The link between obesity and puberty: what is new?

PURPOSE OF REVIEW: The objective of this review is to assess the most recent literature on pubertal trends in boys and girls as well as evaluate genetic, epigenetic, and environmental factors implicated in the timing of pubertal progression. RECENT FINDINGS: Recent studies confirm the previously described link between increased adiposity and earlier onset of puberty in girls, and more recent studies shed light onto the previously unclear situation in boys as a preponderance of recent longitudinal studies suggests that increased adiposity is linked with earlier pubertal timing also in boys. Discoveries of novel pathways highlights the complexity of pubertal development and suggest mechanistic links between nutrition, obesity, leptin, insulin resistance, and puberty. Furthermore, genetic and epigenetic variants can be linked to early puberty. Other factors, such as prenatal and postnatal environment, gut microbiota, and endocrine-disrupting chemicals have also been linked to both obesity and earlier puberty. SUMMARY: Understanding how the interactions of these factors contribute the relationship between obesity and early pubertal onset is crucial as early puberty has been linked with long-term consequences, such as short stature, earlier type 2 diabetes, cardiovascular disease, and poor psychological and behavioral outcomes.

A novel truncating variant in ring finger protein 113A (RNF113A) confirms the association of this gene with X-linked trichothiodystrophy.

We describe an 11-year old boy with severe global developmental delays, failure to thrive and growth retardation, refractory seizures with recurrent status epilepticus, hypogammaglobulinemia, hypergonadotropic hypogonadism, and duodenal strictures. He had facial and skin findings compatible with trichothiodystrophy, including sparse and brittle hair, thin eyebrows, and dry skin. Exome sequencing showed a hemizygous, truncating variant in RNF113A, c.903_910delGCAGACCA, predicting p.(Gln302fs*12), that was inherited from his mother. Although his clinical features overlap closely with features described in the two previously reported male first cousins with RNF113A loss of function mutations, the duodenal strictures seen in this patient have not been reported. Interestingly, the patient's mother had short stature and 100% skewed X-inactivation as seen in other obligate female carriers. A second male with developmental delays, microcephaly, seizures, ambiguous genitalia, and facial anomalies that included sparse and brittle hair, thin eyebrows and dry skin was recently reported to have c.897_898delTG, predicting p.(Cys299*) in RNF113A and we provide additional clinical details for this patient. This report further supports deleterious variants in RNF113A as a cause of a novel trichothiodystrophy syndrome.

Health-Care Utilization and Outcomes in Young Adults With Type 1 and Type 2 Diabetes.

Young adulthood can be a challenging time for individuals with diabetes mellitus (DM) as they experience increasing independence and life transitions, which can make it difficult to engage in DM self care. Compared to older adults, young adults are more likely to have higher glycated hemoglobin A1c (HbA1c). They also often have lower adherence to standards of care in DM, and higher utilization of emergency department (ED) visits and hospitalizations for diabetic ketoacidosis. This review describes health-care utilization and explores factors that may contribute to high HbA1c among young adults with DM. In addition, it discusses the unique health-care needs of young adults with DM, examines the role of technology in their DM care, and analyzes the effects of social determinants of health on their health-care utilization.

Modulation of foraging-like behaviors by cholesterol-FGF19 axis.

BACKGROUND: Foraging for food precedes food consumption and is an important component of the overall metabolic programming that regulates feeding. Foraging is governed by central nervous system neuronal circuits but how it is influenced by diet and hormonal signals is still not well understood. RESULTS: In this study, we show that dietary cholesterol exerted suppressive effects on locomotor activity and that these effects were partially mediated by the neuropeptide Agouti-related protein (AgRP). High dietary cholesterol stimulated intestinal expression of fibroblast growth factor 15 (Fgf15), an ortholog of the human fibroblast growth factor 19 (FGF19). Intracerebroventricular infusion of FGF19 peptide reduced exploratory activity in the open field test paradigm. On the other hand, the lack of dietary cholesterol enhanced exploratory activity in the open field test, but this effect was abolished by central administration of FGF19. CONCLUSIONS: Experiments in this study show that dietary cholesterol suppresses locomotor activity and foraging-like behaviors, and this regulation is in part mediated by AgRP neurons. Dietary cholesterol or the central action of FGF19 suppresses exploratory behaviors, and the anxiogenic effects of dietary cholesterol may be mediated by the effect of FGF19 in the mouse brain. This study suggests that dietary cholesterol and intestinal hormone FGF15/19 signal a satiating state to the brain, thereby suppressing foraging-like behaviors.

