The severity and frequency of childhood obesity has increased significantly over the past three to four decades. The health effects of increased body mass index as a child may significantly impact ...obese youth as they age. However, many of the long-term outcomes of childhood obesity have yet to be studied. This article examines the currently available longitudinal data evaluating the effects of childhood obesity on adult outcomes. Consequences of obesity include an increased risk of developing the metabolic syndrome, cardiovascular disease, type 2 diabetes and its associated retinal and renal complications, nonalcoholic fatty liver disease, obstructive sleep apnea, polycystic ovarian syndrome, infertility, asthma, orthopedic complications, psychiatric disease, and increased rates of cancer, among others. These disorders can start as early as childhood, and such early onset increases the likelihood of early morbidity and mortality. Being obese as a child also increases the likelihood of being obese as an adult, and obesity in adulthood also leads to obesity-related complications. This review outlines the evidence for childhood obesity as a predictor of adult obesity and obesity-related disorders, thereby emphasizing the importance of early intervention to prevent the onset of obesity in childhood.
Globally, the proportion of new diagnoses of youth-onset diabetes represented by type 2 diabetes is increasing, and youth with type 2 diabetes commonly have complications and comorbidities, as well ...as a higher rate of mortality. In this review, we summarise what is known about the natural progression of youth-onset type 2 diabetes from published clinical trials and large-scale prospective epidemiological studies. It is important to note that the robust pathophysiological and treatment data specifically related to individuals with a diabetes onset at ≤20 years of age largely hails from the USA. Youth-onset type 2 diabetes is characterised by pathophysiological heterogeneity and inadequate glycaemic control, highlighting the need for new treatment approaches and innovative study designs in populations of varied genetic and cultural backgrounds.
Graphical abstract
Insulin Resistance of Puberty Kelsey, Megan M.; Zeitler, Philip S.
Current Diabetes Reports,
07/2016, Letnik:
16, Številka:
7
Journal Article, Book Review
Recenzirano
Puberty is a time of considerable metabolic and hormonal change. Notably, puberty is associated with a marked decrease in insulin sensitivity, on par with that seen during pregnancy. In otherwise ...healthy youth, there is a nadir in insulin sensitivity in mid-puberty, and then it recovers at puberty completion. However, there is evidence that insulin resistance (IR) does not resolve in youth who are obese going into puberty and may result in increased cardiometabolic risk. Little is known about the underlying pathophysiology of IR in puberty, and how it might contribute to increased disease risk (e.g., type 2 diabetes). In this review, we have outlined what is known about the IR in puberty in terms of pattern, potential underlying mechanisms and other mediating factors. We also outline other potentially related metabolic changes that occur during puberty, and effects of underlying insulin resistant states (e.g., obesity) on pubertal changes in insulin sensitivity.
Hepatic steatosis (HS) is common in adolescents with obesity and polycystic ovary syndrome (PCOS). Gut microbiota are altered in adults with obesity, HS, and PCOS, which may worsen metabolic ...outcomes, but similar data is lacking in youth.
Thirty-four adolescents with PCOS and obesity underwent stool and fasting blood collection, oral glucose tolerance testing, and MRI for hepatic fat fraction (HFF). Fecal bacteria were profiled by high-throughput 16S rRNA gene sequencing.
50% had HS (N = 17, age 16.2±1.5 years, BMI 38±7 kg/m2, HFF 9.86.5, 20.7%) and 50% did not (N = 17, age 15.8±2.2 years, BMI 35±4 kg/m2, HFF 3.82.6, 4.4%). The groups showed no difference in bacterial α-diversity (richness p = 0.202; evenness p = 0.087; and diversity p = 0.069) or global difference in microbiota (β-diversity). Those with HS had lower % relative abundance (%RA) of Bacteroidetes (p = 0.013), Bacteroidaceae (p = 0.009), Porphyromonadaceae (p = 0.011), and Ruminococcaceae (p = 0.008), and higher Firmicutes:Bacteroidetes (F:B) ratio (47.8% vs. 4.3%, p = 0.018) and Streptococcaceae (p = 0.034). Bacterial taxa including phyla F:B ratio, Bacteroidetes, and family Bacteroidaceae, Ruminococcaceae and Porphyromonadaceae correlated with metabolic markers.
