Various environmental stressors, such as extreme temperatures (hot and cold), pathogens, predators and insufficient food, can threaten life. Remarkable progress has recently been made in ...understanding the central circuit mechanisms of physiological responses to such stressors. A hypothalamomedullary neural pathway from the dorsomedial hypothalamus (DMH) to the rostral medullary raphe region (rMR) regulates sympathetic outflows to effector organs for homeostasis. Thermal and infection stress inputs to the preoptic area dynamically alter the DMH → rMR transmission to elicit thermoregulatory, febrile and cardiovascular responses. Psychological stress signalling from a ventromedial prefrontal cortical area to the DMH drives sympathetic and behavioural responses for stress coping, representing a psychosomatic connection from the corticolimbic emotion circuit to the autonomic and somatic motor systems. Under starvation stress, medullary reticular neurons activated by hunger signalling from the hypothalamus suppress thermogenic drive from the rMR for energy saving and prime mastication to promote food intake. This Perspective presents a combined neural network for environmental stress responses, providing insights into the central circuit mechanism for the integrative regulation of systemic organs.
Thermoregulatory behaviour, such as migration to a comfortable thermal environment, is a representative innate animal behaviour and facilitates effective autonomic regulation of body temperature with ...a reduced cost of resources. Here we determine the central thermosensory ascending pathway that transmits information on environmental temperature from cutaneous thermoreceptors to elicit thermoregulatory behaviour. To examine the contribution of the spinothalamocortical pathway, which is known to mediate thermosensory transmission for perception of skin temperature, we lesioned thalamic regions mediating this pathway in rats. Thalamic-lesioned rats showed compromised electroencephalographic responses in the primary somatosensory cortex to changes in skin temperature, indicating functional ablation of the spinothalamocortical pathway. However, these lesioned rats subjected to a two-floor innocuous thermal plate preference test displayed intact heat- and cold-avoidance thermoregulatory behaviours. We then examined the involvement of the lateral parabrachial nucleus (LPB), which mediates cutaneous thermosensory signaling to the thermoregulatory center for autonomic thermoregulation. Inactivation of neurons in the LPB eliminated both heat- and cold-avoidance thermoregulatory behaviours and ablated heat defense. These results demonstrate that the LPB, but not the thalamus, mediates the cutaneous thermosensory neural signaling required for behavioural thermoregulation, contributing to understanding of the central circuit that generates thermal comfort and discomfort underlying thermoregulatory behaviours.
Energy homeostasis of mammals is maintained by balancing energy expenditure within the body and energy intake through feeding. Several lines of evidence indicate that brown adipose tissue (BAT), a ...sympathetically activated thermogenic organ, turns excess energy into heat to maintain the energy balance in rodents and humans, in addition to its thermoregulatory role for the defense of body core temperature in cold environments. Elucidating the central circuit mechanism controlling BAT thermogenesis dependent on nutritional conditions and food availability in relation to energy homeostasis is essential to understand the etiology of symptoms caused by energy imbalance, such as obesity. The central thermogenic command outflow to BAT descends through an excitatory neural pathway mediated by hypothalamic, medullary and spinal sites. This sympathoexcitatory thermogenic drive is controlled by tonic GABAergic inhibitory signaling from the thermoregulatory center in the preoptic area, whose tone is altered by body core and cutaneous thermosensory inputs. This circuit controlling BAT thermogenesis for cold defense also functions for the development of fever and psychological stress-induced hyperthermia, indicating its important role in the defense from a variety of environmental stressors. When food is unavailable, hunger-driven neural signaling from the hypothalamus activates GABAergic neurons in the medullary reticular formation, which then block the sympathoexcitatory thermogenic outflow to BAT to reduce energy expenditure and simultaneously command the masticatory motor system to promote food intake—effectively commanding responses to survive starvation. This article reviews the central mechanism controlling BAT thermogenesis in relation to the regulation of energy and thermal homeostasis dependent on food availability.
The recent discovery of the medullary circuit driving “hunger responses” – reduced thermogenesis and promoted feeding – has greatly expanded our knowledge on the central neural networks for energy ...homeostasis. However, how hypothalamic hunger and satiety signals generated under fasted and fed conditions, respectively, control the medullary autonomic and somatic motor mechanisms remains unknown. Here, in reviewing this field, we propose two hypothalamomedullary neural pathways for hunger and satiety signaling. To trigger hunger signaling, neuropeptide Y activates a group of neurons in the paraventricular hypothalamic nucleus (PVH), which then stimulate an excitatory pathway to the medullary circuit to drive the hunger responses. In contrast, melanocortin‐mediated satiety signaling activates a distinct group of PVH neurons, which then stimulate a putatively inhibitory pathway to the medullary circuit to counteract the hunger signaling. The medullary circuit likely contains inhibitory and excitatory premotor neurons whose alternate phasic activation generates the coordinated masticatory motor rhythms to promote feeding.
Energy homeostasis is maintained by the central neural circuits that consist of the hypothalamic circuits evaluating nutritional status and the medullary motor circuits controlling energy expenditure and intake. Here, two key pathways that transmit hypothalamic hunger and satiety signals to the medullary motor systems to drive appropriate responses for energy homeostasis are proposed.
