ABSTRACT
STUDY OBJECTIVES: Hypoglossal nerve stimulation (HGNS) has been widely used to treat obstructive sleep apnea in selected patients. Here we evaluate rates of revision and explant related to HGNS implantation and assess types of adverse events contributing to revision and explant. METHODS: Post-market surveillance data for HGNS implanted between January 1, 2018 and March 31, 2022, were collected. Event rates and risk were calculated using the post-market surveillance event counts and sales volume over the same period. Indications were categorized for analysis. Descriptive statistics were reported and freedom from explant or revision curves were grouped by year of implantation. RESULTS: Of the 20,881 HGNS implants assessed, rates of explant and revision within the first year were 0.723% and 1.542%, respectively. The most common indication for explant was infection (0.378%) and for revision was surgical correction (0.680%). Of the 5,820 devices with three-year post-implantation data, the rate of explant was 2.680% and of revision was 3.557%. During this same interval, elective removal (1.478%) was the most common indication, and for revisions, surgical correction (1.134%). CONCLUSIONS: The efficacy of HGNS is comparable in the real world setting to published clinical trial data. Rates of explant and revision are low, supporting a satisfactory safety profile for this technology.
ABSTRACT
STUDY OBJECTIVES: We evaluated the accuracy of ChatGPT in addressing insomnia-related queries for patient education and assessed ChatGPT's ability to provide varied responses based on differing prompting scenarios. METHODS: Four identical sets of 20 insomnia-related queries were posed to ChatGPT. Each set differed by the context in which ChatGPT was prompted: no prompt, patient-centered, physician-centered, and with references and statistics. Responses were reviewed by 2 academic sleep surgeons, 1 academic sleep medicine physician, and 2 sleep medicine fellows across 4 domains: clinical accuracy, prompt adherence, referencing, and statistical precision, using a binary grading system. Flesch-Kincaid grade-level scores were calculated to estimate the grade level of the responses, with statistical differences between prompts analyzed via analysis of variance and Tukey's test. Interrater reliability was calculated using Fleiss's kappa. RESULTS: The study revealed significant variations in the Flesch-Kincaid grade-level scores across 4 prompts: unprompted (13.2 ± 2.2), patient-centered (8.1 ± 1.9), physician-centered (15.4 ± 2.8), and with references and statistics (17.3 ± 2.3, P < .001). Despite poor Fleiss kappa scores, indicating low interrater reliability for clinical accuracy and relevance, all evaluators agreed that the majority of ChatGPT's responses were clinically accurate, with the highest variability on Form 4. The responses were also uniformly relevant to the given prompts (100% agreement). Eighty percent of the references ChatGPT cited were verified as both real and relevant, and only 25% of cited statistics were corroborated within referenced articles. CONCLUSIONS: ChatGPT can be used to generate clinically accurate responses to insomnia-related inquiries. CITATION: Alapati R, Campbell D, Molin N, et al. Evaluating insomnia queries from an artificial intelligence chatbot for patient education. J Clin Sleep Med. 2024;20(4):583-594.
Subject(s)
Artificial Intelligence , Sleep Initiation and Maintenance Disorders , Humans , Sleep Initiation and Maintenance Disorders/diagnosis , Reproducibility of Results , Patient Education as Topic , SoftwareABSTRACT
Adipokines are a growing group of secreted proteins that play important roles in obesity, sleep disturbance, and metabolic derangements. Due to the complex interplay between adipokines, sleep, and metabolic regulation, an integrated approach is required to better understand the significance of adipokines in these processes. In the present study, we created and analyzed a network of six adipokines and their molecular partners involved in sleep disturbance and metabolic dysregulation. This network represents information flow from regulatory factors, adipokines, and physiologic pathways to disease processes in metabolic dysfunction. Analyses using network metrics revealed that obesity and obstructive sleep apnea were major drivers for the sleep associated metabolic dysregulation. Two adipokines, leptin and adiponectin, were found to have higher degrees than other adipokines, indicating their central roles in the network. These adipokines signal through major metabolic pathways such as insulin signaling, inflammation, food intake, and energy expenditure, and exert their functions in cardiovascular, reproductive, and autoimmune diseases. Leptin, AMP activated protein kinase (AMPK), and fatty acid oxidation were found to have global influence in the network and represent potentially important interventional targets for metabolic and sleep disorders. These findings underscore the great potential of using network based approaches to identify new insights and pharmaceutical targets in metabolic and sleep disorders.