Obese adolescents with PCOS and HS have differences in composition of gut microbiota, which correlate with metabolic markers, suggesting a modifying role of gut microbiota in HS and PCOS.
Aims/hypothesis
Our aim was to explore metabolic pathways linking overnutrition in utero to development of adiposity in normal-weight children.
Methods
We included 312 normal-weight youth exposed or ...unexposed to overnutrition in utero (maternal BMI ≥25 kg/m
2
or gestational diabetes). Fasting insulin, glucose and body composition were measured at age ~10 years (baseline) and ~16 years (follow-up). We examined associations of overnutrition in utero with baseline fasting insulin, followed by associations of baseline fasting insulin with adiposity (BMI
z
score BMIZ, subcutaneous adipose tissue SAT, visceral adipose tissue VAT), insulin resistance (HOMA-IR) and fasting glucose during follow-up.
Results
>All participants were normal weight at baseline (BMIZ −0.32 ± 0.88), with no difference in BMIZ for exposed vs unexposed youth (
p
= 0.14). Of the study population, 47.8% were female sex and 47.4% were of white ethnicity. Overnutrition in utero corresponded with 14% higher baseline fasting insulin (geometric mean ratio 1.14 95% CI 1.01, 1.29), even after controlling for VAT/SAT ratio. Higher baseline fasting insulin corresponded with higher BMIZ (0.41 95% CI 0.26, 0.55), SAT (13.9 95% CI 2.4, 25.4 mm
2
), VAT (2.0 95% CI 0.1, 3.8 mm
2
), HOMA-IR (0.87 95% CI 0.68, 1.07) and fasting glucose (0.23 95% CI 0.09, 0.38 SD).
Conclusions/interpretation
Overnutrition in utero may result in hyperinsulinaemia during childhood, preceding development of adiposity. However, our study started at age 10 years, so earlier metabolic changes in response to overnutrition were not taken into account. Longitudinal studies in normal-weight youth starting earlier in life, and with repeated measurements of body weight, fat distribution, insulin sensitivity, beta cell function and blood glucose levels, are needed to clarify the sequence of metabolic changes linking early-life exposures to adiposity and dysglycaemia.
Graphical abstract
Abstract
Context
Alterations in gut microbiota relate to the metabolic syndrome, but have not been examined in at-risk obese youth with polycystic ovary syndrome (PCOS).
Objective
Compare the ...composition and diversity of the gut microbiota and associations with metabolic and hormonal measures between 2 groups of female adolescents with equal obesity with or without PCOS.
Design
Prospective, case-control cross-sectional study.
Setting
Tertiary-care center.
Participants
A total of 58 obese female adolescents (n = 37 with PCOS; 16.1 ± 0.3 years of age; body mass index BMI 98.5th percentile) and (n = 21 without PCOS; 14.5 ± 0.4 years of age; BMI 98.7th percentile).
Outcomes
Bacterial diversity, percent relative abundance (%RA), and correlations with hormonal and metabolic measures.
Results
Participants with PCOS had decreased α-diversity compared with the non-PCOS group (Shannon diversity P = 0.045 and evenness P = 0.0052). β-diversity, reflecting overall microbial composition, differed between groups (P < 0.001). PCOS had higher %RA of phyla Actinobacteria (P = 0.027), lower Bacteroidetes (P = 0.004), and similar Firmicutes and Proteobacteria. PCOS had lower %RA of families Bacteroidaceae (P < 0.001) and Porphyromonadaceae (P = 0.024) and higher Streptococcaceae (P = 0.047). Lower bacterial α-diversity was strongly associated with higher testosterone concentrations. Several individual taxa correlated with testosterone and metabolic measures within PCOS and across the entire cohort. Receiver operative curve analysis showed 6 taxa for which the %RA related to PCOS status and lower Bacteroidaceae conferred a 4.4-fold likelihood ratio for PCOS.
