Metabolic homeostasis is orchestrated by the hypothalamus through the neuroendocrine and the autonomic nervous systems. The hypothalamic nuclei respond to the peptide leptin secreted from adipose tissue to suppress feeding and increase energy expenditure by promoting fat metabolism via sympathetic activity. Another important, but perhaps less appreciated function of central leptin signaling is to elevate peripheral insulin sensitivity. Environmental and genetic risk factors that affect hypothalamic leptin signaling can lead to obesity and type 2 diabetes mellitus (T2DM). Here, we discovered that LIM domain only 4, LMO4, is a novel protein participating in central leptin signaling. In a process strikingly similar to T2DM in humans, CaMKIIα-Cre;LMO4flox/flox mice, which have LMO4 knocked out in the postnatal brain including the hypothalamus, develop visceral adiposity, reduced insulin sensitivity, obesity and diabetes when fed with regular chow. Central leptin signaling was significantly lost in key hypothalamic nuclei of mutant mice. Caloric restriction prevents obesity but not insulin resistance in these mice. Taken together, our results suggest that LMO4 function in the brain is required for central leptin signaling to control fat metabolism and peripheral insulin sensitivity.

Metabolic homeostasis is orchestrated by the hypothalamus through the neuroendocrine and the autonomic nervous systems. The hypothalamic nuclei respond to the peptide leptin secreted from adipose tissue to suppress feeding and increase energy expenditure by promoting fat metabolism via sympathetic activity. Another important, but perhaps less appreciated function of central leptin signaling is to elevate peripheral insulin sensitivity. Environmental and genetic risk factors that affect hypothalamic leptin signaling can lead to obesity and type 2 diabetes mellitus (T2DM). Here, we discovered that LIM domain only 4, LMO4, is a novel protein participating in central leptin signaling. In a process strikingly similar to T2DM in humans, CaMKIIα-Cre;LMO4flox/flox mice, which have LMO4 knocked out in the postnatal brain including the hypothalamus, develop visceral adiposity, reduced insulin sensitivity, obesity and diabetes when fed with regular chow. Central leptin signaling was significantly lost in key hypothalamic nuclei of mutant mice. Caloric restriction prevents obesity but not insulin resistance in these mice. Taken together, our results suggest that LMO4 function in the brain is required for central leptin signaling to control fat metabolism and peripheral insulin sensitivity.

Purpose: National prevalence of childhood overweight and obesity has plateaued in recent years, but rates remain high, with approximately 10% among children“high weight.” The relationship between adiposity and serum 25-hydroxyvitamin D [25(OH)D] status has been well-explored in older individuals, with inconsistent results. Furthermore, previous studies have suggested a relationship between adequate consumption of calcium and vitamin D and healthy weight status in older children and adults. However, in the infant population, there are few studies detailing the interaction between body composition and serum 25(OH)D or intake of calcium and vitamin D. Our study aims were to assess the association between serum 25(OH)D and body composition and to examine the association between adiposity and dietary intake of calcium and vitamin D in a sample of infants and toddlers. Methods: Our population included healthy male and female infants and toddlers from Pittsburgh, PA who participated in the “Practices Affecting Vitamin D Status in Pittsburgh Infants and Toddlers” study. Parents completed a Vitamin D and Sunlight Exposure Questionnaire, which assessed dietary intake of foods high in calcium and vitamin D as well as daily sunlight exposure (≥2 hours vs. >2 hours). Anthropometric measures and bloodwork for serum 25(OH)D were obtained during at the time of the study visit. Weight-for-length (WFL) percentile status was determined using WHO growth standards (low weight97.7 %ile) and WFL z-scores were calculated. ANOVA was used to compare mean serum 25(OH)D and calcium and vitamin D intake by WFL status. Chi square analysis was used to evaluate the relationship between serum 25(OH) D status (deficient =/mL, insufficient = 12-20 ng/mL, sufficient >20 ng/mL), calcium intake status (sufficient = >700 mg), vitamin D intake status (sufficient = >400 IU) and WFL percentile status. Pearson’s correlation coefficient was used to assess the strength and significance of associations between serum 25(OH)D, calcium and vitamin D intake and WFL z-score. The analysis was repeated after subdivision by race and sun exposure. Results: 125 infants and toddlers (9 to 24 months of age, 68% African American) participated in the study. Approximately 11% of the population had a high weight. Mean vitamin D intake (~600 IU/d) and median calcium intake (~1550 mg/d) exceeded recommendations. Prevalence of high weight was higher among children with adequate intake compared to those who consumed less than the recommendations (calcium: 41% vs. 36%, respectively; vitamin D: 45% vs. 29%, respectively). However, this difference was not statistically significant. Mean serum 25(OH)D level (37 ng/mL) was sufficient. When compared across WFL status, neither mean serum 25(OH)D nor mean intake of calcium and vitamin D varied significantly. No significant correlation was found between WFL and serum 25(OH)D for the cohort or any of the subgroups examined. Conclusions: Rates of infant overweight and obesity in our sample are similar in comparison with the national average. Our results do not support a relationship between calcium and vitamin D intake on weight status or an association between serum vitamin D and body composition in children of this age. Future studies are needed to re-examine these relationships in a larger group of children of more evenly distributed weight status.