ABSTRACT
Adipokines are a growing group of peptide or protein hormones that play important roles in whole body metabolism and metabolic diseases. Sleep is an integral component of energy metabolism, and sleep disturbance has been implicated in a wide range of metabolic disorders. Accumulating evidence suggests that adipokines may play a role in mediating the close association between sleep disorders and systemic metabolic derangements. In this review, we briefly summarize a group of selected adipokines and their identified function in metabolism. Moreover, we provide a balanced overview of these adipokines and their roles in sleep physiology and sleep disorders from recent human and animal studies. These studies collectively demonstrate that the functions of adipokine in sleep physiology and disorders could be largely twofold: (1) adipokines have multifaceted roles in sleep physiology and sleep disorders, and (2) sleep disturbance can in turn affect adipokine functions that likely contribute to systemic metabolic derangements.
Subject(s)
Adipokines/metabolism , Metabolic Diseases/metabolism , Sleep Wake Disorders/metabolism , Adipokines/physiology , Animals , Humans , Metabolic Diseases/physiopathology , Sleep , Sleep Apnea, Obstructive , Sleep Wake Disorders/physiopathologyABSTRACT
Median nerve anatomy is of great interest to clinicians and scientists given the importance of this nerve and its association with diseases. A rare anatomical variant of the median nerve in the distal forearm and wrist was discovered during a cadaveric dissection. The median nerve was deep to the flexor digitorum superficialis (FDS) in the carpal tunnel. It underwent a 360-degree spin before emerging at the lateral edge of FDS. The recurrent motor branch moved from medial to lateral on the deep surface of the median nerve, as it approached the distal carpal tunnel. This variant doesn't fall into any of Lanz's four groups of median nerve anomalies. We propose a fifth group that involves variations in the course of the median nerve. This report underscores the importance of recognizing variants of the median nerve anatomy in the forearm and wrist during surgical interventions, such as for carpal tunnel syndrome.
ABSTRACT
OBJECTIVE Motorcycle helmets have been shown to decrease the incidence and severity of traumatic brain injury due to motorcycle crashes. Despite this proven efficacy, some previous reports and speculation suggest that helmet use is associated with a higher likelihood of cervical spine injury (CSI). In this study, the authors examine 1061 cases of motorcycle crash victims who were treated during a 5-year period at a Level 1 trauma center to investigate the association of helmet use with the incidence and severity of CSI. The authors hypothesized that wearing a motorcycle helmet during a motorcycle crash is not associated with an increased risk of CSI and may provide some protective advantage to the wearer. METHODS The authors performed a retrospective review of all cases in which the patient had been involved in a motorcycle crash and was evaluated at a single Level 1 trauma center in Wisconsin between January 1, 2010, and January 1, 2015. Biometric, clinical, and imaging data were obtained from a trauma registry database. The patients were then divided into 2 distinct groups based on whether or not they were wearing helmets at the time of the accident. Baseline and functional characteristics were compared between the 2 groups. The Student t-test was used for continuous variables, and Pearson's chi-square analysis was used for categorical variables. RESULTS In total, 1061 patient charts were examined containing data on 738 unhelmeted (69.6%) and 323 helmeted (30.4%) motorcycle riders. On average, helmeted riders had a much lower Injury Severity Score (p < 0.001). Cervical spine injury occurred in 114 unhelmeted riders (15.4%) compared with only 24 helmeted riders (7.4%) (p < 0.001), with an adjusted odds ratio of 2.3 (95% CI 1.44-3.61, p = 0.0005). In the unhelmeted group, 10.8% of patients were found to have a cervical spine fracture compared with only 4.6% of patients in the helmeted group (p = 0.001). Additionally, ligamentous injury occurred more frequently in unhelmeted riders (1.9% vs 0.3%, p = 0.04). No difference was found in the occurrence of cervical strain, cord contusion, or nerve root injury (all p > 0.05). CONCLUSIONS The results of this study demonstrate a statistically significant lower likelihood of suffering a CSI among helmeted motorcyclists. Unhelmeted riders sustained a statistically significant higher number of vertebral fractures and ligamentous injuries. The study findings reported here confirm the authors' hypothesis that helmet use does not increase the risk of developing a cervical spine fracture and may provide some protective advantage.