Aims/Introduction
Non‐alcoholic fatty liver disease (NAFLD) is often observed in individuals with type 2 diabetes mellitus, and it is known that the presence of type 2 diabetes mellitus leads to the ...aggravation of NAFLD. The aim of this study was to compare the possible effects of three kinds of oral hypoglycemic agents on NAFLD in individuals with type 2 diabetes mellitus.
Materials and Methods
We carried out a prospective clinical trial (a randomized and open‐label study) in patients with type 2 diabetes mellitus and NAFLD. A total of 98 patients were randomly allocated either to the dapagliflozin (n = 32), pioglitazone (n = 33) or glimepiride (n = 33) group, and the patients took these drugs for 28 weeks. The primary end‐point was the change of the liver‐to‐spleen ratio on abdominal computed tomography.
Results
There was no difference in baseline clinical characteristics among the three groups. Dapagliflozin, pioglitazone and glimepiride ameliorated hyperglycemia similarly. Bodyweight and visceral fat area were significantly decreased only in the dapagliflozin group. Serum adiponectin levels were markedly increased in the pioglitazone group compared with the other two groups. Dapagliflozin and pioglitazone, but not glimepiride, significantly increased the liver‐to‐spleen ratio, and the effects of dapagliflozin and pioglitazone on the liver‐to‐spleen ratio were comparable.
Conclusions
The present study showed that the decrease of visceral fat area and the increase of adiponectin level contributed to the improvement of NAFLD in patients with type 2 diabetes mellitus. Furthermore, dapagliflozin and pioglitazone exerted equivalent beneficial effects on NAFLD in patients with type 2 diabetes mellitus, although it seemed that these two drugs had different mechanisms of action.
Dapagliflozin and pioglitazone exerted equivalent beneficial effects on non‐alcoholic fatty liver disease in subjects with type 2 diabetes mellitus, although it seemed that these two drugs had different mechanisms of action. Dapagliflozin reduced hepatic fat storage mainly through a decrease of fat quantity, but pioglitazone improved hepatic steatosis through upgrading fat quality. Lowered plasma glucose by glimepiride might inhibit worsening of hepatic steatosis.
Psychological stress‐induced hyperthermia is a fundamental autonomic response in mammals. However, the central circuitry underlying this stress response is poorly understood. Here, we sought to ...identify sympathetic premotor neurons that mediate a hyperthermic response to social defeat stress, a psychological stress model. Intruder rats that were defeated by a dominant resident conspecific exhibited a rapid increase in abdominal temperature by up to 2.0 °C. In these defeated rats, we found that expression of Fos, a marker of neuronal activation, was increased in the rostral medullary raphe region centered in the rostral raphe pallidus and adjacent raphe magnus nuclei. In this region, Fos expression was observed in a large population of neurons expressing vesicular glutamate transporter 3 (VGLUT3), which are known as sympathetic premotor neurons controlling non‐shivering thermogenesis in brown adipose tissue (BAT) and thermoregulatory constriction of skin blood vessels, and also in a small population of tryptophan hydroxylase‐positive serotonergic neurons. Intraperitoneal injection of diazepam, an anxiolytic agent, but not indomethacin, an antipyretic, significantly reduced both the stress‐induced hyperthermia and Fos expression in these medullary raphe neuronal populations. Systemic blockade of β3‐adrenoreceptors, which are abundantly expressed in BAT, also attenuated the stress‐induced hyperthermia. These results suggest that psychological stress signals activate VGLUT3‐expressing medullary raphe sympathetic premotor neurons, which then drive hyperthermic effector responses including BAT thermogenesis through β3‐adrenoreceptors.
Psychological stress‐induced hyperthermia is a fundamental autonomic response in mammals. However, the central circuitry underlying this stress response is poorly understood.
The bidirectional controller of the thermoregulatory center in the preoptic area (POA) is unknown. Using rats, here, we identify prostaglandin EP3 receptor-expressing POA neurons (POA
neurons) as a ...pivotal bidirectional controller in the central thermoregulatory mechanism. POA
neurons are activated in response to elevated ambient temperature but inhibited by prostaglandin E
, a pyrogenic mediator. Chemogenetic stimulation of POA
neurons at room temperature reduces body temperature by enhancing heat dissipation, whereas inhibition of them elicits hyperthermia involving brown fat thermogenesis, mimicking fever. POA
neurons innervate sympathoexcitatory neurons in the dorsomedial hypothalamus (DMH) via tonic (ceaseless) inhibitory signaling. Although many POA
neuronal cell bodies express a glutamatergic messenger RNA marker, their axons in the DMH predominantly release γ-aminobutyric acid (GABA), and their GABAergic terminals are increased by chronic heat exposure. These findings demonstrate that tonic GABAergic inhibitory signaling from POA
neurons is a fundamental determinant of body temperature for thermal homeostasis and fever.