Metabolic homeostasis is orchestrated by the hypothalamus through the neuroendocrine and the autonomic nervous systems. The hypothalamic nuclei respond to the peptide leptin secreted from adipose tissue to suppress feeding and increase energy expenditure by promoting fat metabolism via sympathetic activity. Another important, but perhaps less appreciated function of central leptin signaling is to elevate peripheral insulin sensitivity. Environmental and genetic risk factors that affect hypothalamic leptin signaling can lead to obesity and type 2 diabetes mellitus (T2DM). Here, we discovered that LIM domain only 4, LMO4, is a novel protein participating in central leptin signaling. In a process strikingly similar to T2DM in humans, CaMKIIα-Cre;LMO4flox/flox mice, which have LMO4 knocked out in the postnatal brain including the hypothalamus, develop visceral adiposity, reduced insulin sensitivity, obesity and diabetes when fed with regular chow. Central leptin signaling was significantly lost in key hypothalamic nuclei of mutant mice. Caloric restriction prevents obesity but not insulin resistance in these mice. Taken together, our results suggest that LMO4 function in the brain is required for central leptin signaling to control fat metabolism and peripheral insulin sensitivity.

Des altérations intra-osseuses liées à l’adiposité médullaire et à ses répercussions sur l’inflammation peuvent jouer un rôle important dans la physiopathologie de certaines maladies de la moelle osseuse (MO). Ces altérations locales, actuellement mal connues, correspondent à une modification de la répartition des différents constituants du tissu osseux et impliquent des interactions entre ostéogenèse et adipogenèse. Des études récentes ont démontré que la MO jaune constitue un tissu adipeux spécifique, différent des tissus adipeux blanc ou brun. Ces études suggèrent qu’elle pourrait avoir un rôle dans la pathogénie d’un grand nombre de pathologies de la moelle osseuse, notamment à la hanche.La spectroscopie par IRM (IRMS) présente l’intérêt d’évaluer, de façon quantitative et non invasive, le contenu graisseux au sein de la MO jaune, en complément des informations diagnostiques obtenues avec séquences IRM conventionnelles. Grâce aux IRM 3T, une amélioration de la qualité spectrale avec des temps d’acquisition adaptés à la pratique clinique peut être espérée. Or, cette technique n’a quasiment pas été évaluée à la hanche et aucune évaluation de la reproductibilité ni aucunes valeurs normales n’ont été étudiées, validées et publiées à ce jour.Le but de ce travail de recherche a donc été d’établir le rôle de la spectroscopie 1H par IRM 3T dans l’évaluation quantitative de la moelle osseuse de la hanche.Notre travail s’est articulé autour de trois axes, donnant lieu au développement des 3 parties de cette thèse.La première étude a porté sur la mise au point de la technique spectroscopique à la hanche et sur l’évaluation de la reproductibilité de cette technique avec une machine IRM 3 Tesla, puisque cela n’avait pas été étudié.J’ai démontré que la spectroscopie 1H MR à 3 Tesla est une technique fiable, permettant l’obtention de valeurs de contenu graisseux hautement reproductibles au sein de la moelle osseuse de la hanche et qu’aucune différence statistiquement significative du contenu graisseux n’existait entre les deux hanches. Ce travail a été accepté pour publication.Sur cette