Subject(s)
Accidents, Traffic , Cervical Cord/injuries , Cervical Vertebrae/injuries , Head Protective Devices , Motorcycles , Spinal Cord Injuries/epidemiology , Adult , Cervical Cord/diagnostic imaging , Cervical Vertebrae/diagnostic imaging , Female , Humans , Incidence , Male , Middle Aged , Severity of Illness Index , Spinal Cord Injuries/diagnostic imaging , Spinal Cord Injuries/etiology , Spinal Cord Injuries/prevention & control , Trauma CentersABSTRACT
BACKGROUND: The NeuroPace RNS System is a method recently approved by the U.S. Food and Drug Administration for closed-loop direct brain stimulation in selected patients with drug-resistant partial seizures. The long-term risks of implant site infection and accompanying bone flap osteomyelitis associated with responsive neurostimulation (RNS) devices have not been fully appreciated. CASE DESCRIPTION: We report 3 cases of refractory partial epilepsy that were treated with RNS therapy in conjunction with antiepileptic drugs. Patients underwent invasive epilepsy monitoring and resection of seizure foci. All patients continued to have debilitating partial seizures and underwent implantation of the RNS device, which resulted in various degrees of symptomatic relief. On average, the battery of the implantable pulse generator was replaced every 2 years. All 3 patients developed implant site infection and bone flap osteomyelitis with multiple implantable pulse generator replacements, and the RNS devices were removed. Bone flaps were removed in 2 patients because of significant osteomyelitis and were reconstructed in a delayed fashion with customized cranial implants. No patient had evidence of meningitis or cerebritis. The patients were treated via a multidisciplinary approach, and all patients recovered well with satisfactory wound healing and seizure control. CONCLUSIONS: Implant site infection and bone flap osteomyelitis are significant adverse events associated with the RNS device. The incidence of infection in this series (10%) is comparable to the incidence reported in the long-term trial. The infection risk is mainly associated with reoperations and increases with multiple implantable pulse generator replacements. The RNS device may benefit from reducing technical risk factors that are associated with postoperative bone and soft tissue infections.
Subject(s)
Epilepsy/therapy , Osteomyelitis/etiology , Osteomyelitis/therapy , Osteotomy/adverse effects , Surgical Wound Infection/etiology , Surgical Wound Infection/therapy , Adult , Bone Transplantation/adverse effects , Deep Brain Stimulation , Electrodes, Implanted/adverse effects , Epilepsy/complications , Humans , Male , Middle Aged , Radiography , Skull/diagnostic imaging , Young AdultABSTRACT
Pneumocephalus is a collection of air within in the intracranial cavity, most commonly seen following traumatic injury or cranial surgeries. Esophageal injury and cerebrospinal fluid (CSF) leak are rare complications that may occur following anterior cervical discectomy and fusion (ACDF). We present a novel case of pneumocephalus arising from unrestricted leakage of CSF via coincident esophageal injury and durotomy in a patient who underwent an ACDF after trauma. A 21-year-old man presented to an outside hospital with C5/C6 subluxation, complete spinal cord injury, and quadriplegia from a motor vehicle accident. He underwent an ACDF, during which a CSF leak was observed. He was then transferred to our institution for rehabilitation and tracheostomy placement 1 week after the ACDF surgery. Following the tracheostomy, the patient developed intractable fevers and nonspecific symptoms. A CT scan demonstrated frontal pneumocephalus without mass effect. Air was found in the retropharyngeal space. There were no accumulations of CSF in the neck. Extravasation of contrast around instrumentation at C5/C6 on a cine esophagogram demonstrated an esophageal perforation at that level. Pneumocephalus may form when large volumes of CSF escape from the intracranial space and air is drawn into the space by the negative pressure. In this unusual case, the esophageal perforation promoted the formation of the pneumocephalus. Treatment included closure of both defects, disrupting the suspected communication between the intracranial space and the esophagus.
