Commentary
Abstract
Obesity during pregnancy is a major health problem in the United States. In this issue of the JCI, Most et al. fill an important gap in our understanding of energy homeostasis in pregnancy. The researchers measured energy intake, energy expenditure, and body composition in obese pregnant women. They demonstrated that energy intake need not increase in order for obese women to gain the recommended amounts of weight during pregnancy. Additionally, all of the gestational weight gain scenarios (inadequate, recommended, or excess) resulted in similar maternal and fetal perinatal outcomes. This evidence should guide new recommendations on this important topic.
Authors
Sarah S. Comstock
Abstract
Fasting requires complex endocrine and metabolic interorgan crosstalk, which involves shifting from glucose to fatty acid oxidation, derived from adipose tissue lipolysis, in order to preserve glucose for the brain. The glucose-alanine (Cahill) cycle is critical for regenerating glucose. In this issue of JCI, Petersen et al. report on their use of an innovative stable isotope tracer method to show that skeletal muscle–derived alanine becomes rate controlling for hepatic mitochondrial oxidation and, in turn, for glucose production during prolonged fasting. These results provide new insight into skeletal muscle–liver metabolic crosstalk during the fed-to-fasting transition in humans.
Authors
Theresia Sarabhai, Michael Roden
Abstract
Mucus obstruction is a hallmark of cystic fibrosis (CF) airway disease, leading to chronic infection, dysregulated inflammation, and progressive lung disease. As mucus hyperexpression is a key component in the initiation and perpetuation of airway obstruction, the triggers underlying mucin release must be identified and understood. In this issue of the JCI, Chen et al. sought to delineate the mechanisms that allow IL-1α/IL-1β to perpetuate the mucoinflammatory environment characteristic of the CF airway. The authors demonstrated that IL-1α and IL-1β stimulated non-CF human bronchial epithelial (HBE) cells to upregulate and secrete both MUC5B and MUC5AC in a dose-dependent manner, an effect that was neutralized by the inhibition of the IL-1α/IL-1β receptor (IL-1R1). Further experiments using mouse models and excised lung tissue identified contributors that drive a vicious feedback cycle of hyperconcentrated mucus secretions and persistent inflammation in the CF airway, factors that are likely at the nidus of progressive lung disease.
Authors
Susan E. Birket, Steven M. Rowe
Abstract
Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic illness of systemic inflammation and organ dysfunction, with unknown etiology. Although therapies targeting IL-6 have been proven effective, a subset of patients with iMCD are resistant to this approach. In this issue of the JCI, Fajgenbaum et al. performed an in-depth analysis of serum inflammatory markers in three iMCD patients refractory to IL-6 blockade, and identified activation of the mTOR pathway associated with symptom flares. Treatment with sirolimus, an mTOR inhibitor, induced remission in all three patients. This study models a precision medicine approach to discovering therapies for rare diseases.
Authors
Robert M. Stern, Nancy Berliner
Abstract
Genome-wide association studies (GWAS) have provided a wealth of information on potential disease-associated genes in the human population. In particular, several loci have been associated with type 2 diabetes (T2D). However, due to the complexity of the disease, it has been a challenge to unravel the exact effects of specific loci on T2D pathogenesis. In this issue of the JCI, Keller and colleagues developed a systems genetic approach to identify insulin secretion–associated genes in nondiabetic mice followed by tissue-level and functional phenotyping. Several of the loci identified were syntenic with human T2D-related loci, indicating that this approach may be feasible for discerning genetic variation in nondiabetic individuals that may lead to the development of T2D.
Authors
Mark A. Herman, Jonathan E. Campbell, David A. D’Alessio
Abstract
Recent work demonstrated a role for myeloid-derived suppressor cells (MDSCs) in the antimicrobial response in newborns, but the signals guiding their differentiation remained unknown. In this issue of the JCI, Liu et al. demonstrate that lactoferrin (LF) converts newborn neutrophils and monocytes to MDSCs via the low-density lipoprotein receptor–related protein-2 (LRP2) receptor and NF-κB activation. Due to their strong antimicrobial activity, adoptive transfer of MDSCs generated by in vitro culture with LF prolonged the survival of newborn mice with necrotizing enterocolitis, a severe pathology in preterm infants. These findings indicate a surprising protective role of MDSCs in newborns and demonstrate the potential of MDSC therapy for the treatment of infants with diseases associated with deregulated inflammation.
