Loss of transient receptor potential channel 5 causes obesity and postpartum depression.

Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of Trpc5 from oxytocin neurons in the hypothalamic paraventricular nucleus caused obesity in both sexes and postpartum depressive behavior in females, while Trpc5 overexpression in oxytocin neurons in knock-in mice reversed these phenotypes. We demonstrate that TRPC5 plays a pivotal role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care.

A light-responsive neural circuit suppresses feeding.

Light plays an essential role in a variety of physiological processes, including vision, mood, and glucose homeostasis. However, the intricate relationship between light and an animal's feeding behavior has remained elusive. Here, we found that light exposure suppresses food intake, whereas darkness amplifies it in male mice. Interestingly, this phenomenon extends its reach to diurnal male Nile grass rats and healthy humans. We further show that lateral habenula (LHb) neurons in mice respond to light exposure, which in turn activates 5-HT neurons in the dorsal Raphe nucleus (DRN). Activation of the LHb → 5-HTDRN circuit in mice blunts darkness-induced hyperphagia, while inhibition of the circuit prevents light-induced anorexia. Together, we discovered a light responsive neural circuit that relays the environmental light signals to regulate feeding behavior in mice.Significance statement Feeding behavior is influenced by a myriad of sensory inputs, but the impact of light exposure on feeding regulation has remained enigmatic. Here, we showed that light exposure diminishes food intake across both nocturnal and diurnal species. Delving deeper, our findings revealed that the LHb → 5-HTDRN neural circuit plays a pivotal role in mediating light-induced anorexia in mice. These discoveries not only enhance our comprehension of the intricate neuronal mechanisms governing feeding in response to light but also offer insights for developing innovative strategies to address obesity and eating disorders.

Neural circuits expressing the serotonin 2C receptor regulate memory in mice and humans.

Declined memory is a hallmark of Alzheimer's disease (AD). Experiments in rodents and human postmortem studies suggest that serotonin (5-hydroxytryptamine, 5-HT) plays a role in memory, but the underlying mechanisms are unknown. Here, we investigate the role of 5-HT 2C receptor (5-HT2CR) in regulating memory. Transgenic mice expressing a humanized HTR2C mutation exhibit impaired plasticity of hippocampal ventral CA1 (vCA1) neurons and reduced memory. Further, 5-HT neurons project to and synapse onto vCA1 neurons. Disruption of 5-HT synthesis in vCA1-projecting neurons or deletion of 5-HT2CRs in the vCA1 impairs neural plasticity and memory. We show that a selective 5-HT2CR agonist, lorcaserin, improves synaptic plasticity and memory in an AD mouse model. Cumulatively, we demonstrate that hippocampal 5-HT2CR signaling regulates memory, which may inform the use of 5-HT2CR agonists in the treatment of dementia.

Therapeutic Strategies Against Metabolic Imbalance in a Male Mouse Model With 5-HT2CR Loss-of-Function.

The serotonin 2C receptor (5-HT2CR)-melanocortin pathway plays well-established roles in the regulation of feeding behavior and body weight homeostasis. Dysfunctions in this system, such as loss-of-function mutations in the Htr2c gene, can lead to hyperphagia and obesity. In this study, we aimed to investigate the potential therapeutic strategies for ameliorating hyperphagia, hyperglycemia, and obesity associated with a loss-of-function mutation in the Htr2c gene (Htr2cF327L/Y). We demonstrated that reexpressing functional 5-HT2CR solely in hypothalamic pro-opiomelanocortin (POMC) neurons is sufficient to reduce food intake and body weight in Htr2cF327L/Y mice subjected to a high-fat diet (HFD). In addition, 5-HT2CR expression restores the responsiveness of POMC neurons to lorcaserin, a selective agonist for 5-HT2CR. Similarly, administration of melanotan II, an agonist of the melanocortin receptor 4 (MC4R), effectively suppresses feeding and weight gain in Htr2cF327L/Y mice. Strikingly, promoting wheel-running activity in Htr2cF327L/Y mice results in a decrease in HFD consumption and improved glucose homeostasis. Together, our findings underscore the crucial role of the melanocortin system in alleviating hyperphagia and obesity related to dysfunctions of the 5-HT2CR, and further suggest that MC4R agonists and lifestyle interventions might hold promise in counteracting hyperphagia, hyperglycemia, and obesity in individuals carrying rare variants of the Htr2c gene.