Subject(s)
Cerebrospinal Fluid Leak/diagnosis , Cervical Vertebrae/surgery , Diskectomy/adverse effects , Esophageal Perforation/diagnosis , Pneumocephalus/diagnosis , Spinal Cord Injuries/surgery , Cerebrospinal Fluid Leak/etiology , Cervical Vertebrae/injuries , Esophageal Perforation/etiology , Humans , Male , Pneumocephalus/etiology , Postoperative Complications/diagnosis , Postoperative Complications/etiology , Spinal Cord Injuries/complications , Spinal Cord Injuries/diagnosis , Young AdultABSTRACT
BACKGROUND: Giant intracranial arteriovenous malformations (AVMs) are rare cerebrovascular lesions that pose management challenges. OBJECTIVE: To further clarify outcomes in patients with giant cerebral AVMs managed with conservative or interventional therapies. METHODS: We performed a retrospective review of all patients diagnosed with AVMs evaluated at our institution from 1990 to 2013. Patients with a single intracranial AVM >6 cm were included. Patients were divided into 2 groups: conservative management or intervention (microsurgery, radiosurgery, or embolization). Functional outcome was assessed with the modified Rankin Scale (mRS) and compared between the 2 groups. RESULTS: A total of 55 patients with giant AVMs were included, and 35 patients (63.6%) had clinical follow-up with a mean of 11.8 years. Spetzler-Martin grades were as follows: grade III, n = 2 (3.6%); grade IV, n = 15 (27.3%); and grade V, n = 38 (69.1%). Twenty-four patients (43.6%) were conservatively managed. The patients in the conservatively managed group had larger AVMs (P < .05) with more frequent involvement of the temporal lobe (P = .02). Five patients (26.3%) in the conservatively managed group and 5 (31.3%) in the intervention group experienced hemorrhage during follow-up, translating to an annualized risk of 2.7% and 4.1%, respectively. No significant difference in risk of first subsequent hemorrhage was observed (P = .78). Despite comparable mRS scores at presentation, we observed a trend toward better outcomes (mRS < 2) in patients undergoing conservative management (P = .06) compared with the intervention group at last follow-up. CONCLUSION: This study suggests that interventions for giant AVMs should be considered cautiously because hemorrhagic risk is similar regardless of management strategy and functional outcome is likely to be same or better in the conservatively managed population. ABBREVIATIONS: AVM, arteriovenous malformationmRS, modified Rankin Scale.
Subject(s)
Conservative Treatment/methods , Embolization, Therapeutic/methods , Intracranial Arteriovenous Malformations/therapy , Microsurgery/methods , Radiosurgery/methods , Adult , Aged , Embolization, Therapeutic/adverse effects , Female , Follow-Up Studies , Humans , Male , Microsurgery/adverse effects , Middle Aged , Radiosurgery/adverse effects , Retrospective Studies , Survival Analysis , Treatment OutcomeABSTRACT
Here we describe a patient with bilateral pulmonary emboli (PE) associated with thrombin-based hemostatic matrix (TBHM) use in the setting of a possible venous injury during transforaminal lumbar interbody fusion in the treatment of degenerative spondylolisthesis at L4-5. TBHM products are gelatin granules mixed with human or bovine thrombin. They have been used in a wide variety of surgical procedures to facilitate local hemostasis though their use is not without complications. This is the first reported patient, to our knowledge, with a TBHM-related PE following spinal fusion. As TBHM is a widely used intraoperative hemostatic agent, surgeons should be aware of the risk of TBHM-associated PE, particularly when there is the potential for intravascular injection or dissemination. While our experience indicates that common pharmacological prophylaxis such as subcutaneous heparin is likely ineffective in reducing occurrence of PE in the setting of TBHM use, the PE was successfully treated with standard systemic anticoagulation. The authors would also add that when iliac injury is encountered during discectomy or interbody fusion through a posterior approach, use of TBHM may be a life-saving technique. Postoperatively, vascular surgery consultation is recommended and consideration should be given to systemic anticoagulation.
