Limb-Clasping Response in NMDA Receptor Palmitoylation-Deficient Mice.

Proper regulation of N-methyl-D-aspartate-type glutamate receptor (NMDA receptor) expression is responsible for excitatory synaptic functions in the mammalian brain. NMDA receptor dysfunction can cause various neuropsychiatric disorders and neurodegenerative diseases. Posttranslational protein S-palmitoylation, the covalent attachment of palmitic acid to intracellular cysteine residues via thioester bonds, occurs in the carboxyl terminus of GluN2B, which is the major regulatory NMDA receptor subunit. Mutations of three palmitoylatable cysteine residues in the membrane-proximal cluster of GluN2B to non-palmitoylatable serine (3CS) lead to the dephosphorylation of GluN2B Tyr1472 in the hippocampus and cerebral cortex, inducing a reduction in the surface expression of GluN2B-containig NMDA receptors. Furthermore, adult GluN2B 3CS homozygous mice demonstrated a definite clasping response without abnormalities in the gross brain structure, other neurological reflexes, or expression levels of synaptic proteins in the cerebrum. This behavioral disorder, observed in the GluN2B 3CS knock-in mice, indicated that complex higher brain functions are coordinated through the palmitoylation-dependent regulation of NMDA receptors in excitatory synapses.

Dissolved N2O concentrations in oil palm plantation drainage in a peat swamp of Malaysia.

Oil palm plantations in Southeast Asia are the largest supplier of palm oil products and have been rapidly expanding in the last three decades even in peat-swamp areas. Oil palm plantations on peat ecosystems have a unique water management system that lowers the water table and, thus, may yield indirect N2O emissions from the peat drainage system. We conducted two seasons of spatial monitoring for the dissolved N2O concentrations in the drainage and adjacent rivers of palm oil plantations on peat swamps in Sarawak, Malaysia, to evaluate the magnitude of indirect N2O emissions from this ecosystem. In both the dry and wet seasons, the mean and median dissolved N2O concentrations exhibited over-saturation in the drainage water, i.e., the oil palm plantation drainage may be a source of N2O to the atmosphere. In the wet season, the spatial distribution of dissolved N2O showed bimodal peaks in both the unsaturated and over-saturated concentrations. The bulk δ15N of dissolved N2O was higher than the source of inorganic N in the oil palm plantation (i.e., N fertilizer and soil organic nitrogen) during both seasons. An isotopocule analysis of the dissolved N2O suggested that denitrification was a major source of N2O, followed by N2O reduction processes that occurred in the drainage water. The δ15N and site preference mapping analysis in dissolved N2O revealed that a significant proportion of the N2O produced in peat and drainage is reduced to N2 before being released into the atmosphere.

Two Siblings Showing a Mild Phenotype of Joubert Syndrome with a Specific CEP290 Variant.

Joubert syndrome (JS) is a genetic neurodevelopmental disorder characterized by lower brainstem dysplasia and cerebellar vermis agenesis termed molar tooth sign (MTS), psychomotor retardation, abnormal respiratory pattern in infancy, and oculomotor abnormalities. Arima syndrome (AS), which is a severe form of JS, is characterized by severe psychomotor retardation, congenital visual impairment, progressive renal dysfunction, and lower brainstem dysplasia from early infancy. Numerous patients with AS expire in early childhood. Recently, c.6012-12T> A in the CEP290 gene was reported as a specific variant of AS. Herein, we report the cases of two siblings showing a phenotype of JS with compound heterozygous mutations (c.6012-12T > A / c.5924delT) in the CEP290 gene. The older sister (aged 19 years) had hypotonia, hypertelorism, and anteverted nares since birth. As a neonate, she developed a transient abnormal respiratory pattern and nystagmus, and brain magnetic resonance imaging (MRI) showed MTS. The younger sister (aged 13 years) exhibited mild hypotonia and pendular nystagmus as a neonate; MRI revealed MTS. Both sisters had psychomotor retardation, oculomotor dysfunction, and bilateral renal cysts with normal renal function. They can walk and have simple conversation. They do not meet the diagnostic criteria for AS, and their symptoms were milder than those of previously reported cases with this specific mutation. This report indicates the expanding spectrum of the CEP290 variant.

Assessing the changes in river water quality across a land-use change (forest to oil palm plantation) in peninsular Malaysia using the stable isotopes of water and nitrate.

