BMI in childhood and adolescence is associated with impaired reproductive function-a population-based cohort study from birth to age 50 years.

STUDY QUESTION: What is the association between childhood and adolescent BMI and reproductive capacity in women? SUMMARY ANSWER: Adolescent girls with obesity had an increased risk of infertility and childlessness in adulthood independently of their marital status or the presence of polycystic ovary syndrome (PCOS). WHAT IS KNOWN ALREADY: Girls with obesity (BMI (kg/m2)>95th percentile) more often exhibit menstrual irregularities and infertility problems as compared to those with normal weight, and premenarcheal girls with obesity have an increased risk of childlessness and infertility in adulthood. Follow-up studies on the relation between childhood and adolescence growth patterns and fertility or parity throughout the reproductive life span are limited. STUDY DESIGN, SIZE, DURATION: A prospective, population-based cohort study (the Northern Finland birth cohort 1966) was performed with 5889 women born in 1966 and followed from birth to age 50 years. Postal questionnaires at ages 31 and 46 years addressed questions on reproductive capacity evaluated by decreased fecundability, need for infertility assessment and treatment by 46 years of age. Childlessness and number of children by age 50 years were recovered from registers. Women who did not report ever having attempted to achieve pregnancy (n = 1507) were excluded. The final study population included 4382 women who attempted to achieve pregnancy before age 46 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on BMI were collected by trained personnel at all stages. We assessed association with both prospectively measured BMI at various time points and with early adiposity phenotypes derived from linear mixed models including the timing and the BMI at adiposity peak (AP) and adiposity rebound (AR). Self-reported infertility assessments and treatments were assessed at ages 31 and 46 years. Data on deliveries were collected from the national birth register. Decreased fecundability was defined at age 31 years as time to achieve pregnancy over 12 months. Logistic regression analyses were conducted with adjustments for marital status, education level and smoking at age 31 years. Women with PCOS were excluded from stratification-based sensitivity analyses. Obesity at a specific age group was defined by having at least one BMI value above the 95th percentile during the related period. MAIN RESULTS AND THE ROLE OF CHANCE: BMI at the age of AR (5-7 years) was not associated with fertility outcomes after adjustments, but girls with AR <5.1 years had a higher risk of remaining childless compared to girls with AR over 5.1 years (adjusted odds ratio (OR): 1.45 (1.10-1.92)). At ages 7-10 and 11-15 years, obesity was associated with decreased fecundability (adjusted OR 2.05 (1.26-3.35) and 2.04 (1.21-3.44), respectively) and a lower number of children. At age 11-15 years, both overweight and obesity were associated with a higher risk of childlessness (adjusted OR 1.56 (1.06-2.27), 1.77 (1.02-3.07), respectively), even after excluding women with PCOS. Underweight at age 11-15 years was associated with an increased risk for infertility treatment (adjusted OR 1.55 (1.02-2.36)) and a tendency for an increased risk for infertility assessment (adjusted OR 1.43 (0.97-2.10)) after excluding women with PCOS. LIMITATIONS, REASON FOR CAUTION: Despite a high participation rate throughout the follow-up, some growth data for children over the different age groups were missing. Infertility outcomes were self-reported. A potential over-diagnosis of obesity may have reduced the significance of the association between childhood obesity and fertility outcomes, and the diagnosis of PCOS was self-reported. WIDER IMPLICATIONS OF THE FINDINGS: This study supports previous results showing that girls with obesity in late childhood and in adolescence displayed reduced fertility and an increased risk of remaining childless in adulthood, independently of marital history and PCOS in adulthood. These findings corroborate the body of evidence for a causal relation between early adiposity and the reproductive functions in women. We recommend reinforcing the prevention of obesity in school-age girls to reduce the risk of impaired reproductive functions. STUDY FUNDING/COMPETING INTEREST(S): NFBC1966 received financial support from University of Oulu Grant no. 65354, Oulu University Hospital Grant no. 2/97, 8/97, Ministry of Health and Social Affairs Grant no. 23/251/97, 160/97, 190/97, National Institute for Health and Welfare, Helsinki Grant no. 54121, Regional Institute of Occupational Health, Oulu, Finland Grant no. 50621, 54231. The Finnish Medical Foundation, the North Ostrobothnia Regional Fund, the Academy of Finland (project grants 315921, 104781, 120315, 129269, 1114194, 24300796), Center of Excellence in Complex Disease Genetics and SALVE, the Sigrid Juselius Foundation, Biocenter Oulu, University Hospital Oulu and University of Oulu (75617), Jalmari ja Rauha Ahokkaan säätiö, The Finnish Medical Foundation, Medical Research Center Oulu, National Institute for Health Research (UK). M. R. J., S. S. and R. N. received funding by the Academy of Finland (#268336) and the European Union's Horizon 2020 research and innovation program (under Grant agreement no. 633595 for the DynaHEALTH action and GA 733206 for LifeCycle). The funders had no role in study design, in the collection, analysis and interpretation of the data, in the writing of the article and in the decision to submit it for publication. The authors have no conflict of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Vitamin D status and correlates of low vitamin D in schizophrenia, other psychoses and non-psychotic depression - The Northern Finland Birth Cohort 1966 study.