Subject(s)
Hemostatics/adverse effects , Pulmonary Embolism/etiology , Spinal Fusion/methods , Diskectomy , Gelatin/adverse effects , Humans , Iliac Artery/injuries , Lumbar Vertebrae/surgery , Retrospective Studies , Spinal Fusion/adverse effects , Spondylolisthesis/surgery , Thrombin/adverse effectsABSTRACT
Transgenic overexpression of CTRP9, a secreted hormone downregulated in obesity, confers striking protection against diet-induced obesity and type 2 diabetes. However, the physiological relevance of this adiponectin-related plasma protein remains undefined. Here, we used gene targeting to establish the metabolic function of CTRP9 in a physiological context. Mice lacking CTRP9 were obese and gained significantly more body weight when fed standard laboratory chow. Increased food intake, due in part to upregulated expression of hypothalamic orexigenic neuropeptides, contributed to greater adiposity in CTRP9 knockout mice. Although the frequency of food intake remained unchanged, CTRP9 knockout mice increased caloric intake by increasing meal size and decreasing satiety ratios. The absence of CTRP9 also resulted in peripheral tissue insulin resistance, leading to increased fasting insulin levels, impaired hepatic insulin signaling, and reduced insulin tolerance. Increased expression of lipogenic genes, combined with enhanced caloric intake, contributed to hepatic steatosis in CTRP9 knockout mice. Loss of CTRP9 also resulted in reduced skeletal muscle AMPK activation and mitochondrial content. Together, these results provide the genetic evidence for a physiological role of CTRP9 in controlling energy balance via central and peripheral mechanisms.
Subject(s)
Adiponectin/physiology , Eating/genetics , Fatty Liver/genetics , Glycoproteins/physiology , Insulin Resistance/genetics , Adiponectin/genetics , Adiposity/genetics , Animals , Body Weight/genetics , Energy Metabolism/genetics , Female , Gene Deletion , Gene Targeting , Glycoproteins/genetics , Male , Mice , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
CTRP4 is a unique member of the C1q family, possessing two tandem globular C1q domains. Its physiological function is poorly defined. Here, we show that CTRP4 is an evolutionarily conserved, â¼34-kDa secretory protein expressed in the brain. In human, mouse, and zebrafish brain, CTRP4 expression begins early in development and is widespread in the central nervous system. Neurons, but not astrocytes, express and secrete CTRP4, and secreted proteins form higher-order oligomeric complexes. CTRP4 is also produced by peripheral tissues and circulates in blood. Its serum levels are increased in leptin-deficient obese (ob/ob) mice. Functional studies suggest that CTRP4 acts centrally to modulate energy metabolism. Refeeding following an overnight fast induced the expression of CTRP4 in the hypothalamus. Central administration of recombinant protein suppressed food intake and altered the whole-body energy balance in both chow-fed and high-fat diet-fed mice. Suppression of food intake by CTRP4 is correlated with a decreased expression of orexigenic neuropeptide (Npy and Agrp) genes in the hypothalamus. These results establish CTRP4 as a novel nutrient-responsive central regulator of food intake and energy balance.