5-HT Neurons Integrate GABA and Dopamine Inputs to Regulate Meal Initiation.

Obesity is a growing global health epidemic with limited effective therapeutics. Serotonin (5-HT) is one major neurotransmitter which remains an excellent target for new weight-loss therapies, but there remains a gap in knowledge on the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using a closed-loop optogenetic feeding paradigm, we showed that the 5-HTDRN→arcuate nucleus (ARH) circuit plays an important role in regulating meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response to GABAergic inputs can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the instrumental role of dopaminergic inputs via dopamine receptor D2 in 5-HTDRN neurons in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, which allows for the initiation of a meal.

Quantitative assessment of left ventricular myocardial work in patients with different types of atrial fibrillation by non-invasive pressure-strain loop technique.

OBJECTIVE: This study aimed to analyze myocardial work in patients with atrial fibrillation (AF) using a noninvasive pressure strain loop (PSL) technique to provide a basis for the quantitative assessment of left ventricular (LV) systolic function. METHODS: LV myocardial work of 107 AF patients (56 with paroxysmal atrial fibrillation and 51 with persistent atrial fibrillation) and 55 healthy individuals were assessed by the noninvasive PSL and then compared. RESULTS: Global longitudinal strain (GLS) in absolute values, global work index (GWI), global constructive work (GCW), and global work efficiency (GWE) were significantly lower in the AF group than control group, whereas peak strain dispersion (PSD) and global wasted work (GWW) were significantly higher (P < .05). Further subdivision according to the AF type revealed that, compared with the controls, GLS in absolute values and GWE decreased significantly; PSD and GWW increased significantly in the paroxysmal AF group (P < .05). Nevertheless, GWI and GCW were not significantly different between paroxysmal AF and control groups (P > .05). Compared to paroxysmal AF, persistent AF induced a further decrease in absolute GLS and GWE and a further increase in GWW (P < .05), but PSD did not increase further (P > .05). Multiple linear regression analysis showed that GWI and GCW were independently associated with systolic blood pressure. GWW was associated with types of AF and left atrial volume index (LAVI). GWE was correlated with age, types of AF, disease duration, and LAVI. Receiver operating characteristic curve analysis showed that the area under the curve predicting myocardial injury was higher for GWE and GWW than for GLS (area under the curve:  .880,  .846, and  .821, respectively). CONCLUSIONS: Non-invasive PSL can quantitatively assess LV systolic function in patients with different kinds of AF and detect early subclinical myocardial injury in patients with paroxysmal AF. GWE and GWW outperform GLS and LV ejection fraction when assessing myocardial injury. Systolic blood pressure, type of AF, LVAI, disease duration, and age may be associated with myocardial injury in patients with AF.

Multi-slice computed tomographic analysis and identification of remarkable anatomical types of segmental bronchi in bilateral inferior lobes: based on extensive data.