Land conversion from natural forests to plantations (e.g., oil palm) in Southeast Asia is one of the most intensive land-use changes occurring worldwide. To clarify the effects of oil palm plantations on water quality, we conducted multipoint river and stream water sampling in peninsular Malaysia at the end of the rainy season over a 3-year period (2013-2015). We measured the major dissolved ions and stable isotope ratios of water (δ2H-H2O and δ18O-H2O) and nitrate (δ15N-NO3- and δ18O-NO3-) in water from the upper streams in mountainous forests to the midstream areas of two major rivers in peninsular Malaysia. The electrical conductivity increased, and the d-excess value (as an index of the degree of evaporation) decreased with increasing distance from the headwaters, suggesting the effect of evaporative enrichment and the addition of pollutants. We separated the sampling points into four groups (G1-G4) through cluster analysis of the water quality data. From the land use/land cover (LULC) classification maps developed from satellite images and local information, we found that G1 and G2 mainly consisted of sampling points in forested areas, while G3 and G4 were located in oil-palm-affected areas. The concentrations of major ions were higher in the oil palm areas, indicating the effects of fertilizer and limestone (i.e., pH adjustment) applications. The dissolved inorganic nitrogen concentration did not differ among the groups, but the dissolved organic carbon, total dissolved nitrogen, and δ15N-NO3- were higher in the oil palm area than in the forested area. Although the nitrogen concentration was low, even in the oil palm area, the significantly higher δ15N-NO3- in the oil palm area indicated substantial denitrification. This implies that denitrification contributed to the lowering of the NO3- concentration in rivers in the oil palm area, in addition to nutrient uptake by oil palm trees.

Coordination chemogenetics for activation of GPCR-type glutamate receptors in brain tissue.

Direct activation of cell-surface receptors is highly desirable for elucidating their physiological roles. A potential approach for cell-type-specific activation of a receptor subtype is chemogenetics, in which both point mutagenesis of the receptors and designed ligands are used. However, ligand-binding properties are affected in most cases. Here, we developed a chemogenetic method for direct activation of metabotropic glutamate receptor 1 (mGlu1), which plays essential roles in cerebellar functions in the brain. Our screening identified a mGlu1 mutant, mGlu1(N264H), that was activated directly by palladium complexes. A palladium complex showing low cytotoxicity successfully activated mGlu1 in mGlu1(N264H) knock-in mice, revealing that activation of endogenous mGlu1 is sufficient to evoke the critical cellular mechanism of synaptic plasticity, a basis of motor learning in the cerebellum. Moreover, cell-type-specific activation of mGlu1 was demonstrated successfully using adeno-associated viruses in mice, which shows the potential utility of this chemogenetics for clarifying the physiological roles of mGlu1 in a cell-type-specific manner.

Long-Term Outcomes of Longitudinal Efficacy Study With Tolvaptan in ADPKD.

INTRODUCTION: The effects of long-term and uninterrupted tolvaptan treatment on autosomal dominant polycystic kidney disease (ADPKD) are unclear. Therefore, a more than 3-year continuous treatment study was performed. METHODS: From the Kyorin University cohort, 299 patients were surveyed and 179 patients were indicated for tolvaptan having a total kidney volume (TKV) ≥750 ml, TKV slope ≥5%/yr, and estimated glomerular filtration rate (eGFR) ≥15 ml/min per 1.73 m2. Among 179 patients, 118 patients consented to the study. RESULTS: Retrospective pretreatment and prospective on-treatment periods had a median of 1.8 and 4.0 years, respectively. During the 5 treatment-years, the log10(TKV) slope/yr decreased from the pretreatment period (P < 0.0001) and the estimated height-adjusted TKV growth rate α (eHTKV-α, %/yr) decreased from baseline (P < 0.0001). The decline in eGFR improved in female patients (P < 0.0001), but not in males (P = 0.6321). Furthermore, during the 5 treatment-years, eGFR remained significantly better in the group with a percent decrease in eHTKV-α from baseline to the first treatment-year ≥ the median (2.94%) than in the group with a decrease <2.94%. The free-water clearance was higher in males than in females irrespective of treatment. CONCLUSION: The TKV growth rate decreased in 4 years with tolvaptan in both sexes. The insignificant effects of tolvaptan on the eGFR slope in males were likely due to androgen stimulation of cystogenesis and analytical difficulty of longitudinal changes in nonlinear trajectories of eGFR. The larger decrease in eHTKV-α in the first year was related to a better renal prognosis. The vasopressin-mediated water reabsorption was activated more in females than males irrespective of tolvaptan administration.