Hepatic venous pressure gradient (HVPG) is the gold standard index for evaluating portal hypertension; however, measuring HVPG is invasive. Although transient elastography (TE) is the most common ...procedure for evaluating organ stiffness, accurate measurement of spleen stiffness (SS) is difficult. We developed a device to demonstrate the diagnostic precision of TE and suggest this technique as a valuable new method to measure SS.
Of 292 consecutive patients enrolled in this single-centre, translational, cross-sectional study from June through September in 2019, 200 underwent SS measurement (SSM) using an M probe (training set, n = 130; inspection set, n = 70). We performed TE with B-mode imaging using an ultrasound-fusion method, printed new devices with a three-dimensional printer, and attached the magnetic position sensor to the convex and M probes. We evaluated the diagnostic precision of TE to evaluate the risk of esophagogastric varices (EGVs).
The median spleen volume was 245 mL (range, 64-1,720 mL), and it took 2 minutes to acquire a B-mode image using the ultrasound-fusion method. The median success rates of TE were 83.3% and 57.6% in patients with and without the new device, respectively (p<0.001); it was 76.9% and 35.0% in patients with and without splenomegaly (<100 mL), respectively (p<0.001). In the prediction of EGVs, the areas under the receiver operating characteristic curve were 0.921 and 0.858 in patients with and without the new device, respectively (p = 0.043). When the new device was attached, the positive and negative likelihood ratios were 3.44 and 0.11, respectively. The cut-off value of SSM was 46.0 kPa. Data that were similar between the validation and training sets were obtained.
The SS can be precisely measured using this new device with TE and ultrasound-fusion method. Similarly, we can estimate the bleeding risk due to EGV using this method.
Aim
Liver stiffness measured using transient elastography (TE) is affected by tissue viscosity. The role of intrahepatic lymphatic fluid in liver stiffness is unclear. The present study aimed to ...investigate the effects of lymphatic vessel dilatation on liver stiffness.
Methods
Patients with chronic liver disease (n = 116) were enrolled from June 2018 to March 2020. All specimens were acquired by laparoscopic liver biopsy. Biopsy samples were stained with D2‐40 for lymphatic vessel quantification based on a five‐point scale for each specimen. Independent associations of liver stiffness measured by TE, strain elasticity (liver fibrosis index), and controlled attenuation parameter with fibrosis, lymphatic vessels, alanine aminotransferase, bilirubin, and steatosis were evaluated.
Results
Fibrosis, splenic stiffness measurement, and splenic volume were significantly correlated with the area of lymphatic vessels. Fibrosis, lymphatic vessels, and alanine aminotransferase were independent factors significantly associated with liver stiffness measurement (LSM; standardized coefficient β = 0.375, P < 0.001; β = 0.342, P < 0.001; and β = 0.359, P < 0.001, respectively). Fibrosis was the only independent factor significantly associated with liver fibrosis index (β = 0.360, P < 0.001), whereas the fat deposit area was the only independent factor significantly associated with controlled attenuation parameter (β = 0.455, P < 0.001). The areas under the receiver operating characteristic curves for diagnosing controlled ascites based on LSM, liver fibrosis index, splenic stiffness measurement, collagen proportionate area, and area of lymphatic vessels were 0.94, 0.66, 0.76, 0.64, and 0.79, respectively.
Conclusions
Lymphatic vessel dilatation can affect liver stiffness measured using TE. Liver stiffness measurement is a predictive factor for ascites.
The accuracy of attenuation coefficients and B-mode ultrasound for distinguishing between S0 (healthy, < 5% fat) and S1–3 (steatosis ≥ 5%) livers compared to a controlled attenuation parameter is ...unclear. This meta-analysis aimed to comprehensively assess the diagnostic performance of B-mode ultrasound imaging for evaluating steatosis of ≥ 5%. We searched the PubMed, Embase, and Web of Science databases for studies on the accuracy of B-mode ultrasound for differentiating S0 from S1–3 in adults with chronic liver disease. A bivariate random-effects model was performed to estimate the pooled sensitivity, specificity, positive (PLR) and negative likelihood ratios (NLR), and diagnostic odds ratios (DORs). Subgroup analyses by attenuation coefficient, conventional B-mode ultrasound findings, and B-mode ultrasound findings without semi-quantification methods were performed. Liver steatosis was scored as follows: S0, < 5%; S1, 5–33%; S2, 33–66%; and S3, > 66%. Nineteen studies involving 3240 patients were analyzed. The pooled sensitivity and specificity of B-mode ultrasound for detecting S1 were 0.70 (95% confidence interval CI, 0.63–0.77) and 0.86 (95% CI 0.82–0.89), respectively. The pooled PLR, NLR, and DOR were 4.90 (95% CI 3.69–6.51), 0.35 (95% CI 0.27– 0.44), and 14.1 (95% CI 8.7–23.0), respectively. The diagnostic accuracy was better in patients with attenuation coefficients (area under the curve AUC, 0.89; sensitivity, 0.75; specificity, 0.86) than in those with conventional B-mode findings (AUC, 0.80; sensitivity, 0.59; specificity, 0.83). In particular, the diagnostic value was better when the attenuation coefficient guided by B-mode ultrasound was utilized. To screen patients with steatosis of ≥ 5%, attenuation coefficient should be used.
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