The Significance of Hypothalamic Inflammation and Gliosis for the Pathogenesis of Obesity in Humans.

Accumulated preclinical literature demonstrates that hypothalamic inflammation and gliosis are underlying causal components of diet-induced obesity in rodent models. This review summarizes and synthesizes available translational data to better understand the applicability of preclinical findings to human obesity and its comorbidities. The published literature in humans includes histopathologic analyses performed postmortem and in vivo neuroimaging studies measuring indirect markers of hypothalamic tissue microstructure. Both support the presence of hypothalamic inflammation and gliosis in children and adults with obesity. Findings predominantly point to tissue changes in the region of the arcuate nucleus of the hypothalamus, although findings of altered tissue characteristics in whole hypothalamus or other hypothalamic regions also emerged. Moreover, the severity of hypothalamic inflammation and gliosis has been related to comorbid conditions, including glucose intolerance, insulin resistance, type 2 diabetes, and low testosterone levels in men, independent of elevated body adiposity. Cross-sectional findings are augmented by a small number of prospective studies suggesting that a greater degree of hypothalamic inflammation and gliosis may predict adiposity gain and worsening insulin sensitivity in susceptible individuals. In conclusion, existing human studies corroborate a large preclinical literature demonstrating that hypothalamic neuroinflammatory responses play a role in obesity pathogenesis. Extensive or permanent hypothalamic tissue remodeling may negatively affect the function of neuroendocrine regulatory circuits and promote the development and maintenance of elevated body weight in obesity and/or comorbid endocrine disorders.

Impaired Brain Satiety Responses After Weight Loss in Children With Obesity.

CONTEXT: Obesity interventions often result in increased motivation to eat. OBJECTIVE: We investigated relationships between obesity outcomes and changes in brain activation by visual food cues and hormone levels in response to obesity intervention by family-based behavioral treatment (FBT). METHODS: Neuroimaging and hormone assessments were conducted before and after 24-week FBT intervention in children with obesity (OB, n = 28), or children of healthy weight without intervention (HW, n = 17), all 9- to 11-year-old boys and girls. We evaluated meal-induced changes in neural activation to high- vs low-calorie food cues across appetite-processing brain regions and gut hormones. RESULTS: Among children with OB who underwent FBT, greater declines of BMI z-score were associated with lesser reductions after the FBT intervention in meal-induced changes in neural activation to high- vs low-calorie food cues across appetite-processing brain regions (P < 0.05), and the slope of relationship was significantly different compared with children of HW. In children with OB, less reduction in brain responses to a meal from before to after FBT was associated with greater meal-induced reduction in ghrelin and increased meal-induced stimulation in peptide YY and glucagon-like peptide-1 (all P < 0.05). CONCLUSION: In response to FBT, adaptations of central satiety responses and peripheral satiety-regulating hormones were noted. After weight loss, changes of peripheral hormone secretion support weight loss, but there was a weaker central satiety response. The findings suggest that even when peripheral satiety responses by gut hormones are intact, the central regulation of satiety is disturbed in children with OB who significantly improve their weight status during FBT, which could favor future weight regain.

ASB4 modulates central melanocortinergic neurons and calcitonin signaling to control satiety and glucose homeostasis.