PKD1-Associated Arachnoid Cysts in Autosomal Dominant Polycystic Kidney Disease.

OBJECTIVES: the prevalence of intracranial aneurysms and arachnoid cysts is higher in patients with autosomal dominant polycystic kidney disease (ADPKD) than in the general population. A genotype correlation was reported for intracranial aneurysms, but it is unclear for arachnoid cysts. Therefore, the genotype correlation with intracranial aneurysms and arachnoid cysts was investigated in ADPKD. MATERIALS AND METHODS: intracranial aneurysms and arachnoid cysts were screened by magnetic resonance imaging (MRI), and PKD genotypes were examined using next-generation sequencing for 169 patients with ADPKD. RESULTS: PKD1-, PKD2- and no-mutation were identified in 137, 24 and 8 patients, respectively. Intracranial aneurysms and arachnoid cysts were found in 34 and 25 patients, respectively, with no significant difference in frequency. Genotype, sex, estimated glomerular filtration rate and age at ADPKD diagnosis significantly affected the age at brain MRI. The proportional hazard risk analyzed using the age at brain MRI adjusted by these four variables was 5.0-times higher in the PKD1 group than in the PKD2 group for arachnoid cysts (P = 0.0357), but it was not different for intracranial aneurysms (P = 0.1605). Arachnoid cysts were diagnosed earlier in the PKD1 group than in the PKD2 group (54.8 vs 67.7 years, P = 0.0231), but no difference was found for intracranial aneurysms (P = 0.4738) by Kaplan-Meier analysis. CONCLUSIONS: this study demonstrated the correlation between arachnoid cysts and PKD1 mutation. The reported association of arachnoid cysts with advanced renal disease may be due to the common correlation of these factors with PKD1 mutation.

Lung injury associated with electronic cigarettes inhalation diagnosed by transbronchial lung biopsy.

A 46-year-old healthy man developed respiratory distress, night sweats, fever, and weight loss after using electronic cigarettes (e-cigs) for approximately 1 month. He presented to the hospital when the symptoms worsened 2 months after onset. The findings of bronchoalveolar lavage (BAL) fluid examination and the following transbronchial lung biopsy examination led to the diagnosis of acute alveolitis: intra-alveolar fibrosis accompanied with exudate containing abundant lipid-laden macrophages, eosinophils, and neutrophils. Eventually, e-cig-induced acute lung injury was diagnosed. The symptoms were rapidly alleviated upon e-cig use termination and methylprednisolone pulse therapy, and no subsequent recurrence was observed. There have been only a few reported cases of e-cig-induced lung injury. In e-cig users presenting with atypical pneumonia, close examination by BAL and biopsy should be performed to verify the presence or absence of lipid-laden macrophages.

Arima syndrome caused by CEP290 specific variant and accompanied with pathological cilium; clinical comparison with Joubert syndrome and its related diseases.

OBJECTIVE: Arima syndrome (AS) is a rare disease and its clinical features mimic those of Joubert syndrome or Joubert syndrome-related diseases (JSRD). Recently, we clarified the AS diagnostic criteria and its severe phenotype. However, genetic evidence of AS remains unknown. We explored causative genes of AS and compared the clinical and genetic features of AS with the other JSRD. PATIENTS AND METHODS: We performed genetic analyses of 4 AS patients of 3 families with combination of whole-exome sequencing and Sanger sequencing. Furthermore, we studied cell biology with the cultured fibroblasts of 3 AS patients. RESULTS: All patients had a specific homozygous variant (c.6012-12T>A, p.Arg2004Serfs*7) or compound heterozygous variants (c.1711+1G>A; c.6012-12T>A, p.Gly570Aspfs*19;Arg2004Serfs*7) in centrosomal protein 290 kDa (CEP290) gene. These unique variants lead to abnormal splicing and premature termination. Morphological analysis of cultured fibroblasts from AS patients revealed a marked decrease of the CEP290-positive cell number with significantly longer cilium and naked and protruded ciliary axoneme without ciliary membrane into the cytoplasm. CONCLUSION: AS resulted in cilia dysfunction from centrosome disruption. The unique variant of CEP290 could be strongly linked to AS pathology. Here, we provided AS specific genetic evidence, which steers the structure and functions of centrosome that is responsible for normal ciliogenesis. This is the first report that has demonstrated the molecular basis of Arima syndrome.