base, nous avons établi, au cours de la 2ème étude, des valeurs de normalité du contenu graisseux du fémur proximal chez des sujets sains en tenant en compte de l’âge et du sexe de l’individu, étape indispensable pour disposer de données de référence lors de l’évaluation des conditions pathologiques affectant la moelle osseuse à la hanche. Ce travail est actuellement soumis à publication.La 3ème étude, en cours, porte sur la recherche et l’identification potentielle de spectres anormaux de la moelle osseuse de la hanche chez des patients présentant une ONTF ou souffrant d’anorexie mentale. A l’heure actuelle, le recrutement de patients porteurs d’une ONTF est presque terminé et nous disposons de quelques résultats préliminaires. Quant au recrutement des patients atteints d’anorexie mentale, il est actuellement en cours. / Some bone alterations seem to be linked to medullary adiposity that could play a major role in the physiopathology of several disorders involving bone marrow. Although the mechanisms intervening between osteogenesis and adipogenesis are not completely understood, they could be responsible for modifications of bone marrow composition. Some recent studies have demonstrated that yellow bone marrow represents a specific fat tissue, different from white or brown adipose tissues.Moreover these studies suggested that yellow bone marrow could have a significant role in the pathogenesis of several bone marrow diseases, especially involving the hip.MRI spectroscopy permits a quantitative non-invasive evaluation of the fat content of bone marrow, completing the diagnostic findings obtained with traditional IRM examination. 3 T MRI enables an improvement of spectra quality with relatively short acquisition time and it is adequate to clinical practice.The value of this technique has been poorly evaluated at the hip and no reproducibility studies or no normal values have been determined or published so far.The goal of the present research was to assess the role of 1H MR spectroscopy in the quantitative evaluation of hip bone marrow.This aim of this research project was threefold.The first axis of research was oriented to set the spectroscopic technique and to evaluate its reproducibility in the evaluation of hip bone marrow using a 3 T magnet. To the best of our knowledge this had not been assessed earlier. We demonstrated that 1H 3 T MRI spectroscopy is a reliable technique that permits to obtain highly reproducible fat content values of the hip bone marrow. Moreover we proved that no statistical significant difference existed when comparing left and right fat content values in the same individual. The results of this work have been accepted for publication.On this basis we obtained, within the second axis of this research project, normal hip fat content values in healthy subjects taking into account the age and the gender. This study enables to dispose of normal reference values in order to assess pathological conditions of hip bone marrow.The third axis of this project is on going. It concerns the research and the identification of possible abnormal spectra of hip bone marrow in patients affected from femoral head osteonecrosis or anorexia nervosa. At this time point, the recruitment of patients with osteonecrosis is over and we dispose of some preliminary results. The recruitment of patients affected from anorexia nervosa is currently in course.