Conclusion
Alterations in the gut microbiota exist in obese adolescents with PCOS versus obese adolescents without PCOS and these changes relate to markers of metabolic disease and testosterone. Further work is needed to determine if microbiota changes are reflective of, or influencing, hormonal metabolism.
Abstract The regulatory circuits dictating CD8 + T cell responsiveness versus exhaustion during anti-tumor immunity are incompletely understood. Here we report that tumor-infiltrating ...antigen-specific PD-1 + TCF-1 − CD8 + T cells express the immunosuppressive cytokine Fgl2. Conditional deletion of Fgl2 specifically in mouse antigen-specific CD8 + T cells prolongs CD8 + T cell persistence, suppresses phenotypic and transcriptomic signatures of T cell exhaustion, and improves control of the tumor. In a mouse model of chronic viral infection, PD-1 + CD8 + T cell-derived Fgl2 also negatively regulates virus-specific T cell responses. In humans, CD8 + T cell-derived Fgl2 is associated with poorer survival in patients with melanoma. Mechanistically, the dampened responsiveness of WT Fgl2 -expressing CD8 + T cells, when compared to Fgl2 -deficient CD8 + T cells, is underpinned by the cell-intrinsic interaction of Fgl2 with CD8 + T cell-expressed FcγRIIB and concomitant caspase 3/7-mediated apoptosis. Our results thus illuminate a cell-autonomous regulatory axis by which PD-1 + CD8 + T cells both express the receptor and secrete its ligand in order to mediate suppression of anti-tumor and anti-viral immunity.
Abstract
Context
Obesity is known to impact reproductive function in adults, but little is known about its effects on reproductive hormones during puberty.
Objective
To assess sex differences in ...effects of obesity on reproductive hormones and their relation to insulin sensitivity and secretion.
Design
Cross-sectional study including anthropometrics, serum and urine reproductive hormone concentrations, and intravenous glucose tolerance testing (IVGTT) to assess acute insulin response to glucose (AIRg), and insulin sensitivity (Si).
Setting
Outpatient academic clinical research center.
Patients
Girls (52%) and boys (48%) who were normal weight (NW; n = 51, BMI-Z score = −0.11 ± 0.77, age = 11.5 ± 1.7 years) and obese (n = 53, BMI-Z score = 2.22 ± 0.33, age = 10.9 ± 1.5 years), Tanner stage 2 to 3.
Results
Boys with obesity had lower total testosterone (P < 0.0001) and higher concentrations of the urinary estradiol metabolite, E1c, (P = 0.046) than boys with NW. Girls with obesity had higher free androgen index (FAI; P = 0.03) than NW girls. Both boys and girls with obesity had lower sex hormone-binding globulin (SHBG; P < 0.0001) than NW. AIRg was inversely related to SHBG in boys (R = 0.6, P < 0.0001) and girls (R = 0.53, P = 0.0001). Si correlated with higher SHBG in boys (R2 = 0.67, P < 0.0001) and girls (R = 0.5, P = 0.0003), higher total testosterone for boys (R = 0.39, P = 0.01), and lower FAI for girls (R = −0.2, P = 0.04).
Conclusion
Youth with obesity have lower SHBG than youth with NW, but obesity has differential effects on reproductive hormones in girls versus boys, which are apparent early in puberty. Ongoing longitudinal studies will evaluate the impact of obesity on reproductive hormones in girls and boys as puberty progresses.
Study assessed sex differences in effects of obesity on reproductive hormones in early puberty and found that obesity has differential effects on reproductive hormones in girls and boys.
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