Pathologic Active mTOR Mutation in Brain Malformation with Intractable Epilepsy Leads to Cell-Autonomous Migration Delay.

The activation of phosphatidylinositol 3-kinase-AKTs-mammalian target of rapamycin cell signaling pathway leads to cell overgrowth and abnormal migration and results in various types of cortical malformations, such as hemimegalencephaly (HME), focal cortical dysplasia, and tuberous sclerosis complex. However, the pathomechanism underlying abnormal cell migration remains unknown. With the use of fetal mouse brain, we performed causative gene analysis of the resected brain tissues from a patient with HME and investigated the pathogenesis. We obtained a novel somatic mutation of the MTOR gene, having approximately 11% and 7% mutation frequency in the resected brain tissues. Moreover, we revealed that the MTOR mutation resulted in hyperphosphorylation of its downstream molecules, S6 and 4E-binding protein 1, and delayed cell migration on the radial glial fiber and did not affect other cells. We suspect cell-autonomous migration arrest on the radial glial foot by the active MTOR mutation and offer potential explanations for why this may lead to cortical malformations such as HME.

Successful desensitization therapy involving fluoroquinolone for the treatment of a solitary tuberculoma: A case report and literature review.

The patient was a 31-year-old female with no previous health problems; however, during a health checkup in 2013, a nodule (2.5 cm in diameter) was identified in the S10 area of the left lung. No clinical symptoms were apparent. Positron emission tomography/computed tomography revealed an accumulation in the same region. The patient was suspected of having lung cancer, and video-assisted thoracoscopic surgery was performed. A histopathological examination of the resected specimen revealed epithelioid granulomas accompanied by caseous necrosis in the lesion. The culture was positive for Mycobacterium tuberculosis, which led to the final diagnosis of tuberculoma. Initially, the patient underwent anti-M.tuberculosis treatment [isoniazid (INH) + rifampicin (RFP) + ethambutol (EB) + pyrazinamide (PZA)]. However, two weeks later, the development of epatic dysfunction necessitated suspension of the medication. Treatment was resumed following improvement of the hepatic function. However, this relapsed two weeks later, resulting in discontinuation of the treatment. The patient was negative for each of the four drugs in the drug-induced lymphocyte stimulation test (DLST), and drug-induced hepatotoxicity (DIH) attributable to the anti-tuberculous drugs that were administered. Therefore, desensitization therapy was initiated. EB + PZA were changed to levofloxacin (LVFX) at an initial dose of 250 mg/day (dose level increased to the maintenance dose). Subsequently, desensitization therapy with RFP and INH was applied in accordance with the Japanese Society for Tuberculosis protocol. After each drug dose level reached the maintenance dose level, the therapy was completed following administration of the drugs for the recommended duration of 6 months. There were no signs of relapse 6 months following completion of the therapy. Therefore, the patient responded well to the substitute therapy with LVFX and desensitization therapy, and the present case report provided information regarding the treatment of tuberculoma.

Remission of ALK-negative primary pulmonary inflammatory myofibroblastic tumor on treatment with clarithromycin: A case report and review of the literature.

Inflammatory myofibroblastic tumors (IMTs) belong to an intermediate group of soft-tissue tumors, they are relatively rare but exhibit a wide range of pathologies, from benign to malignant. At present, no standard treatment has been established, however, it is known to be important to determine the grade of malignancy of the tumor, prior to treatment. The present study reports a 73-year-old female patient with no clinical manifestations, who, when examined radiographically at a health check exhibited bilateral thoracic infiltrative shadows and nodular shadows by chest CT. A metastatic tumor or an organizing pneumonia were suspected. Blood examination showed no abnormal findings, and a pathological diagnosis of IMT was given from the histological findings of the tissue extracted by video-assisted thoracic surgery. Histological analysis established the lack of expression of anaplastic lymphoma kinase (ALK1) and immunoglobulin subtype G4 (IgG4). Alteration of the radiological shadows was observed over several weeks, and after concluding that chronic inflammation was worsening the patient's condition, clarithromycin was administered as a long-term macrolide therapy. The IMT decreased in size, and eight months later it had almost resolved. The patient was last reported to be maintaining a stable condition with no relapse. Some IMT cases have malignant pathology, and should be carefully followed-up. However, in the present case, where the IMT is both ALK1-negative and IgG4-negative, its biological immune responsiveness appears to differ from positive cases, and an inflammatory response was predominant. Clarithromycin, has immunomodulatory and anti-inflammatory effects and appeared to be effective in treating the IMT of the patient in the present study.