There is limited knowledge available on the association of vitamin D with psychiatric disorders in young adults. We aimed to investigate vitamin D levels and associating factors in schizophrenia, other psychoses and non-psychotic depression. We studied 4,987 participants from the Northern Finland Birth Cohort 1966 (31 years) with available serum 25-hydroxyvitamin D [25(OH)D] measurements. The final sample was divided into four groups: schizophrenia (n = 40), other psychoses (n = 24), non-psychotic depression (n = 264) and control (n = 4659). To account for the influence of environmental and technical covariates, we generated a vitamin D score variable with correction for season, sex, batch effect and latitude. We further examined how vitamin D levels correlate with anthropometric, lifestyle, socioeconomic and psychiatric measures. Neither serum 25(OH)D concentration nor vitamin D score differed between schizophrenia, other psychoses, non-psychotic depression and control group. The prevalence of vitamin D deficiency was 3.2%, insufficiency 25.5%, and sufficiency 71.3%. Low vitamin D score correlated with regular smoking in the group with schizophrenia. No difference was observed in other psychiatric conditions. We did not find any difference in vitamin D status between schizophrenia, psychoses, non-psychotic depression and control groups, but future studies are warranted to elucidate the role of vitamin D in psychiatric conditions.

Age at adiposity rebound in childhood is associated with PCOS diagnosis and obesity in adulthood-longitudinal analysis of BMI data from birth to age 46 in cases of PCOS.

BACKGROUND: Adiposity rebound (AR), the second BMI rise in childhood at around the age of 6 years, is associated with obesity and metabolic alteration in later life. Given that polycystic ovary syndrome (PCOS) has a strong metabolic component, early life growth patterns could reveal a risk of PCOS. Thus, we aimed to investigate the associations between age at AR and PCOS diagnosis and BMI later in life. MATERIALS AND METHODS: This study is part of a prospective, population-based longitudinal study, where women with PCOS diagnosis by age 46 (n = 280) were compared with asymptomatic women (CTRLs, n = 1573). Weight and height data from birth to age 13 years, at age at menarche, and at ages 31 and 46 years were analyzed RESULTS: Women with PCOS had lower birth weight (3357 ± 477 vs. 3 445 ± 505 g, p < 0.001), earlier age at AR (5.2 ± 1.0 vs. 5.6 ± 0.90 years, p < 0.001) and higher BMI from AR onwards compared with controls. Early timing of AR was associated with PCOS diagnosis independently of BMI (OR 1.62, 95% Cl 1.37-1.92). Women with PCOS and early AR had higher BMI at 31 and 46 years when compared to controls with early AR. The age at AR did not associate with T levels at ages 31 or 46 years. CONCLUSIONS: Early AR was associated with PCOS diagnosis and high BMI in adulthood. Adolescent girls with early AR and persisting obesity should be screened for PCOS symptoms, such as persistent irregular cycles and hirsutism.