Background: The progress of interventional respiratory medicine necessitates a comprehensive knowledge of the segmental bronchi because of their complexity in branching patterns. Therefore, based on extensive research data, we aimed to examine the anatomical diversity and sex-related variations of the segmental bronchial branching patterns in the bilateral inferior lobes. Methods: Following the exclusion and inclusion criteria, a total of 10,000 participants who underwent multi-slice computed tomography (MSCT) scans from September 2019 to December 2021 at Cheeloo College of Medicine, Shandong University were enrolled in this retrospective study. The computed tomography (CT) data were utilized to generate three-dimensional (3D) and virtual bronchoscopy (VB) simulations of a bronchial tree using the syngo.via post-processing workstation. The distinct bronchial patterns in the bilateral inferior lobes were then found and categorized using the reconstructed images. The proportions of different types of bronchial branches and their sex-related correlations were analyzed by cross-tabulation and chi-square analysis. Results: Our findings primarily identified four types of bronchial branching patterns in the right inferior lobe (RIL), i.e., (B6, B7, B8, B9+10), 71.44%; (B6, B7, B8+9, B10), 16.06%; (B6, B7+8, B9+10), 7.40%; (B6, B7, B8+9+10), 5.10%; and four types in the left inferior lobe (LIL), i.e., (B6, B7+8, B9+10), 82.89%; (B6, B7+8, B9, B10), 13.53%; (B6, B7, B8+9, B10), 2.88%; (B6, B7, B8+9+10), 0.70%. Besides various research methods and outcomes, this study has revealed the types of bronchial branches that were not seen in previous studies. In addition, the proportion of bronchial branches in the LIL did not differ significantly between males and females (P>0.05). However, there was a significant difference in the proportion of bronchial branches in the RIL between sexes (P<0.05). Conclusions: The current study has validated the segmental bronchial variations in the bilateral inferior lobes. The diagnosis of symptomatic patients as well as the performance of interventions like bronchoscopies, endotracheal intubation, and lung resections may be significantly influenced by our findings in the clinical setting.

Leptin signaling and its central role in energy homeostasis.

Leptin plays a critical role in regulating appetite, energy expenditure and body weight, making it a key factor in maintaining a healthy balance. Despite numerous efforts to develop therapeutic interventions targeting leptin signaling, their effectiveness has been limited, underscoring the importance of gaining a better understanding of the mechanisms through which leptin exerts its functions. While the hypothalamus is widely recognized as the primary site responsible for the appetite-suppressing and weight-reducing effects of leptin, other brain regions have also been increasingly investigated for their involvement in mediating leptin's action. In this review, we summarize leptin signaling pathways and the neural networks that mediate the effects of leptin, with a specific emphasis on energy homeostasis.

Evaluation of Left Atrial Function in Patients with Paroxysmal Atrial Fibrillation Using Left Atrial Automatic Myocardial Functional Imaging Ultrasonography.

Aim: To evaluate volume and strain of the left atrium (LA) in people suffering from paroxysmal atrial fibrillation which is not valvular (NVPAF) using the new technology of left atrial automatic myocardial function imaging (AFILA) and to analyze prognostic factors in patients with NVPAF by follow-up. Methods: Between August 2019 and August 2022, a total of 80 NVPAF patients and 60 normal control patients who were hospitalized in the Department of Cardiology were included in the study. The LA volume and strain parameters of the two groups were analyzed. The differences in LA function (LAF) parameters were compared between the two groups to generate the receiver operating characteristic curve (ROC) and calculate the area under the curve (AUC), sensitivity, and specificity of each parameter. Follow-up was conducted on the 80 NVPAF patients included, their treatment methods after admission and their rehospitalization due to heart events were recorded, and independent risk factors influencing the prognosis of NVPAF were obtained. Results: A total of 140 patients participated in the study, including 80 in the NVPAF group and 60 in the normal control group. There was no statistically significant difference in age and sex between the two groups. Compared to the normal group, the LA minimum volume (LAVmin), LA maximum volume (LAVmax), and volume at onset of LA contraction (LAVpreA) in the NVPAF group were significantly increased. The LA emptying fraction (LAEF) was significantly decreased, and LA reservoir strain (S_R), LA conduit strain (S_CD), and LA contractile strain (S_CT) were significantly compromised (P < 0.05). There was no significant difference in LA evacuation volume (LAEV) reduction (P > 0.05). Logistic regression analysis of LAF parameters in NVPAF patients showed that LAEF and S_R were independently correlated with NVPAF (odds ratio values: 0.883 (0.827-0.943), P < 0.001; 0.916 (0.569-1.474), P = 0.047). The ROC curve results showed that LAEF had a high efficiency in the diagnosis of NVPAF, with P < 0.001, AUC of 0.843, sensitivity of 0.788, and specificity of 0.867. For the LA strain parameters, the S_R test efficiency was higher, with P < 0.001, AUC of 0.762, sensitivity of 0.713, and specificity of 0.783. There was a strong correlation between S_R and LAEF in patients with no end event and those with end event. The ROC curve revealed that the S_R was better than LAEF in predicting prognosis of patients with AF (AUC = 0.914, P < 0.0001 vs. AUC = 0.876, P < 0.0001). S_R of 10.5 and LAEF of 21 were the cut-off values for endpoint events in NVPAF patients, with sensitivity of 0.909 and 0.727 and specificity of 0.904 and 0.901, respectively. Conclusions: AFILA ultrasound technology comprehensively evaluated the LA size and function in patients with NVPAF. The LAEF and S_R were independently correlated with NVPAF and can determine the prognosis of patients with NVPAF.