Subject(s)
Adipokines/metabolism , Body Weight/physiology , Cytokines/metabolism , Eating/physiology , Energy Metabolism/physiology , Hypothalamus/metabolism , Zebrafish/metabolism , Adipokines/genetics , Agouti-Related Protein/biosynthesis , Agouti-Related Protein/genetics , Animals , Cytokines/genetics , Humans , Male , Mice , Neuropeptide Y/biosynthesis , Neuropeptide Y/genetics , Protein Structure, Tertiary , Rats , Zebrafish/geneticsABSTRACT
Cells turn on autophagy, an intracellular recycling pathway, when deprived of nutrients. How autophagy is regulated by hormonal signals in response to major changes in metabolic state is not well understood. Here, we provide evidence that myonectin (CTRP15), a skeletal muscle-derived myokine, is a novel regulator of cellular autophagy. Starvation activated liver autophagy, whereas nutrient supplementation following food deprivation suppressed it; the former and latter correlated with reduced and increased expression and circulating levels of myonectin, respectively, suggestive of a causal link. Indeed, recombinant myonectin administration suppressed starvation-induced autophagy in mouse liver and cultured hepatocytes, as indicated by the inhibition of LC3-dependent autophagosome formation, p62 degradation, and expression of critical autophagy-related genes. Reduction in protein degradation is mediated by the PI3K/Akt/mTOR signaling pathway; inhibition of this pathway abrogated the ability of myonectin to suppress autophagy in cultured hepatocytes. Together, our results reveal a novel skeletal muscle-liver axis controlling cellular autophagy, underscoring the importance of hormone-mediated tissue cross-talk in maintaining energy homeostasis.
Subject(s)
Autophagy/drug effects , Cytokines/pharmacology , Liver/cytology , Muscle Proteins/pharmacology , Muscle, Skeletal/metabolism , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Animals , Cell Line , Dietary Supplements , Gene Expression Regulation/drug effects , Homeostasis/drug effects , Humans , Male , Mice , Microtubule-Associated Proteins/metabolism , Proteolysis/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Rats , Recombinant Proteins/pharmacology , Starvation/metabolism , Starvation/pathology , Transcription Factor TFIIH , Transcription Factors/metabolismABSTRACT
CTRP9 is a secreted multimeric protein of the C1q family and the closest paralog of the insulin-sensitizing adipokine, adiponectin. The metabolic function of this adipose tissue-derived plasma protein remains largely unknown. Here, we show that the circulating levels of CTRP9 are downregulated in diet-induced obese mice and upregulated upon refeeding. Overexpressing CTRP9 resulted in lean mice that dramatically resisted weight gain induced by a high-fat diet, largely through decreased food intake and increased basal metabolism. Enhanced fat oxidation in CTRP9 transgenic mice resulted from increases in skeletal muscle mitochondrial content, expression of enzymes involved in fatty acid oxidation (LCAD and MCAD), and chronic AMPK activation. Hepatic and skeletal muscle triglyceride levels were substantially decreased in transgenic mice. Consequently, CTRP9 transgenic mice had a greatly improved metabolic profile with markedly reduced fasting insulin and glucose levels. The high-fat diet-induced obesity, insulin resistance, and hepatic steatosis observed in wild-type mice were prevented in transgenic mice. Consistent with the in vivo data, recombinant protein significantly enhanced fat oxidation in L6 myotubes via AMPK activation and reduced lipid accumulation in H4IIE hepatocytes. Collectively, these data establish CTRP9 as a novel metabolic regulator and a new component of the metabolic network that links adipose tissue to lipid metabolism in skeletal muscle and liver.