Metabolic profiling of polycystic ovary syndrome reveals interactions with abdominal obesity.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with metabolic disturbances including obesity, insulin resistance and diabetes mellitus. Here we investigate whether changes in the metabolic profile of PCOS women are driven by increased tendency to obesity or are specific features of PCOS related to increased testosterone levels. DESIGN AND METHODS: We conducted an NMR metabolomics association study of PCOS cases (n=145) and controls (n=687) nested in a population-based birth cohort (n=3127). Subjects were 31 years old at examination. The main analyses were adjusted for waist circumference (WC) as a proxy measure of central obesity. Subsequently, metabolite concentrations were compared between cases and controls within pre-defined WC strata. In each stratum, additional metabolomics association analyses with testosterone levels were conducted separately among cases and controls. RESULTS: Overall, women with PCOS showed more adverse metabolite profiles than the controls. Four lipid fractions in different subclasses of very low density lipoprotein (VLDL) were associated with PCOS, after adjusting for WC and correction for multiple testing (P<0.002). In stratified analysis the PCOS women within large WC strata (⩾98 cm) had significantly lower high density lipoprotein (HDL) levels, Apo A1 and albumin values compared with the controls. Testosterone levels were significantly associated with VLDL and serum lipids in PCOS cases with large WC but not in the controls. The higher testosterone levels, adjusted for WC, associated adversely with insulin levels and HOMA IR in cases but not in the controls. CONCLUSIONS: Our findings show that both abdominal obesity and hyperandrogenism contribute to the dyslipidaemia and other metabolic traits of PCOS which all may negatively contribute to the long-term health of women with PCOS.

Hyperemesis gravidarum and cardiometabolic risk factors in adolescents: a follow-up of the Northern Finland Birth Cohort 1986.

OBJECTIVE: To investigate the long-term consequences of prenatal exposure to maternal hyperemesis gravidarum upon offspring cardiometabolic risk factors. DESIGN: This study is part of the prospective follow-up of the Northern Finland Birth Cohort 1986. SETTING: Between 1 July 1985 and 30 June 1986 all pregnant women in two provinces of Finland were recruited at first antenatal visit (99% of eligible participated). POPULATION: A total of 8953 women with liveborn singleton offspring who consented to having their children followed-up were included. METHODS: Hyperemesis gravidarum (HG) was defined as hospitalisation during pregnancy for HG based on the International Classification of Disease (ICD) code. Women who were not hospitalised for HG during pregnancy were used as a reference group. Data on pregnancy and birth outcomes were obtained via medical records and questionnaires; 6462 adolescents, aged 16 years, underwent anthropometric measurements (HG n = 42, reference n = 6420) and 5648 adolescents had a fasting blood sample taken (HG n = 36, reference n = 5612). MAIN OUTCOME MEASURES: Body mass index (BMI), blood pressure, fasting glucose, and lipid levels in offspring. RESULTS: Multivariate regression analyses showed no differences in offspring BMI (kg/m2 ; adjusted percentage difference HG versus reference, 2.2; 95% CI -0.1, 4.6), systolic blood pressure (adjusted difference 2.1 mmHg; 95% CI -1.5, 5.6), and fasting blood glucose (mmol/l; adjusted percentage difference, 2.3; 95% CI -0.6, 5.4), between adolescents born to mothers with and without HG. CONCLUSIONS: We found no evidence that prenatal exposure to HG has negative consequences for cardiometabolic health of offspring at the age of 16 years. TWEETABLE ABSTRACT: Hyperemesis gravidarum does not affect cardiometabolic health in adolescent offspring.

Maternal Body Weight and Gestational Diabetes Differentially Influence Placental and Pregnancy Outcomes.

CONTEXT: Maternal obesity and gestational diabetes mellitus (GDM) can both contribute to adverse neonatal outcomes. The extent to which this may be mediated by differences in placental metabolism and nutrient transport remains to be determined. OBJECTIVE: Our objective was to examine whether raised maternal body mass index (BMI) and/or GDM contributed to a resetting of the expression of genes within the placenta that are involved in energy sensing, oxidative stress, inflammation, and metabolic pathways. METHODS: Pregnant women from Spain were recruited as part of the "Study of Maternal Nutrition and Genetics on the Foetal Adiposity Programming" survey at the first antenatal visit (12-20 weeks of gestation) and stratified according to prepregnancy BMI and the incidence of GDM. At delivery, placenta and cord blood were sampled and newborn anthropometry measured. RESULTS: Obese women with GDM had higher estimated fetal weight at 34 gestational weeks and a greater risk of preterm deliveries and cesarean section. Birth weight was unaffected by BMI or GDM; however, women who were obese with normal glucose tolerance had increased placental weight and higher plasma glucose and leptin at term. Gene expression for markers of placental energy sensing and oxidative stress, were primarily affected by maternal obesity as mTOR was reduced, whereas SIRT-1 and UCP2 were both upregulated. In placenta from obese women with GDM, gene expression for AMPK was also reduced, whereas the downstream regulator of mTOR, p70S6KB1 was raised. CONCLUSIONS: Placental gene expression is sensitive to both maternal obesity and GDM which both impact on energy sensing and could modulate the effect of either raised maternal BMI or GDM on birth weight.

