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Orexins (hypocretins), novel peptides expressed in specific neurons of the lateral hypothalamic area (LHA), stimulate feeding when injected intracerebroventricularly. We investigated their role in feeding in the rat by measuring hypothalamic prepro-orexin mRNA levels under contrasting conditions of increased hunger. Prepro-orexin mRNA levels increased significantly after 48 h of fasting (by 90-170%; P < 0.05) and after acute (6 h) hypoglycemia when food was withheld (by 90%; P < 0.02). By contrast, levels were unchanged during chronic food restriction, streptozotocin-induced diabetes, hypoglycemia when food was available, voluntary overconsumption of palatable food, or glucoprivation induced by systemic 2-deoxy-D-glucose. Orexin expression was not obviously related to changes in body weight, insulin, or leptin, but was stimulated under conditions of low plasma glucose in the absence of food. Orexins may participate in the short-term regulation of energy homeostasis by initiating feeding in response to falls in glucose and terminating it after food ingestion. The LHA is known to contain neurons that are stimulated by falls in circulating glucose but inhibited by feeding-related signals from the viscera; orexin neurons may correspond to this neuronal population.

The general anatomy of the cardiac conduction system (CCS) has been known for 100 years, but its complex and irregular three-dimensional (3D) geometry is not so well understood. This is largely because the conducting tissue is not distinct from the surrounding tissue by dissection. The best descriptions of its anatomy come from studies based on serial sectioning of samples taken from the appropriate areas of the heart. Low X-ray attenuation has formerly ruled out micro-computed tomography (micro-CT) as a modality to resolve internal structures of soft tissue, but incorporation of iodine, which has a high molecular weight, into those tissues enhances the differential attenuation of X-rays and allows visualisation of fine detail in embryos and skeletal muscle. Here, with the use of a iodine based contrast agent (I2KI), we present contrast enhanced micro-CT images of cardiac tissue from rat and rabbit in which the three major subdivisions of the CCS can be differentiated from the surrounding contractile myocardium and visualised in 3D. Structures identified include the sinoatrial node (SAN) and the atrioventricular conduction axis: the penetrating bundle, His bundle, the bundle branches and the Purkinje network. Although the current findings are consistent with existing anatomical representations, the representations shown here offer superior resolution and are the first 3D representations of the CCS within a single intact mammalian heart.

BackgroundHeart rate recovery (HRR) is a noninvasive assessment of autonomic dysfunction and has been implicated with risk of cardiovascular events and all‐cause mortality. However, evidence has not been systematically assessed. We performed a meta‐analysis of prospective cohort studies to quantify these associations in the general population.Methods and ResultsA literature search using 3 databases up to August 2016 was conducted for studies that reported hazard ratios with 95% CIs for the association between baseline HRR and outcomes of interest. The overall hazard ratios were calculated using a random‐effects model. There were 9 eligible studies in total, with 5 for cardiovascular events enrolling 1061 cases from 34 267 participants, and 9 for all‐cause mortality enrolling 2082 cases from 41 600 participants. The pooled hazard ratios associated with attenuated HRR versus fast HRR that served as the referent were 1.69 (95% CI 1.05–2.71) for cardiovascular events and 1.68 (95% CI 1.51–1.88) for all‐cause mortality. For every 10 beats per minute decrements in HRR, the hazard ratios were 1.13 (95% CI 1.05–1.21) and 1.09 (95% CI 1.01–1.19), respectively. Further analyses suggested that the associations observed between attenuated HRR and risk of fatal cardiovascular events and all‐cause mortality were independent of traditional metabolic factors for cardiovascular disease (all P<0.05).ConclusionsAttenuated HRR is associated with increased risk of cardiovascular events and all‐cause mortality, which supports the recommendation of recording HRR for risk assessment in clinical practice as a routine.

Orexins are novel appetite-stimulating peptides expressed in the lateral hypothalamic area (LHA), and their expression is stimulated by hypoglycemia in fasted rats. We investigated activation of orexin and other neurons during insulin-induced hypoglycemia using the immediate early gene product Fos. Insulin (50 U/kg) lowered plasma glucose by >50% after 5 h and stimulated feeding sixfold compared with saline-injected controls. Hypoglycemic rats allowed to feed and normoglycemic controls both showed sparse Fos-positive (Fos + ) neurons in the LHA and the paraventricular nucleus (PVN) and arcuate nucleus (ARC) and showed none in the nucleus of the solitary tract (NTS), which relays visceral feeding signals to the LHA. In the LHA, total numbers of Fos + neurons were comparable in fed hypoglycemic and control groups (60 ± 6 vs. 52 ± 4 cells/mm 2 , P > 0.05), as were Fos + neurons immunoreactive for orexin (1.4 ± 0.4 vs. 0.6 ± 0.4 cells/mm 2 , P > 0.05). By contrast, hypoglycemic rats that were fasted showed significantly more Fos + nuclei in the LHA (96 ± 10 cells/mm 2 , P < 0.05, vs. both other groups) and Fos + orexin neurons (8.4 ± 3.3 cells/mm 2 , P < 0.001, vs. both other groups). They also showed two-to threefold more Fos + nuclei (P < 0.001) in the PVN and ARC than both fed hypoglycemic rats and controls and showed strikingly abundant Fos + neurons in the NTS and dorsal motor nucleus of the vagus. In parallel studies, whole hypothalamic orexin-A levels were not changed in hypoglycemic rats, whether fasted or freely fed, whereas orexin-B levels were 10-fold higher in hypoglycemic fasted rats than in control and hypoglycemic fed groups. These data support our hypothesis that orexin neurons are stimulated T he lateral hypothalamic area (LHA) is important in the overall regulation of feeding behavior and body weight (1). Specifically, it is crucial for the intense hunger that is caused by hypoglycemia. Eating is one component of the concerted metabolic response that is mounted to restore normal blood glucose levels. Lesions of the LHA abolish the hyperphagic response to hypoglycemia induced by insulin (2) and also to neuroglycopenia caused by 2-deoxyglucose (3).The neurochemical identities of the LHA neurons and pathways that mediate hypoglycemia-induced hyperphagia remain uncertain. The LHA contains glucose-sensitive neurons that are stimulated by hypoglycemia, and these account for ~25% of the LHA neurons (4,5). Hypoglycemia mainly activates LHA glucose-sensitive neurons indirectly (6), and pathways ascending from the brainstem are thought to be particularly important. These include a projection from the nucleus of the solitary tract (NTS) (7,8), which relays information from vagal afferents including glucoreceptors in the gut and liver (9). About 75% of recorded NTS neurons respond with altered electrical activity to blood glucose fluctuations within the physiological range (10).Recent evidence suggests that some of the LHA neurons that respond to hypoglycemia express the peptides known as orexins (11) or hypoc...