Genome-Wide Identification and Characterization of the PP2C Family from Zea mays and Its Role in Long-Distance Signaling.

The protein phosphatase 2C (PP2C) constitutes a large gene family that plays crucial roles in regulating stress responses and plant development. A recent study has shown the involvement of an AtPP2C family member in long-distance nitrogen signaling in Arabidopsis. However, it remains unclear whether maize adopts a similar mechanism. In this study, we conducted a genome-wide survey and expression analysis of the PP2C family in maize. We identified 103 ZmPP2C genes distributed across 10 chromosomes, which were further classified into 11 subgroups based on an evolutionary tree. Notably, cis-acting element analysis revealed the presence of abundant hormone and stress-related, as well as nitrogen-related, cis-elements in the promoter regions of ZmPP2Cs. Expression analysis demonstrated the distinct expression patterns of nine genes under two nitrogen treatments. Notably, the expression of ZmPP2C54 and ZmPP2C85 in the roots was found to be regulated by long-distance signals from the shoots. These findings provide valuable insights into understanding the roles of ZmPP2Cs in long-distance nitrogen signaling in maize.

A dimensionality-reduction genomic prediction method without direct inverse of the genomic relationship matrix for large genomic data.

KEY MESSAGE: A new genomic prediction method (RHPP) was developed via combining randomized Haseman-Elston regression (RHE-reg), PCR based on genomic information of core population, and preconditioned conjugate gradient (PCG) algorithm. Computational efficiency is becoming a hot issue in the practical application of genomic prediction due to the large number of data generated by the high-throughput genotyping technology. In this study, we developed a fast genomic prediction method RHPP via combining randomized Haseman-Elston regression (RHE-reg), PCR based on genomic information of core population, and preconditioned conjugate gradient (PCG) algorithm. The simulation results demonstrated similar prediction accuracy between RHPP and GBLUP, and significantly higher computational efficiency of the former with the increase of individuals. The results of real datasets of both bread wheat and loblolly pine demonstrated that RHPP had a similar or better predictive accuracy in most cases compared with GBLUP. In the future, RHPP may be an attractive choice for analyzing large-scale and high-dimensional data.

Identification of anatomical types of segmental bronchi in left superior and lingular lobes using multi-slice CT.

PURPOSE: The objectives of this study were to evaluate various branching patterns of segmental bronchi in the left superior and lingular lobes and to survey the anatomical diversity and sex-related differences of these branches in a large sample of the study population. MATERIALS AND METHODS: Overall, 10,000 participants (5428 males, and 4572 females, mean age 50 ± 13.5 years [SD] years; age range: 3-91 years) who underwent multi-slice CT (MSCT) scans between September 2019 and December 2021 were retrospectively included. Using the syngo.via post-processing workstation, the data were applied to generate three-dimensional (3D) and virtual bronchoscopy (VB) simulations of a bronchial tree. The reconstructed images were then interpreted to identify and categorize distinct bronchial patterns in the left superior and lingular lobes. Cross-tabulation analysis and the Pearson Chi-square (χ2) test were used to calculate the constituent ratios of bronchial branch types and determine their significance between male and female groups. RESULTS: Our results revealed mainly four distinct types for the left superior lobe (LSL) bronchial tree, i.e., (B1 + 2, B3, 76.13%); (B1 + 2 + 3, 17.32%); (B1 + 3, B2, 5.74%); (B1a + B3, B1b + B2, 0.81%) and two types for the left lingular lobe (LLL) bronchial tree, i.e., (B4, B5, 91.05%); (B4, B5, B*, 8.95%). There were no significant sex-related differences in the proportion of bronchial branches in LLL (P > 0.05). However, sex-related differences were significant in the proportion of bronchial branches in LSL (P < 0.05). CONCLUSION: The current study has validated the presence of segmental bronchial variations in the left superior and lingular lobes. These findings may have a crucial effect on the diagnosis of symptomatic patients, as well as in carrying out procedures such as lung resections, endotracheal intubation, and bronchoscopies.