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels contain multiple S-palmitoylation sites.

Expression of hyperpolarization-activated cyclic nucleotide-gated channels (HCN1-4) on distal dendrites of neurons is suggested to modify synaptic integration in the central nervous system. However, the mechanisms of dendritic localization are not fully understood. Recent studies have revealed that S-palmitoylation plays an important role in the enrichment of various molecules at the postsynaptic membrane. Thus, we performed an acyl-biotinyl exchange assay, and found that HCN1, HCN2, and HCN4, but not HCN3, were S-palmitoylated in HEK293 cells. Mutation of multiple intracellular cysteine residues at the N-terminus of HCN2 was required for complete inhibition of S-palmitoylation. However, this mutagenesis had a minimal effect on surface expression of HCN2 proteins or electrophysiological properties of HCN2 current when expressed in HEK293 cells or in Xenopus oocytes. These findings provide insight into the physiological roles of S-palmitoylation of HCN channels in native neurons.

The Role of ARX in Human Pancreatic Endocrine Specification.

The in vitro differentiation of human embryonic stem cells (hESCs) offers a model system to explore human development. Humans with mutations in the transcription factor Aristaless Related Homeobox (ARX) often suffer from the syndrome X-linked lissencephaly with ambiguous genitalia (XLAG), affecting many cell types including those of the pancreas. Indeed, XLAG pancreatic islets lack glucagon and pancreatic polypeptide-positive cells but retain somatostatin, insulin, and ghrelin-positive cells. To further examine the role of ARX in human pancreatic endocrine development, we utilized genomic editing in hESCs to generate deletions in ARX. ARX knockout hESCs retained pancreatic differentiation capacity and ARX knockout endocrine cells were biased toward somatostatin-positive cells (94% of endocrine cells) with reduced pancreatic polypeptide (rarely detected), glucagon (90% reduced) and insulin-positive (65% reduced) lineages. ARX knockout somatostatin-positive cells shared expression patterns with human fetal and adult δ-cells. Differentiated ARX knockout cells upregulated PAX4, NKX2.2, ISL1, HHEX, PCSK1, PCSK2 expression while downregulating PAX6 and IRX2. Re-expression of ARX in ARX knockout pancreatic progenitors reduced HHEX and increased PAX6 and insulin expression following differentiation. Taken together these data suggest that ARX plays a key role in pancreatic endocrine fate specification of pancreatic polypeptide, somatostatin, glucagon and insulin positive cells from hESCs.

Two siblings with cortical dysplasia: Clinico-electroencephalographic features.

The older of two siblings began to have spasms and partial seizures at 1 month of age. Head magnetic resonance imaging showed an abnormal area in the left temporo-parieto-occipital region. Interictal electroencephalogram (EEG) showed a suppression-burst pattern. Adrenocorticotropic hormone stopped the spasms, but the seizures continued. Clonazepam, carbamazepine, zonisamide, and clobazam were ineffective. She underwent focal resection at age 8 months. Postoperatively, the seizures disappeared. Histopathologically, the lesion appeared to be focal cortical dysplasia type IIa. The younger sibling had spasms from birth. Head magnetic resonance imaging showed left hemi-megalencephaly. Interictal EEG showed a suppression-burst pattern. Phenobarbital, valproic acid, and zonisamide were ineffective. He underwent hemispherotomy at age 2 months and became seizure free. The histopathological features were consistent with those of hemi-megalencephaly. The siblings' EEG and clinical courses had some similarities. These siblings' conditions may have the same genetic background.

Repeated exposure to 5-bromo-2'-deoxyuridine causes decreased proliferation and low-grade inflammation in the lungs of mice.