Subject(s)
Adiponectin/metabolism , Adipose Tissue/physiopathology , Dietary Fats/adverse effects , Glycoproteins/metabolism , Metabolic Diseases/etiology , Metabolic Diseases/physiopathology , Obesity/etiology , Obesity/physiopathology , Adiponectin/genetics , Animals , Glycoproteins/genetics , Male , Metabolic Diseases/prevention & control , Mice , Mice, Inbred C57BL , Mice, Transgenic , Obesity/prevention & controlABSTRACT
CTRP3 is a secreted plasma protein of the C1q family that helps regulate hepatic gluconeogenesis and is downregulated in a diet-induced obese state. However, the role of CTRP3 in regulating lipid metabolism has not been established. Here, we used a transgenic mouse model to address the potential function of CTRP3 in ameliorating high-fat diet-induced metabolic stress. Both transgenic and wild-type mice fed a high-fat diet showed similar body weight gain, food intake, and energy expenditure. Despite similar adiposity to wild-type mice upon diet-induced obesity (DIO), CTRP3 transgenic mice were strikingly resistant to the development of hepatic steatosis, had reduced serum TNF-α levels, and demonstrated a modest improvement in systemic insulin sensitivity. Additionally, reduced hepatic triglyceride levels were due to decreased expression of enzymes (GPAT, AGPAT, and DGAT) involved in triglyceride synthesis. Importantly, short-term daily administration of recombinant CTRP3 to DIO mice for 5 days was sufficient to improve the fatty liver phenotype, evident as reduced hepatic triglyceride content and expression of triglyceride synthesis genes. Consistent with a direct effect on liver cells, recombinant CTRP3 treatment reduced fatty acid synthesis and neutral lipid accumulation in cultured rat H4IIE hepatocytes. Together, these results establish a novel role for CTRP3 hormone in regulating hepatic lipid metabolism and highlight its protective function and therapeutic potential in attenuating hepatic steatosis.
Subject(s)
Adipokines/physiology , Diet, High-Fat , Fatty Liver/etiology , Fatty Liver/prevention & control , Triglycerides/metabolism , Adipokines/genetics , Adipokines/pharmacology , Animals , Fatty Acids/biosynthesis , Hepatocytes/drug effects , Hepatocytes/metabolism , Insulin Resistance , Lipid Metabolism/drug effects , Liver/chemistry , Liver/enzymology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Rats , Recombinant Proteins/pharmacology , Triglycerides/analysis , Triglycerides/genetics , Tumor Cells, Cultured , Tumor Necrosis Factor-alpha/bloodABSTRACT
C1q/TNF-related protein 13 (CTRP13), a hormone secreted by adipose tissue (adipokines), helps regulate glucose metabolism in peripheral tissues. We previously reported that CTRP13 expression is increased in obese and hyperphagic leptin-deficient mice, suggesting that it may modulate food intake and body weight. CTRP13 is also expressed in the brain, although its role in modulating whole-body energy balance remains unknown. Here, we show that CTRP13 is a novel anorexigenic factor in the mouse brain. Quantitative PCR demonstrated that food restriction downregulates Ctrp13 expression in mouse hypothalamus, while high-fat feeding upregulates expression. Central administration of recombinant CTRP13 suppressed food intake and reduced body weight in mice. Further, CTRP13 and the orexigenic neuropeptide agouti-related protein (AgRP) reciprocally regulate each other's expression in the hypothalamus: central delivery of CTRP13 suppressed Agrp expression, while delivery of AgRP increased Ctrp13 expression. Food restriction alone reduced Ctrp13 and increased orexigenic neuropeptide gene (Npy and Agrp) expression in the hypothalamus; in contrast, when food restriction was coupled to enhanced physical activity in an activity-based anorexia (ABA) mouse model, hypothalamic expression of both Ctrp13 and Agrp were upregulated. Taken together, these results suggest that CTRP13 and AgRP form a hypothalamic feedback loop to modulate food intake and that this neural circuit may be disrupted in an anorexic-like condition.