Authors
Rebekka Weber, Viktor Umansky
Abstract
Electronic nicotine delivery systems (ENDS) are rapidly increasing in popularity due to the perception that they may represent a safe alternative to conventional cigarettes. However, a growing body of evidence indicates that ENDS exposure can disrupt maintenance of pulmonary immune homeostasis and antimicrobial immunity. In this issue of the JCI, Madison et al. demonstrate that in mice, chronic ENDS exposure induces profound alterations in lipid homeostasis. ENDS-exposed mice showed irregularities in the surfactant-secreting lamellar bodies within type 2 alveolar cells and increased intracellular phospholipid accumulation within alveolar macrophages. Moreover, ENDS-exposed mice displayed greater inflammation and tissue damage in response to influenza A, which may be due to downregulated expression of a viral pattern–recognition receptor in alveolar macrophages. Collectively, the results of this study identify previously unrecognized adverse effects of ENDS exposure on pulmonary lipid metabolism, although the implication of these effects on long-term respiratory health requires future exploration.
Authors
Aran Singanayagam, Robert J. Snelgrove
Abstract
Dengue viruses (DENV) are the most common cause of mosquito-borne viral illness in the world, affecting approximately 400 million people annually. Symptomatic illness ranges from a mild, self-limiting febrile illness to one manifested by plasma leakage that can lead to vascular collapse and death. In this issue of the JCI, Rathore et al. report that DENV can cause mast cell degranulation independently of mast cell infection, resulting in the release of the vasoactive mediators chymase and tryptase. The authors showed that recombinant chymase and tryptase increased endothelial permeability in a dose-dependent manner in human microvascular endothelial cells. They went on to evaluate the tryptase inhibitor nafamostat mesylate in a mouse model for severe DENV viremia. Strikingly, the potential therapeutic prevented and reversed the tryptase-induced vascular permeability. As there are currently no licensed drugs for the treatment of dengue, these findings present a possible treatment modality for severe disease.
Authors
Anna P. Durbin
Abstract
In this issue of the JCI, Kanter et al. make a strong case for implicating apolipoprotein C3 (APOC3) as a central player in atherosclerotic cardiovascular disease that is commonly seen in individuals with type 1 diabetes mellitus (T1DM). Kanter and colleagues suggest that insulin deficiency elevates plasma APOC3 as well as atherogenic triglyceride-rich (TG-rich) lipoproteins (TRLs). Using two mouse models of T1DM, the authors investigated APOC3-mediated inhibition of both TG hydrolysis by lipoprotein lipase and hepatic uptake of remnant lipoproteins. They suggest that poorly catabolized lipoproteins, enriched in both APOC3 and APOE content, are particularly atherogenic. Notably, treating both mouse models with an APOC3 antisense oligonucleotide lowered both plasma APOC3 and TRLs, and prevented atherosclerosis. These impactful mouse studies were supported by the initial finding that APOC3 predicted coronary artery disease events in participants of the prospective Coronary Artery Calcification in Type 1 Diabetes study with normal TG levels.
Authors
Henry N. Ginsberg, Gissette Reyes-Soffer
Abstract
Ghrelin is a key signal driving energy seeking and storage in order to reverse energy deficit. In line with this view, the metabolic status of an organism predicts sensitivity to ghrelin, with fasting increasing and obesity decreasing ghrelin sensitivity, respectively. However, the mechanism responsible for controlling this sensitivity is unknown. In this issue of the JCI, Mani and colleagues show that plasma levels of plasma liver-enriched antimicrobial peptide-2 (LEAP2), a recently identified hormone that antagonizes the ghrelin receptor, are inversely correlated with those of plasma acyl-ghrelin under conditions of both energy deficit and energy surplus in mice and humans. Their results show that a fall in plasma LEAP2 during energy deficit facilitates the actions of acyl-ghrelin, whereas increased LEAP2 in obesity suppresses the actions of acyl-ghrelin. This important discovery helps reshape our understanding of ghrelin function and may provide a new approach to aiding weight maintenance after diet-induced weight loss.
Authors
Zane B. Andrews
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Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)