Use of left atrial automated functional myocardial imaging to identify patients with paroxysmal atrial fibrillation at high risk of stroke.

Background: Left atrial automated functional myocardial imaging (AFILA) is a new software program for analyzing the structure and function of the left atrium (LA). The present study sought to analyze the correlation between the LA function parameters as measured by AFILA echocardiography and the risk of cerebral ischemic stroke (CIS) in patients with non-valvular paroxysmal atrial fibrillation (NVPAF) to explore the diagnostic value of LA strain in patients with congestive heart failure, hypertension, age of ≥75 years (doubled), diabetes mellitus, stroke or transient ischemic attack (TIA) (doubled), age of 65-74 years, and sex category (female) (CHA2DS2-VASc) scores of <2. Methods: A total of 205 patients with NVPAF were included in the study and divided into the no-CIS group (154 patients) and the CIS group (51 patients). The baseline clinical data for the 2 groups were analyzed, and routine echocardiography examinations were performed. AFILA was used to evaluate the LA function of all the patients. Results: Compared to the no-CIS group, the LA emptying fraction and the LA reservoir strain were decreased, the LA contractile strain (S_CT) was increased, and the S_CT value changed from negative to positive in the CIS group, and the difference between the 2 groups were statistically significant (P<0.001). However, there were no significant differences in the volume at the onset of LA contraction, LA evacuation volume, LA minimum volume, LA maximum volume, and LA conduit strain between the 2 groups. The multifactorial regression analysis showed that age, hypertension, and the S_CT were independently associated risk factors for patients with CIS. After correcting for the clinical factors included in the CHA2DS2-VASc score, the S_CT was shown to predict to NVPAF with stroke [odds ratio (OR): 1.234, 95% confidence interval (CI): 1.101-1.383, P=0.000]. In addition, we included the CHA2DS2-VASc score (instead of age, diabetes, coronary artery disease, and hypertension) in a multiple regression analysis, and found that the S_CT was still significant (OR: 1.252, 95% CI: 1.118-1.402, P=0.000). The difference between the 2 groups in the CHA2DS2-VASc score for the S_CT was statistically significant, especially when the CHA2DS2-VASc score was <2. The S_CT equaled -4.5% was the cut-off value for the presence or absence of CIS in the NVPAF patients, with an area under the curve (AUC) of 0.866, sensitivity of 0.80, and specificity of 0.75 (P<0.0001). Conclusions: Comparison with LA volume parameter, measuring LA strain by AFILA provides a better index for the dynamic assessment of impaired LA function in patients with NVPAF combined with CIS, especially in those with a CHA2DS2-VASc score of <2. In addition, a LA S_CT of >-4.5% is a valuable cut-off for patients with NVPAF. The results of the current study may form the basis for a large prospective multicenter interventional study in which patients with impaired LA S_CT are randomized to receive oral anti-coagulant (OAC) therapy or no OAC therapy for the primary prevention of stroke.

Multi-slice CT Analysis and Identification of Anatomical Types of Segmental Bronchi in Right Superior Lobe.