Subject(s)
Adipokines/metabolism , Body Weight , Eating , Hormones/metabolism , Adipokines/genetics , Adipokines/pharmacology , Agouti-Related Protein/metabolism , Animals , Anorexia/metabolism , Anorexia/physiopathology , Anorexia Nervosa/metabolism , Anorexia Nervosa/physiopathology , Body Weight/drug effects , Diet/adverse effects , Eating/drug effects , HEK293 Cells , Hormones/genetics , Hormones/pharmacology , Humans , Hypothalamus/drug effects , Hypothalamus/metabolism , Male , Mice , Mice, Inbred C57BL , Neuropeptides/metabolism , Obesity/etiology , Obesity/genetics , Phenotype , RNA, Messenger/genetics , RNA, Messenger/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Recombinant Proteins/pharmacologyABSTRACT
C1q/TNF-related proteins (CTRPs) are a family of secreted regulators of glucose and lipid metabolism. Here, we describe CTRP11, a novel and phylogenetically conserved member of the C1q family. Our studies revealed that white and brown adipose are major tissues that express CTRP11, and its expression is acutely regulated by changes in metabolic state. Within white adipose tissue, CTRP11 is primarily expressed by stromal vascular cells. As a secreted multimeric protein, CTRP11 forms disulfide-linked oligomers. Although the conserved N-terminal Cys-28 and Cys-32 are dispensable for the assembly of higher-order oligomeric structures, they are unexpectedly involved in modulating protein secretion. When co-expressed, CTRP11 forms heteromeric complexes with closely related CTRP10, CTRP13, and CRF (CTRP14) via the C-terminal globular domains, combinatorial associations that potentially generate functionally distinct complexes. Functional studies revealed a role for CTRP11 in regulating adipogenesis. Ectopic expression of CTRP11 or exposure to recombinant protein inhibited differentiation of 3T3-L1 adipocytes. The expression of peroxisome proliferator-activated receptor-γ and CAAT/enhancer binding protein-α, which drive the adipogenic gene program, was markedly suppressed by CTRP11. Impaired adipogenesis was caused by a CTRP11-mediated decrease in p42/44-MAPK signaling and inhibition of mitotic clonal expansion, a process essential for adipocyte differentiation in culture. These results implicate CTRP11 as a novel secreted regulator of adipogenesis and highlight the potential paracrine cross-talk between adipocytes and cells of the stromal vascular compartment in maintaining adipose tissue homeostasis.
Subject(s)
Adipogenesis/physiology , Adipokines/biosynthesis , Cell Differentiation/physiology , Gene Expression Regulation/physiology , MAP Kinase Signaling System/physiology , Paracrine Communication/physiology , 3T3-L1 Cells , Adipogenesis/drug effects , Adipokines/genetics , Adipokines/pharmacology , Animals , Cell Differentiation/drug effects , Female , MAP Kinase Signaling System/drug effects , Male , Mice , Mice, Obese , Mitogen-Activated Protein Kinase 1/genetics , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/genetics , Mitogen-Activated Protein Kinase 3/metabolism , Paracrine Communication/drug effects , Protein Structure, Tertiary , Recombinant Proteins/biosynthesis , Recombinant Proteins/genetics , Recombinant Proteins/pharmacologyABSTRACT
Estrogen-related receptors (ERRs) α, ß and γ are orphan nuclear hormone receptors with no known ligands. Little is known concerning the role of ERRß in energy homeostasis, as complete ERRß-null mice die mid-gestation. We generated two viable conditional ERRß-null mouse models to address its metabolic function. Whole-body deletion of ERRß in Sox2-Cre:ERRß(lox/lox) mice resulted in major alterations in body composition, metabolic rate, meal patterns and voluntary physical activity levels. Nestin-Cre:ERRß(lox/lox) mice exhibited decreased expression of ERRß in hindbrain neurons, the predominant site of expression, decreased neuropeptide Y (NPY) gene expression in the hindbrain, increased lean body mass, insulin sensitivity, increased energy expenditure, decreased satiety and decreased time between meals. In the absence of ERRß, increased ERRγ signaling decreased satiety and the duration of time between meals, similar to meal patterns observed for both the Sox2-Cre:ERRß(lox/lox) and Nestin-Cre:ERRß(lox/lox) strains of mice. Central and/or peripheral ERRγ signaling may modulate these phenotypes by decreasing NPY gene expression. Overall, the relative expression ratio between ERRß and ERRγ may be important in modulating ingestive behavior, specifically satiety, gene expression, as well as whole-body energy balance.