Incorporation of 5-bromo-2'-deoxyuridine (BrdU) into proliferating cells has been used to label dividing cells in many tissues. Although BrdU has been shown to be genotoxic, teratogenic and mutagenic, such adverse effects have largely been ignored by researchers. We determined whether long-term BrdU exposure causes any histopathological changes in the lungs of mice. Eight-week-old male C57/BL6J mice were administered BrdU by intraperitoneal injection on 3 consecutive days of each week for 14 weeks. While no obvious structural changes such as tissue damage, fibrosis, emphysema, airway remodeling, vascular thickening or tumorigenesis were noted, a moderate degree of macrophage infiltration was observed in the airways and lung parenchyma in the lungs of the mice exposed repeatedly to BrdU (BrdU-exposed mice). The proliferative activities of the airway and alveolar epithelial and mesenchymal cells were reduced in the BrdU-exposed mice, although the numbers of these cells in the lungs were maintained. Double immunofluorescence study of the lungs of the BrdU-exposed mice showed overexpression of IL-6 in the airway epithelial and alveolar wall cells, some of which were also double-positive for BrdU. These results indicate that long-term exposure to BrdU inhibits cell proliferation and induces low-grade inflammation in the lungs of mice. Our findings underscore the need for caution in the interpretation of studies that involve long-term exposure to BrdU.

Expression of astrocyte-related receptors in cortical dysplasia with intractable epilepsy.

Epilepsy is one of the major neurologic diseases, and astrocytes play important roles in epileptogenesis. To investigate possible roles of astrocyte-related receptors in patients with intractable epilepsy associated with focal cortical dysplasia (FCD) and other conditions, we examined resected epileptic foci from 31 patients, including 23 with FCD type I, IIa, or IIb, 5 with tuberous sclerosis complex, and 3 with low-grade astrocytoma. Control samples were from 21 autopsied brains of patients without epilepsy or neurologic deficits and 5 patients with pathologic gliosis without epilepsy. Immunohistochemical and immunoblot analyses with antibodies against purinergic receptor subtypes P2RY1, P2RY2, P2RY4, potassium channels Kv4.2 and Kir4.1, and metabotropic receptor subtypes mGluR1 and mGluR5 were performed. Anti-glial fibrillary acidic protein, anti-NeuN, and anti-CD68 immunostaining was used to identify astrocytes, neurons, and microglia, respectively. Most glial fibrillary acidic protein-immunopositive astrocyte cells in the brain samples from patients with epilepsy were P2RY1-, P2RY2-, P2RY4-, Kv4.2-, Kir4.1-, mGluR1-, and mGluR5-positive, whereas samples from controls and pathologic gliosis showed lower expression levels of these astrocyte-related receptors. Our findings suggest that, although these receptors are necessary for astrocyte transmission, formation of the neuron-glia network, and other physiologic functions, overexpression in the brains of patients with intractable epilepsy may be associated with activation of intracellular and glio-neuronal signaling pathways that contribute to epileptogenesis.

Promotion of adipogenesis by an EP2 receptor agonist via stimulation of angiogenesis in pulmonary emphysema.

Body weight loss is a common manifestation in patients with chronic obstructive pulmonary disease (COPD), particularly those with severe emphysema. Adipose angiogenesis is a key mediator of adipogenesis and use of pro-angiogenic agents may serve as a therapeutic option for lean COPD patients. Since angiogenesis is stimulated by PGE2, we examined whether ONO-AE1-259, a selective E-prostanoid (EP) 2 receptor agonist, might promote adipose angiogenesis and adipogenesis in a murine model of elastase-induced pulmonary emphysema (EIE mice). Mice were intratracheally instilled with elastase or saline, followed after 4 weeks by intraperitoneal administration of ONO-AE1-259 for 4 weeks. The subcutaneous adipose tissue (SAT) weight decreased in the EIE mice, whereas in the EIE mice treated with ONO-AE1-259, the SAT weight was largely restored, which was associated with significant increases in SAT adipogenesis, angiogenesis, and VEGF protein production. In contrast, ONO-AE1-259 administration induced no alteration in the weight of the visceral adipose tissue. These results suggest that in EIE mice, ONO-AE1-259 stimulated adipose angiogenesis possibly via VEGF production, and thence, adipogenesis. Our data pave the way for the development of therapeutic interventions for weight loss in emphysema patients, e.g., use of pro-angiogenic agents targeting the adipose tissue vascular component.