Programming effects of FTO in the development of obesity.

It is becoming increasingly recognized that early-life nutritional, metabolic and environmental factors can have a long-term impact on the early onset of obesity, type 2 diabetes and cardiovascular diseases. Numerous experimental and epidemiological observations support the concept that an individual's response to their adult lifestyle and nutritional environment depends not only on their genetic susceptibility but also on their previous early-life experiences. The current research challenge is to determine the primary pathways contributing to 'non- or epi-genetic' causes of excess adult weight gain and adiposity. Evidence from the fields of genetic epidemiology, life course modelling and diet-induced foetal programming all support a role for the FTO gene in this complex biological interaction. It may provide a missing link in the developmental regulation of energy metabolism. Our review therefore considers the role of the FTO gene in the early-life determination of body weight, body composition and energy balance. We will summarize current knowledge on FTO biology combining human genetic epidemiology, molecular models and findings from animal studies. Notably, we will focus on the role of FTO in energy balance in humans, the importance of FTO polymorphisms in childhood growth and the impact of foetal nutrition. Ultimately, we propose a new hypothesis for future research designed to understand the role of FTO in setting gene expression in metabolically active tissues.

Suboptimal maternal nutrition during early fetal kidney development specifically promotes renal lipid accumulation following juvenile obesity in the offspring.

Reduced maternal food intake between early-to-mid gestation results in tissue-specific adaptations in the offspring following juvenile-onset obesity that are indicative of insulin resistance. The aim of the present study was to establish the extent to which renal ectopic lipid accumulation, as opposed to other markers of renal stress, such as iron deposition and apoptosis, is enhanced in obese offspring born to mothers nutrient restricted (NR) throughout early fetal kidney development. Pregnant sheep were fed either 100% (control) or NR (i.e. fed 50% of their total metabolisable energy requirement from 30-80 days gestation and 100% at all other times). At weaning, offspring were made obese and, at approximately 1 year, kidneys were sampled. Triglyceride content, HIF-1α gene expression and the protein abundance of the outer-membrane transporter voltage-dependent anion-selective channel protein (VDAC)-I on the kidney cortex were increased in obese offspring born to NR mothers compared with those born to controls, which exhibited increased iron accumulation within the tubular epithelial cells and increased gene expression of the death receptor Fas. In conclusion, suboptimal maternal nutrition coincident with early fetal kidney development results in enhanced renal lipid deposition following juvenile obesity and could accelerate the onset of the adverse metabolic, rather than cardiovascular, symptoms accompanying the metabolic syndrome.

Maternal nutrient restriction during late gestation and early postnatal growth in sheep differentially reset the control of energy metabolism in the gastric mucosa.

Fetal growth restriction followed by accelerated postnatal growth contributes to impaired metabolic function in adulthood. The extent to which these outcomes may be mediated centrally within the hypothalamus, as opposed to in the periphery within the digestive tract, remains unknown. In a sheep model, we achieved intrauterine growth restriction experimentally by maternal nutrient restriction (R) that involved a 40% reduction in food intake through late gestation. R offspring were then either reared singly to accelerate postnatal growth (RA) or as twins and compared with controls also reared singly. From weaning, all offspring were maintained indoors until adulthood. A reduced litter size accelerated postnatal growth for only the first month of lactation. Independently from postnatal weight gain and later fat mass, R animals developed insulin resistance as adults. However, restricted accelerated offspring compared with both the control accelerated and restricted restricted offspring ate less and had higher fasting plasma leptin as adults, an adaptation which was accompanied by changes in energy sensing and cell proliferation within the abomasum. Additionally, although fetal restriction down-regulated gene expression of mammalian target of rapamycin and carnitine palmitoyltransferase 1-dependent pathways in the abomasum, RA offspring compensated for this by exhibiting greater activity of AMP-activated kinase-dependent pathways. This study demonstrates a role for perinatal nutrition in the peripheral control of food intake and in energy sensing in the gastric mucosal and emphasizes the importance of diet in early life in regulating energy metabolism during adulthood.

