information faithfully down long, noisy optical fibers. The fidelity with which an entangled photon pair can be sent down a fiber decreases exponentially with distance, requiring repeater nodes spaced 10 km apart. Liang Jiang et al. report an approach to finding an optimal protocol to carry out the many operations necessary to make quantum information transfer practical. The process of optimization, they explain, is analogous to the ‘‘nesting problem’’ of multiplying a string of large matrices with the minimal number of calculations. Also, the system is self-similar, so the same protocol applies at any length scale. The authors optimize the process for two major types of repeater architectures (BDCZ and CTSL) by adjusting three parameters: the time required to generate entangled pairs, the internodal distances, and the number of steps taken to improve fidelity by ‘‘entanglement purification.’’ Even for optimized protocols, quantum information transfer remains more than two orders of magnitude slower than classical; the authors say that further experimental advances are necessary to make this mode of communication viable. — K.M.