The Families Improving Health Together (FIT) Program: Initial evaluation of retention and research in a multispecialty clinic for children with obesity.

BACKGROUND: Obesity affects ∼17% of US children, with parallel increases in multiple comorbidities, especially among African-, Asian-, Hispanic-, and Native-Americans. Barriers to patient retention in pediatric obesity programs include lack of centralized care, and frequent subspecialty MD visits which conflict with patient school attendance and parental work attendance as well as with support service utilization. Lack of integration of multispecialty clinical care with interdisciplinary research is a major barrier to fuller exploration of the treatment, prevention, and understanding of obesity in childhood. OBJECTIVE: To test the hypothesis, a novel multispecialty/interdisciplinary clinical and research infrastructure with strong emphasis on a primary obesity care physician for children with early-onset (<9 years) obesity (Families Improving health Together [FIT]) could promote lower patient attrition (primary goal) and foster productive research in pediatric obesity (secondary goal). RESULTS: Data support the hypotheses. Over 15 months, FIT reported a >90% participant retention (p < 0.001 vs. expected rate based on other studies of similar programs). Though 90% of children had at least one adiposity-related comorbidity and 70% had at least two, there was no need for additional subspecialist visits with cardiologists, endocrinologists, gastroenterologists, or molecular geneticists. Three abstracts were presented at national meetings, and two manuscripts were published all with junior faculty as primary authors. CONCLUSION: This pilot study suggests that an integrated multispecialty/interdisciplinary approach to children with obesity improves patient retention and can be integrated successfully with research.

Pseudomonas aeruginosa Utilizes Host-Derived Itaconate to Redirect Its Metabolism to Promote Biofilm Formation.

The bacterium Pseudomonas aeruginosa is especially pathogenic, often being associated with intractable pneumonia and high mortality. How P. aeruginosa avoids immune clearance and persists in the inflamed human airway remains poorly understood. In this study, we show that P. aeruginosa can exploit the host immune response to maintain infection. Notably, unlike other opportunistic bacteria, we found that P. aeruginosa alters its metabolic and immunostimulatory properties in response to itaconate, an abundant host-derived immunometabolite in the infected lung. Itaconate induces bacterial membrane stress, resulting in downregulation of lipopolysaccharides (LPS) and upregulation of extracellular polysaccharides (EPS). These itaconate-adapted P. aeruginosa accumulate lptD mutations, which favor itaconate assimilation and biofilm formation. EPS, in turn, induces itaconate production by myeloid cells, both in the airway and systemically, skewing the host immune response to one permissive of chronic infection. Thus, the metabolic versatility of P. aeruginosa needs to be taken into account when designing therapies.

CFTR-PTEN-dependent mitochondrial metabolic dysfunction promotes Pseudomonas aeruginosa airway infection.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor best known for regulating cell proliferation and metabolism. PTEN forms a complex with the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) at the plasma membrane, and this complex is known to be functionally impaired in CF. Here, we demonstrated that the combined effect of PTEN and CFTR dysfunction stimulates mitochondrial activity, resulting in excessive release of succinate and reactive oxygen species. This environment promoted the colonization of the airway by Pseudomonas aeruginosa, bacteria that preferentially metabolize succinate, and stimulated an anti-inflammatory host response dominated by immune-responsive gene 1 (IRG1) and itaconate. The recruitment of myeloid cells induced by these strains was inefficient in clearing the infection and increased numbers of phagocytes accumulated under CFTR-PTEN axis dysfunction. This central metabolic defect in mitochondrial function due to impaired PTEN activity contributes to P. aeruginosa infection in CF.

Characterization of Rare Variants in MC4R in African American and Latino Children With Severe Early-Onset Obesity.

CONTEXT: Mutations in melanocortin receptor (MC4R) are the most common cause of monogenic obesity in children of European ancestry, but little is known about their prevalence in children from the minority populations in the United States. OBJECTIVE: This study aims to identify the prevalence of MC4R mutations in children with severe early-onset obesity of African American or Latino ancestry. DESIGN AND SETTING: Participants were recruited from the weight management clinics at two hospitals and from the institutional biobank at a third hospital. Sequencing of the MC4R gene was performed by whole exome or Sanger sequencing. Functional testing was performed to establish the surface expression of the receptor and cAMP response to its cognate ligand α-melanocyte-stimulating hormone. PARTICIPANTS: Three hundred twelve children (1 to 18 years old, 50% girls) with body mass index (BMI) >120% of 95th percentile of Centers for Disease Control and Prevention 2000 growth charts at an age <6 years, with no known pathological cause of obesity, were enrolled. RESULTS: Eight rare MC4R mutations (2.6%) were identified in this study [R7S, F202L (n = 2), M215I, G252D, V253I, I269N, and F284I], three of which were not previously reported (G252D, F284I, and R7S). The pathogenicity of selected variants was confirmed by prior literature reports or functional testing. There was no significant difference in the BMI or height trajectories of children with or without MC4R mutations in this cohort. CONCLUSIONS: Although the prevalence of MC4R mutations in this cohort was similar to that reported for obese children of European ancestry, some of the variants were novel.

A Putative Acetylation System in Vibrio cholerae Modulates Virulence in Arthropod Hosts.

Acetylation is a broadly conserved mechanism of covalently modifying the proteome to precisely control protein activity. In bacteria, central metabolic enzymes and regulatory proteins, including those involved in virulence, can be targeted for acetylation. In this study, we directly link a putative acetylation system to metabolite-dependent virulence in the pathogen Vibrio cholerae We demonstrate that the cobB and yfiQ genes, which encode homologs of a deacetylase and an acetyltransferase, respectively, modulate V. cholerae metabolism of acetate, a bacterially derived short-chain fatty acid with important physiological roles in a diversity of host organisms. In Drosophila melanogaster, a model arthropod host for V. cholerae infection, the pathogen consumes acetate within the gastrointestinal tract, which contributes to fly mortality. We show that deletion of cobB impairs growth on acetate minimal medium, delays the consumption of acetate from rich medium, and reduces virulence of V. cholerae toward Drosophila These impacts can be reversed by complementing cobB or by introducing a deletion of yfiQ into the ΔcobB background. We further show that cobB controls the accumulation of triglycerides in the Drosophila midgut, which suggests that cobB directly modulates metabolite levels in vivo In Escherichia coli K-12, yfiQ is upregulated by cAMP-cAMP receptor protein (CRP), and we identified a similar pattern of regulation in V. cholerae, arguing that the system is activated in response to similar environmental cues. In summary, we demonstrate that proteins likely involved in acetylation can modulate the outcome of infection by regulating metabolite exchange between pathogens and their colonized hosts.IMPORTANCE The bacterium Vibrio cholerae causes severe disease in humans, and strains can persist in the environment in association with a wide diversity of host species. By investigating the molecular mechanisms that underlie these interactions, we can better understand constraints affecting the ecology and evolution of this global pathogen. The Drosophila model of Vibrio cholerae infection has revealed that bacterial regulation of acetate and other small metabolites from within the fly gastrointestinal tract is crucial for its virulence. Here, we demonstrate that genes that may modify the proteome of V. cholerae affect virulence toward Drosophila, most likely by modulating central metabolic pathways that control the consumption of acetate as well as other small molecules. These findings further highlight the many layers of regulation that tune bacterial metabolism to alter the trajectory of interactions between bacteria and their hosts.