Suboptimal maternal nutrition, during early fetal liver development, promotes lipid accumulation in the liver of obese offspring.

Maternal nutrition during the period of early organ development can modulate the offspring's ability to metabolise excess fat as young adults when exposed to an obesogenic environment. This study examined the hypothesis that exposing offspring to nutrient restriction coincident with early hepatogenesis would result in endocrine and metabolic adaptations that subsequently lead to increased ectopic lipid accumulation within the liver. Pregnant sheep were fed either 50 or 100% of total metabolisable energy requirements from 30 to 80 days gestation and 100% thereafter. At weaning, offspring were made obese, and at ~1 year of age livers were sampled. Lipid infiltration and molecular indices of gluconeogenesis, lipid metabolism and mitochondrial function were measured. Although hepatic triglyceride accumulation was not affected by obesity per se, it was nearly doubled in obese offspring born to nutrient-restricted mothers. This adaptation was accompanied by elevated gene expression for peroxisome proliferator-activated receptor γ (PPARG) and its co-activator PGC1α, which may be indicative of changes in the rate of hepatic fatty acid oxidation. In contrast, maternal diet had no influence on the stimulatory effect of obesity on gene expression for a range of proteins involved in glucose metabolism and energy balance including glucokinase, glucocorticoid receptors and uncoupling protein 2. Similarly, although gene expressions for the insulin and IGF1 receptors were suppressed by obesity they were not influenced by the prenatal nutritional environment. In conclusion, excess hepatic lipid accumulation with juvenile obesity is promoted by suboptimal nutrition coincident with early development of the fetal liver.

Nutritional regulation of fetal growth and implications for productive life in ruminants.

The maternal nutritional and metabolic environment is critical in determining not only the reproductive success but also the long-term health and viability of the offspring. Changes in maternal diet at defined stages of gestation coincident with different stages of development can have pronounced effects on organ and tissue function in later life. This includes adipose tissue for which differential effects are observed between brown and white adipose tissues. One early, critical window of organ development in the ruminant relates to the period covering uterine attachment, or implantation, and rapid placental growth. During this period, there is pronounced cell division within developing organelles in many fetal tissues, leading to their structural development. In sheep, a 50% global reduction in caloric intake over this specific period profoundly affects placental growth and morphology, resulting in reduced placentome weight. This occurs in conjunction with a lower capacity to inactivate maternal cortisol through the enzyme 11ß-hydroxysteroid dehydrogenase type 2 in response to a decrease in maternal plasma cortisol in early gestation. The birth weight of the offspring is, however, unaffected by this dietary manipulation and, although they possess more fat, this adaptation does not persist into adulthood when they become equally obese as those born to control fed mothers. Subsequently, after birth, further changes in fat development occur which impact on both glucocorticoid action and inflammatory responses. These adaptations can include changes in the relative populations of both brown and white adipocytes for which prolactin acting through its receptor appears to have a prominent role. Earlier when in utero nutrient restricted (i.e. between early-to-mid gestation) offspring are exposed to an obesogenic postnatal environment; they exhibit an exaggerated insulin response, which is accompanied by a range of amplified and thus, adverse, physiological or metabolic responses to obesity. These types of adaptations are in marked contrast to the effect of late gestational nutrient restriction, which results in reduced fat mass at birth. As young adults, however, fat mass is increased and, although basal insulin is unaffected, these offspring are insulin resistant. In conclusion, changes in nutrient supply to either the mother and/or her fetus can have profound effects on a range of metabolically important tissues. These have the potential to either exacerbate, or protect from, the adverse effects of later obesity and accompanying complications in the resulting offspring.

Influence of prenatal nutrition and obesity on tissue specific fat mass and obesity-associated (FTO) gene expression.