Background: Fat distribution, rather than total body fat, has been identified as a significant risk factor for chronic disease. Patterning of subcutaneous fat, in particular, may play a pervasive role in shaping the metabolic milieu that is critical for disease development. Several studies have shown that early-life nutrition may influence later body composition. The effect of breastfeeding and formula feeding on early patterns of subcutaneous fat deposition, however, are uncertain. Objective: At a time when early infant growth is emerging as a predictor for later chronic disease, it is the aim of the present analysis to investigate whether feeding style (breastfeeding versus formula feeding) modifies subcutaneous fat growth rates and trajectories in the first year of life with a focus on the historical iterations of WHO infant feeding recommendations (0 to 4 months, 4 to 6 months, and 6 to 12 months of age). Methods: This is an ex post-facto design that utilizes data collected as part of a longitudinal growth study in the first year of life. Subcutaneous fat mass was anthropometrically assessed weekly by skinfold thickness (triceps, quadriceps, calf, subscapular, suprailiac, midaxillary, and abdominal) in 21 infants. Feeding data were collected through daily parental records and are entered here as a categorical variable (predominantly breast fed and predominantly formula fed). Multi-level mixed effects models for repeated measures were used (STATA 14) adjusting for age, sex, weight, birthweight, and number of feeding episodes per day. Statistical significance was accepted at p Results:Infants experienced fat accretion only during the first four months, and this was limited to peripheral skinfolds. Thereafter, subcutaneous skinfolds followed a trend of declining rates. Breastfed and formula fed infants, however, demonstrated different patterns of subcutaneous fat deposition in both the sum of skinfolds and in each skinfold site. During the first four months, formula fed infants experienced greater rates for the subscapular, abdominal, suprailiac, trunk, quadriceps, sum of skinfolds (p Conclusion: Weekly skinfold assessments of seven subcutaneous sites have identified that feeding style predicts differences in deposition patterns in the first year of life. Breastfed infants demonstrated both slower rates of accretion and decline by comparison with their formula fed peers. This analysis further suggests that the first four months may be a critical period for subcutaneous fat deposition. Feeding specific effects were identified for truncal deposition and utilization, which suggests that future studies may benefit from depot-specific inquiries.

Background: Despite several decades of research, the relevance of body fat and body fat distribution to the risk of cardiovascular disease remains unclear. This thesis aims to investigate associations of body-mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) with risk of first-onset cardiovascular disease under a range of different circumstances. Methods: This thesis used individual records from the Emerging Risk Factors Collaboration to calculate risk ratios, and measures of discrimination and reclassification. 118 prospective studies, involving 1,064,541 participants without known history of cardiovascular disease, had information on BMI at baseline examination. 58 of these studies, involving 221,934 participants, had additional information on waist and hip circumference at baseline examination. Serial measurements made in 42,300 participants from 12 studies with concomitant information on these adiposity measures enabled quantification of within-person variability in BMI, WC and WHR. Results: Cross-sectional analyses demonstrated that although the correlations of adiposity measures differed with one another, BMI, WC and WHR were similarly and importantly associated with mediating cardiovascular risk factors, such as blood pressure, fasting glucose and lipids. Within-person variability was lower in BMI (regression dilution ratio: 0.96) than in WC (0.88) and WHR (0.66). The variability of adiposity measures was not materially influenced by several characteristics, although the variability of WHR varied somewhat by sex, diabetes status and baseline WHR values. 1,064,541 individuals with information on BMI recorded 161,903 deaths or non-fatal cardiovascular outcomes during 15.0 million person-years of follow-up. In analyses adjusted for age, sex and smoking status, BMI had positive and nearly loge-linear associations with coronary heart disease and ischaemic stroke (except at BMI values below 20 kg/m2), which were largely explained by the intermediate risk factors noted above. The association between BMI and non-vascular mortality was curvilinear. Data on 221,934 individuals with complete information on weight, height, and waist and hip circumference (14,297 incident cardiovascular outcomes; 1.87 million person-years of follow-up) demonstrated that BMI, WC and WHR were substantially and similarly related to risk of coronary heart disease and ischaemic stroke. For cardiovascular risk prediction, additional information on BMI, WC or WHR to a prediction model containing conventional risk factors did not importantly improve risk discrimination, nor classification of participants to risk categories of predicted 10-year risk. Conclusions: BMI, WC and WHR are similarly associated with risk of cardiovascular disease, with much of the risk explained by intermediate risk factors. These clinical measures of adiposity do not importantly improve cardiovascular risk prediction when additional information is available on blood pressures, history of diabetes and lipids.