Variants in the gene encoding ankyrin repeat and SOCS box-containing 4 (ASB4) are linked to human obesity. Here, we characterized the pathways underlying the metabolic functions of ASB4. Hypothalamic Asb4 expression was suppressed by fasting in wild-type mice but not in mice deficient in AgRP, which encodes Agouti-related protein (AgRP), an appetite-stimulating hormone, suggesting that ASB4 is a negative target of AgRP. Many ASB4 neurons in the brain were adjacent to AgRP terminals, and feeding induced by AgRP neuronal activation was disrupted in Asb4-deficient mice. Acute knockdown of Asb4 in the brain caused marked hyperphagia due to increased meal size, and Asb4 deficiency led to increased meal size and food intake at the onset of refeeding, when very large meals were consumed. Asb4-deficient mice were resistant to the meal-terminating effects of exogenously administered calcitonin and showed decreased neuronal expression of Calcr, which encodes the calcitonin receptor. Pro-opiomelanocortin (POMC) neurons in the arcuate nucleus in mice are involved in glucose homeostasis, and Asb4 deficiency specifically in POMC neurons resulted in glucose intolerance that was independent of obesity. Furthermore, individuals with type 2 diabetes showed reduced ASB4 abundance in the infundibular nuclei, the human equivalent of the arcuate nucleus. Together, our results indicate that ASB4 acts in the brain to improve glucose homeostasis and to induce satiety after substantial meals, particularly those after food deprivation.

A gene-diet interaction controlling relative intake of dietary carbohydrates and fats.

OBJECTIVE: Preference for dietary fat vs. carbohydrate varies markedly across free-living individuals. It is recognized that food choice is under genetic and physiological regulation, and that the central melanocortin system is involved. However, how genetic and dietary factors interact to regulate relative macronutrient intake is not well understood. METHODS: We investigated how the choice for food rich in carbohydrate vs. fat is influenced by dietary cholesterol availability and agouti-related protein (AGRP), the orexigenic component of the central melanocortin system. We assessed how macronutrient intake and different metabolic parameters correlate with plasma AGRP in a cohort of obese humans. We also examined how both dietary cholesterol levels and inhibiting de novo cholesterol synthesis affect carbohydrate and fat intake in mice, and how dietary cholesterol deficiency during the postnatal period impacts macronutrient intake patterns in adulthood. RESULTS: In obese human subjects, plasma levels of AGRP correlated inversely with consumption of carbohydrates over fats. Moreover, AgRP-deficient mice preferred to consume more calories from carbohydrates than fats, more so when each diet lacked cholesterol. Intriguingly, inhibiting cholesterol biosynthesis (simvastatin) promoted carbohydrate intake at the expense of fat without altering total caloric consumption, an effect that was remarkably absent in AgRP-deficient mice. Finally, feeding lactating C57BL/6 dams and pups a cholesterol-free diet prior to weaning led the offspring to prefer fats over carbohydrates as adults, indicating that altered cholesterol metabolism early in life programs adaptive changes to macronutrient intake. CONCLUSIONS: Together, our study illustrates a specific gene-diet interaction in modulating food choice.

Continuous Glucose Monitoring to Diagnose Hypoglycemia Due to Late Dumping Syndrome in Children After Gastric Surgeries.

Gastrostomy tubes (G-tubes) and Nissen fundoplication are common surgical interventions for feeding difficulties and gastroesophageal reflux disease in children. A potential yet often missed, complication of these procedures is dumping syndrome. We present 3 pediatric patients with postprandial hypoglycemia due to late dumping syndrome after gastric surgeries. All patients received gastrostomy tubes for feeding intolerance: 2 had Nissen fundoplication for gastroesophageal reflux disease, and 1 had tracheoesophageal repair. All patients underwent multiple imaging studies in an to attempt to diagnose dumping syndrome. Continuous glucose monitoring (CGM) was essential for detecting asymptomatic hypoglycemia and glycemic excursions occurring with feeds that would have gone undetected with point-of-care (POC) blood glucose checks. CGM was also used to monitor the effectiveness of treatment strategies and drive treatment plans. These cases highlight the utility of CGM in diagnosing postprandial hypoglycemia due to late dumping syndrome, which is infrequently diagnosed by imaging studies and intermittent POC blood glucose measurements.