The recent discovery of an association between body composition, energy intake and the fat mass and obesity-associated (FTO) gene represents a promising new therapeutic target in obesity prevention. In a well, pre-established large animal model, we investigated the regulation of FTO gene expression under conditions either leading to obesity or increased risk of obesity related disorders: i) a sedentary 'Western' lifestyle and ii) prenatal exposure to nutrient restriction. Pregnant sheep were either fed to fully meet their nutritional requirements throughout gestation or 50% of this amount from early-to-mid gestation. Following weaning, offspring were either made obese through exposure to a sedentary obesogenic environment or remained lean. A significant positive relationship between placental FTO gene expression and fetal weight was found at 110 days gestation. In both the newborn and adult offspring, the hypothalamus was the major site of FTO gene expression. Hypothalamic FTO gene expression was upregulated by obesity and was further increased by prenatal nutrient restriction. Importantly, we found a strong negative relationship between the hypothalamic FTO gene expression and food intake in lean animals only that may imply FTO as a novel controller of energy intake. In contrast, FTO gene expression in the heart was downregulated in obese offspring born to nutrient restricted mothers. In addition, FTO gene expression was unaffected by obesity or prenatal diet in insulin-dependent tissues, where it changed with age possibly reflecting adaptations in cellular energetic activity. These findings extend information gained from human epidemiology and provide new insights into the regulation of in vivo energy metabolism to prevent obesity.

Session on 'Obesity'. Adipose tissue development, nutrition in early life and its impact on later obesity.

It is now apparent that one key factor determining the current obesity epidemic within the developed world is the extent to which adipose tissue growth and function can be reset in early life. Adipose tissue can be either brown or white, with brown fat being characterised as possessing a unique uncoupling protein (uncoupling protein 1) that enables the rapid generation of heat by non-shivering thermogenesis. In large mammals this function is recruited at approximately the time of birth, after which brown fat is lost, not normally reappearing again throughout the life cycle. The origin and developmental regulation of brown fat in large mammals is therefore very different from that of small mammals in which brown fat is retained throughout the life cycle and may have the same origin as muscle cells. In contrast, white adipose tissue increases in mass after birth, paralleled by a rise in glucocorticoid action and macrophage accumulation. This process can be reset by changes in the maternal nutritional environment, with the magnitude of response being further determined by the timing at which such a challenge is imposed. Importantly, the long-term response within white adipocytes can occur in the absence of any change in total fat mass. The present review therefore emphasises the need to further understand the developmental regulation of the function of fat through the life cycle in order to optimise appropriate and sustainable intervention strategies necessary not only to prevent obesity in the first place but also to reverse excess fat mass in obese individuals.

The differential effects of the timing of maternal nutrient restriction in the ovine placenta on glucocorticoid sensitivity, uncoupling protein 2, peroxisome proliferator-activated receptor-gamma and cell proliferation.

Nutrient restriction (NR) during critical windows of pregnancy has differential effects on placento-fetal growth and development. Our study, therefore, investigated developmental and metabolic adaptations within the ovine placenta following NR at different critical windows during the first 110 days of gestation (term=147 days). Thus, the effects of NR on cell proliferation, glucocorticoid sensitivity, IGF1 and 2 receptor, peroxisome proliferator-activated receptor gamma (PPARG), and uncoupling protein (UCP)2 gene expression in the placenta were examined. Singleton bearing sheep (n=4-8 per group) were fed either 100% of their total metabolizable energy requirements throughout the study or 50% of this amount between 0-30, 31-65, 66-110, and 0-110 days gestation. A significant reduction in cell proliferation and increased gene expression for the glucocorticoid and IGF2 receptors, PPARG, and UCP2 were detected in placentae sampled from mothers who were nutrient restricted between days 66 and 110 of gestation, only, relative to controls. This window of gestation coincides with the maximum placental growth and the start of exponential growth of the fetus when there are substantially increased metabolic demands on the placenta compared with earlier in gestation. Consequently, increased glucocorticoid sensitivity and suppressed IGF2 action could contribute to a switch in the placenta from proliferation to differentiation, thereby improving its nutrient transfer capacity. Upregulation of PPARG and UCP2 would promote placental fatty acid metabolism thereby limiting glucose utilization. These compensatory placental responses may serve to maintain fetal growth but could result in adverse adaptations such as the early onset of the metabolic syndrome in later life.

Effect of maternal nutrient restriction from early to midgestation on cardiac function and metabolism after adolescent-onset obesity.