PURPOSE: The aims were to assess different branching patterns of segmental bronchi in the right superior lobe (RSL), as well as to investigate the anatomical diversity and sex-related variations of these branches in a large sample of the research population. METHODS: 10,000 participants (5428 males, and 4,572 females, mean age 50+/-13.5 years [SD] years; age range: 3-91 years) who underwent multi-slice CT (MSCT) scans from September 2019 to December 2021 were retrospectively included. The data were applied to generate three-dimensional (3D) and virtual bronchoscopy (VB) simulations of a bronchial tree using the syngo.via post-processing workstation. Following that, the reconstructed images were interpreted to identify and categorize various bronchial patterns in the RSL. Cross-tabulation analysis and the Pearson chi-square test (χ2) were used to calculate the component ratios of bronchial branch types and determine their relevance between male and female groups. RESULTS: Our results revealed mainly six types for the RSL bronchial tree, i.e., (B1, B2, B3, 60.70%); (B1+2, B3, 18.72%); (B2+3, B1, 6.68%); (B1+3, B2, 7.57%); (B1, B2, B3, B*, 3.19%); (B1a+B3, B1b+B2, 3.14%). There were significant sex-related differences in the proportion of bronchial branches in the RSL (P< 0.05). CONCLUSION: The current study has validated the presence of segmental bronchial variations in the RSL. These findings may have significant implications for diagnosing symptomatic patients and performing particular procedures, including bronchoscopy, endotracheal intubation, and lung resection.

Anoctamin 4 channel currents activate glucose-inhibited neurons in the mouse ventromedial hypothalamus during hypoglycemia.

Glucose is the basic fuel essential for maintenance of viability and functionality of all cells. However, some neurons - namely, glucose-inhibited (GI) neurons - paradoxically increase their firing activity in low-glucose conditions and decrease that activity in high-glucose conditions. The ionic mechanisms mediating electric responses of GI neurons to glucose fluctuations remain unclear. Here, we showed that currents mediated by the anoctamin 4 (Ano4) channel are only detected in GI neurons in the ventromedial hypothalamic nucleus (VMH) and are functionally required for their activation in response to low glucose. Genetic disruption of the Ano4 gene in VMH neurons reduced blood glucose and impaired counterregulatory responses during hypoglycemia in mice. Activation of VMHAno4 neurons increased food intake and blood glucose, while chronic inhibition of VMHAno4 neurons ameliorated hyperglycemia in a type 1 diabetic mouse model. Finally, we showed that VMHAno4 neurons represent a unique orexigenic VMH population and transmit a positive valence, while stimulation of neurons that do not express Ano4 in the VMH (VMHnon-Ano4) suppress feeding and transmit a negative valence. Together, our results indicate that the Ano4 channel and VMHAno4 neurons are potential therapeutic targets for human diseases with abnormal feeding behavior or glucose imbalance.

Identification of anatomical types of segmental bronchi in right middle lobe using multi-slice CT.

PURPOSE: The objectives of this study were to evaluate the various branching patterns of segmental bronchi in the right middle lobe (RML) and to survey the anatomical diversity and sex-related differences of these branches in a large sample of the study population. MATERIALS AND METHODS: In this retrospective board-approved study with informed consent, 10,000 participants (5428 males and 4,572 females, mean age 50 ± 13.5 years [SD]; age range: 3-91 years) who underwent multi-slice CT (MSCT) scans from September 2019 to December 2021 were retrospectively included. The data were applied to generate three-dimensional (3D) and virtual bronchoscopy (VB) simulations of a bronchial tree using the syngo.via post-processing workstation. The reconstructed images were then interpreted to locate and classify distinct bronchial patterns in the RML. Cross-tabulation analysis and the Pearson chi-square test were used to calculate the constituent ratios of bronchial branch types and determine their significance between male and female groups. RESULTS: Our results revealed that the segmental bronchial ramifications of the RML were classified into two types mainly, i.e., bifurcation (B4, B5, 91.42%) and trifurcation (B4, B5, B*, 8.58%). There were no significant sex-related differences in the proportion of bronchial branches in the RML (P > 0.05). CONCLUSION: The current study has confirmed the presence of segmental bronchial variations in the RML lobe using 3D reconstruction and virtual bronchoscopy. These findings may have significant implications for the diagnosis of symptomatic patients and for carrying out specific procedures like bronchoscopy, endotracheal intubation, and lung resection.