Twenty years of pediatric diabetes surveillance: what do we know and why it matters.

SEARCH for Diabetes in Youth (SEARCH) was initiated in 2000 as a multicenter study to address major gaps in the understanding of childhood diabetes in the United States. An active registry of youth diagnosed with diabetes at age <20 years since 2002 assessed prevalence, annual incidence, and trends by age, race/ethnicity, sex, and diabetes type. An observational cohort nested within the population-based registry was established to assess the natural history and risk factors for acute and chronic diabetes-related complications, as well as the quality of care and quality of life of children and adolescents with diabetes from diagnosis into young adulthood. SEARCH findings have contributed to a better understanding of the complex and heterogeneous nature of youth-onset diabetes. Continued surveillance of the burden and risk of type 1 and type 2 diabetes is important to track and monitor incidence and prevalence within the population. SEARCH reported evidence of early diabetes complications highlighting that continuing the long-term follow-up of youth with diabetes is necessary to further our understanding of its natural history and to develop the most appropriate approaches to primary, secondary, and tertiary prevention of diabetes and its complications. This review summarizes two decades of research and suggests avenues for further work.

Connections Between Obesity and Puberty: Invited by Manuel Tena-Sempere, Cordoba.

The relationship between obesity and puberty remains controversial. Whereas cross-sectional and longitudinal studies show a clear shift toward earlier puberty in obese girls, the trend in obese boys remains less obvious. Overweight boys mature earlier whereas obese boys mature later compared to healthy weight boys. Newer epidemiologic studies attempt to address these knowledge gaps. This review provides a detailed overview of the recent literature regarding secular trends in pubertal onset and tempo, and the connection with obesity. Additionally, this review summarizes potential mediators that permit obesity to promote early puberty. Other factors such as socioeconomic status, in utero exposures, nutritional, and even endocrine disrupting chemicals can cause perturbation of both metabolism and the endocrine axis that can ultimately have effects on pubertal development.

Spatially patterned gene expression for guided neurite extension.

Axon pathfinding by localized expression of guidance molecules is critical for the proper development of the nervous system. In this report, we present a well-defined spatially patterned gene expression system to investigate neurite guidance in vitro. Nonviral gene delivery was patterned by combining substrate-mediated gene delivery with soft lithography techniques, and the amount of protein produced at the region of localized expression was varied by altering the vector concentration and the width of the pattern, highlighting the flexibility of the system. A neuronal coculture model was used to investigate responses to spatial patterns of nerve growth factor (NGF) expression. The soluble NGF gradient elicited a guidance cue, and the degree of guidance was governed by the distance a neuron was cultured from the pattern and the time between accessory cell and neuron seedings. A portion of the diffusible NGF bound to the culture surface in the extracellular space, and the surface-associated NGF supported neuron survival and neurite outgrowth. However, the surface-bound NGF gradient alone did not elicit a guidance signal, and in fact masked the guidance cue by soluble NGF gradients. Mathematical modeling of NGF diffusion was used to predict the concentration gradients, and both the absolute and fractional gradients capable of guiding neurites produced by patterned gene expression differed substantially from the values obtained with existing engineered protein gradients. Spatially patterned gene expression provides a versatile tool to investigate the factors that may promote neurite guidance.

Non-viral gene delivery transfection profiles influence neuronal architecture in an in vitro co-culture model.