Metabolic homeostasis is orchestrated by the hypothalamus through the neuroendocrine and the autonomic nervous systems. The hypothalamic nuclei respond to the peptide leptin secreted from adipose tissue to suppress feeding and increase energy expenditure by promoting fat metabolism via sympathetic activity. Another important, but perhaps less appreciated function of central leptin signaling is to elevate peripheral insulin sensitivity. Environmental and genetic risk factors that affect hypothalamic leptin signaling can lead to obesity and type 2 diabetes mellitus (T2DM). Here, we discovered that LIM domain only 4, LMO4, is a novel protein participating in central leptin signaling. In a process strikingly similar to T2DM in humans, CaMKIIα-Cre;LMO4flox/flox mice, which have LMO4 knocked out in the postnatal brain including the hypothalamus, develop visceral adiposity, reduced insulin sensitivity, obesity and diabetes when fed with regular chow. Central leptin signaling was significantly lost in key hypothalamic nuclei of mutant mice. Caloric restriction prevents obesity but not insulin resistance in these mice. Taken together, our results suggest that LMO4 function in the brain is required for central leptin signaling to control fat metabolism and peripheral insulin sensitivity.

Anovulation accounts for approximately 12 percent of all female infertility in the United States. Prior studies suggest women with high body mass index (BMI) have an increased risk of infertility, particularly obese women with abnormal cycle lengths. To date no studies have examined the relationship between measures of adiposity, including BMI and percent body fat measured by DXA scan (%BF), and anovulation among women with regular menstrual cycles assessed with biomarkers. We evaluated this association using data from the BioCycle study, a prospective cohort of 259 women with regular menstrual cycles. All measures of adiposity and covariates were collected at baseline. Anovulation was assessed via luteinizing hormone and progesterone levels in urine samples collected 16 times throughout two menstrual cycles. A total of 34 women had at least one anovulatory cycle during the study. Unadjusted models for BMI show a significant decrease in risk comparing highest BMI quartile to the lowest, (OR: 0.29; 95% CI .090-.968). Once multivariable logistic regression was used to adjust for age no significant associations were found in any BMI quartile, but point estimates did not change significantly. Similar trends were found using other measures of adiposity. Results show that there is a non-significant inverse trend between adiposity and anovulation in healthy women with regular menstrual cycles. This relationship can possibly be explained by age due to the influence of time since menarche (TSM). Further research is needed to examine this relationship.

Male infertility is a significant public health problem. Although male factors are estimated to contribute to 50% of infertility, epidemiologic research on predictors of male infertility is scarce, and few modifiable risk factors have been identified. In particular, not much is known about the risk factors that determine semen quality in healthy males attempting to conceive. This dissertation uses data from Pregnancy Study Online (PRESTO), a preconception cohort of pregnancy planners residing in North America, to examine the role of several anthropometric and lifestyle exposures on semen quality. A subset of male participants provided data on semen volume, sperm concentration, and sperm motility using a novel in-home semen testing device. In the first study, we examined the effects of three anthropometric factors, body mass index (BMI), waist circumference, and weight gained since age 17 years, on semen quality. We found that men in the highest categories of BMI and waist circumference had poorer semen quality, particularly sperm concentration, motility, and total motile sperm count. Results were slightly stronger for waist circumference. Adult weight gain, however, was not appreciably associated with semen quality. Few studies have investigated the effect of marijuana use on semen quality. In the second paper we used PRESTO data to investigate the relationship between current marijuana use and semen parameters. We found that current male marijuana use was not appreciably associated with semen quality. Further control for potential confounders, including BMI, had little influence on the study results. In addition, results were similar among non-smokers of tobacco. The third paper focused on sugar-sweetened beverages (SSB) consumption and semen quality. We found that men who consumed higher quantities of SSB had poorer semen quality, particularly lower sperm concentration, total sperm count, and total motile sperm count. Adjustment for caffeine intake or current BMI had little effect on the results; however, the association between total SSB consumption was stronger among overweight and obese men. In conclusion, we observed that higher BMI and waist circumference were associated with decreased semen quality. In addition, increased sugar-sweetened beverage consumption may increase the risk of being classified as having low semen quality. Given that these exposures are common and modifiable, they may be important targets for public health interventions. / 2024-08-31T00:00:00Z