Multifunctional Droplets Formed by Interfacially Self-Assembled Fluorinated Magnetic Nanoparticles for Biocompatible Single Cell Culture and Magnet-Driven Manipulation.

The ability to encapsulate and manipulate droplets with a picoliter volume of samples and reagents shows great potential for practical applications in chemistry, biology, and materials science. Magnetic control is a promising approach for droplet manipulation due to its ability for wireless control and its ease of implementation. However, it is challenged by the poor biocompatibility of magnetic materials in aqueous droplets. Moreover, current droplet technology is problematic because of the molecule leakage between droplets. In the paper, we propose multifunctional droplets with the surface coated by a layer of fluorinated magnetic nanoparticles for magnetically actuated droplet manipulation. Multifunctional droplets show excellent biocompatibility for cell culture, nonleakage of molecules, and high response to a magnetic field. We developed a strategy of coating the F-MNP@SiO2 on the outer surface of droplets instead of adding magnetic material into droplets to enable droplets with a highly magnetic response. The encapsulated bacteria and cells in droplets did not need to directly contact with the magnetic materials at the outer surface, showing high biocompatibility with living cells. These droplets can be precisely manipulated based on magnet distance, the time duration of the magnetic field, the droplet size, and the MNP composition, which well match with theoretical analysis. The precise magnetically actuated droplet manipulation shows great potential for accurate and sensitive droplet-based bioassays like single cell analysis.

Hypothalamic Grb10 enhances leptin signalling and promotes weight loss.

Leptin acts on hypothalamic neurons expressing agouti-related protein (AgRP) or pro-opiomelanocortin (POMC) to suppress appetite and increase energy expenditure, but the intracellular mechanisms that modulate central leptin signalling are not fully understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an adaptor protein that binds to the insulin receptor and negatively regulates its signalling pathway, can interact with the leptin receptor and enhance leptin signalling. Ablation of Grb10 in AgRP neurons promotes weight gain, while overexpression of Grb10 in AgRP neurons reduces body weight in male and female mice. In parallel, deletion or overexpression of Grb10 in POMC neurons exacerbates or attenuates diet-induced obesity, respectively. Consistent with its role in leptin signalling, Grb10 in AgRP and POMC neurons enhances the anorexic and weight-reducing actions of leptin. Grb10 also exaggerates the inhibitory effects of leptin on AgRP neurons via ATP-sensitive potassium channel-mediated currents while facilitating the excitatory drive of leptin on POMC neurons through transient receptor potential channels. Our study identifies Grb10 as a potent leptin sensitizer that contributes to the maintenance of energy homeostasis by enhancing the response of AgRP and POMC neurons to leptin.

Human loss-of-function variants in the serotonin 2C receptor associated with obesity and maladaptive behavior.

Serotonin reuptake inhibitors and receptor agonists are used to treat obesity, anxiety and depression. Here we studied the role of the serotonin 2C receptor (5-HT2CR) in weight regulation and behavior. Using exome sequencing of 2,548 people with severe obesity and 1,117 control individuals without obesity, we identified 13 rare variants in the gene encoding 5-HT2CR (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Knock-in male mice harboring a human loss-of-function HTR2C variant developed obesity and reduced social exploratory behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity. Using the 5-HT2CR agonist lorcaserin, we found that depolarization of appetite-suppressing proopiomelanocortin neurons was impaired in knock-in mice. In conclusion, we demonstrate that 5-HT2CR is involved in the regulation of human appetite, weight and behavior. Our findings suggest that melanocortin receptor agonists might be effective in treating severe obesity in individuals carrying HTR2C variants. We suggest that HTR2C should be included in diagnostic gene panels for severe childhood-onset obesity.