Gene delivery from tissue engineering scaffolds can induce expression of tissue inductive factors to stimulate the cellular processes required for regeneration. Transfected cells secrete diffusible proteins that can create local concentration gradients, depending on the number, distribution, and expression level of transfected cells. These gradients are linked to cellular organization and tissue architecture during embryogenesis. In this report, we investigate neuronal architecture and neurite guidance in response to the concentration gradients achieved by localized secretion of a neurotrophic factor from transfected cells. A co-culture model was employed to examine neuronal responses to multiple transfection profiles, which affects the local concentration of secreted nerve growth factor (NGF). Neuronal architecture, as defined by number of neurites per neuron and length of neurites, was influenced by the transfection profile. Low levels of NGF production by few transfected cells produced longer primary neurites with less branching relative to the higher expression levels or increased numbers of transfected cells. Furthermore, for low NGF production by few transfected cells, the growth cone of the axons was marked by longer extensions and larger surface area, suggesting the presence of a guidance cue. Control studies with varying NGF concentrations did not substantially alter the neuronal architecture, further supporting an effect of localized concentration gradients, and not simply the concentration. Mathematical modeling of NGF diffusion was employed to predict the concentration gradients produced by the transfection profiles, and the resultant gradients were correlated to the cellular response. This report connects the transfection profile, concentration gradients, and the resulting cellular architecture, suggesting a critical design consideration for the application of gene delivery to regenerative medicine.

Balancing cell migration with matrix degradation enhances gene delivery to cells cultured three-dimensionally within hydrogels.

In regenerative medicine, hydrogels are employed to fill defects and support the infiltration of cells that can ultimately regenerate tissue. Gene delivery within hydrogels targeting infiltrating cells has the potential to promote tissue formation, but the delivery efficiency of non-viral vectors within hydrogels is low, hindering their applicability in tissue regeneration. To improve their functionality, we have conducted a mechanistic study to investigate the contribution of cell migration and matrix degradation on gene delivery. In this report, lipoplexes were entrapped within hydrogels based on poly(ethylene glycol) (PEG) crosslinked with peptides containing matrix metalloproteinase degradable sequences. The mesh size of these hydrogels is substantially less than the size of the entrapped lipoplexes, which can function to retain vectors. Cell migration and transfection were simultaneously measured within hydrogels with varying density of cell adhesion sites (Arg-Gly-Asp peptides) and solids content. Increasing RGD density increased expression levels up to 100-fold, while greater solids content sustained expression levels for 16days. Increasing RGD density and decreasing solids content increased cell migration, which indicates expression levels increase with increased cell migration. Initially exposing cells to vector resulted in transient expression that declined after 2days, verifying the requirement of migration to sustain expression. Transfected cells were predominantly located within the population of migrating cells for hydrogels that supported cell migration. Although the small mesh size retained at least 70% of the lipoplexes in the absence of cells after 32days, the presence of cells decreased retention to 10% after 16days. These results indicate that vectors retained within hydrogels contact migrating cells, and that persistent cell migration can maintain elevated expression levels. Thus, matrix degradation and cell migration are fundamental design parameters for maximizing gene delivery within hydrogels.

Patterned transgene expression in multiple-channel bridges after spinal cord injury.

Patterning of gene delivery on sub-millimeter length scales within tissue engineering scaffolds is fundamental to recreating the complex architectures of tissues. Surface-mediated delivery of lipoplexes mixed with fibronectin was investigated to pattern vectors within 250 microm channels in poly(lactide-co-glycolide) (PLG) bridges. Initial studies performed in vitro on PLG surfaces indicated that a DNA density of 0.07 microg mm(-2) inside each channel with a weight ratio of DNA to fibronectin of 1:20 maximized the number of transfected cells and the levels of transgene expression. Patterned vectors encoding for nerve growth factor (NGF) resulted in localized neurite extension within the channel. Translation to three-dimensional multiple-channel bridges enabled patterned transfection of different vectors throughout the channels for DNA:fibronectin ratios of 1:4 and multiple DNA depositions, with a large increase of neural cell bodies and neurite extension for delivery of DNA encoding for NGF. In vivo, the immobilization of non-viral vectors within the channels resulted in localized transfection within the pore structure of the bridge immediately around the channels of the bridge containing DNA. This surface immobilization strategy enables patterned gene delivery in vitro and in vivo on length scales of hundreds of microns and may find utility in strategies aimed at regenerating tissues with complex architectures.