Maternal nutrient restriction (NR) from early to midgestation has marked effects on endocrine sensitivity and organ function of the resulting offspring. We hypothesized that early NR may reset the expression profile of genes central to myocardial energy metabolism, influencing ectopic lipid deposition and cardiac function in the obese adult offspring. NR offspring were exposed to an "obesogenic" environment, and their cardiac function and molecular indexes of myocardial energy metabolism were assessed to explore the hypothesis that an obese individual's risk of heart disease may be modified after maternal NR. Pregnant sheep were fed 100% (control) or 50% (NR) energy requirement from days 30 to 80 of gestation and 100% energy requirement thereafter. At weaning, offspring were exposed to an obesogenic environment or remained lean. At approximately 1 yr of age, the hemodynamic response of these offspring to hypotension, together with left ventricular expression profiles of fatty acid-binding protein 3 (FABP3), peroxisome proliferator-activated receptor-gamma (PPARgamma) and its coactivator (PGC)-1alpha, acetyl-CoA carboxylase (ACC), AMP-activated protein kinase (AMPK)-alpha(2), and voltage-dependent anion channel 1 (VDAC1), was determined. Obesity produced left ventricular hypertrophy in all animals, with increased ectopic (myocardial) lipid in NR offspring. Obesity per se significantly reduced myocardial transcript expression of PGC-1alpha, AMPKalpha(2), VDAC1, and ACC and increased expression of PPARgamma and FABP3. However, although NR animals were similarly obese, their transcript expression of ACC, PPARgamma, and FABP3 was similar to that of lean animals, indicating altered cardiac energy metabolism. Indeed, blunted tachycardia and an amplified inotropic response to hypotension characterized cardiac function in obese NR offspring. The results suggest that maternal NR during early organogenesis can precipitate an altered myocardial response to hypotension and increased myocardial lipid deposition in the adult offspring after adolescent-onset obesity, potentially rendering these individuals more at risk of early heart failure as they age.

Maternal nutrient restriction between early and midgestation and its impact upon appetite regulation after juvenile obesity.

The impact of maternal nutrient restriction during early-to-midgestation, a period coinciding with early fetal brain development, on appetite regulation and energy balance in the offspring after juvenile obesity was examined. Pregnant sheep were either fed to meet fully their nutritional requirements throughout gestation or 50% of this amount between 30 and 80 d gestation. After weaning, offspring were either made obese through exposure to a sedentary obesogenic environment or remained lean. Maternal nutrient restriction had no effect on birth weight or subsequent growth. At 1 wk of age, only, gene expression for neuropeptide Y in the hypothalamus was reduced in nutrient-restricted offspring. By 1 yr of age, all O animals had increased plasma leptin, nonesterified fatty acids, and insulin, with the latter effect amplified in NR offspring. Fasting plasma glucose, triglycerides, and cortisol were unaffected by obesity. The entrained reduction in physical activity that led to obesity persisted when all animals were maintained within individual pens. However, NRO offspring exhibited reduced daily food intake and were, therefore, no longer in positive "energy balance." This adaptation was accompanied by elevated hypothalamic gene expression for the melanocortin-4 and insulin receptors, AMP-activated kinase, and acetyl coenzyme A carboxylase alpha. In conclusion, nutrient restriction specifically targeted over the period of early fetal brain development contributes to a profoundly different adaptation in energy balance after juvenile obesity. The extent to which this adaptive response may benefit the offspring or result in an exacerbated risk of type 2 diabetes remains to be established.

Childhood obesity and insulin resistance in a Yucatan mini-piglet model: putative roles of IGF-1 and muscle PPARs in adipose tissue activity and development.

OBJECTIVE: To explore metabolic and cellular modifications induced during childhood obesity, in a novel animal model of obese mini-piglets. DESIGN: A total of 10 four-month old Yucatan mini-pigs were followed from prepuberty to adulthood. Animals were divided into two groups. The first one had been overfed (OF) a western-type diet and the second one had been normally fed a control recommended human-type diet (NF). MEASUREMENTS: Plasma insulin-like growth factor 1 (IGF-1), insulin, leptin, nonesterified fatty acids, triglycerides (TGs) and glucose were determined at sexual maturity and at young adulthood. Quantitative gene expressions of peroxysome-proliferator-activated receptors (PPARs), glucose transporter 4, insulin receptor, IGF-1, leptin and interleukin-6 (IL-6) in skeletal muscle, adipose tissue and liver were also measured at both stages. Adult insulin sensitivity was measured via euglycaemic-hyperinsulinaemic clamps. RESULTS: Increased body weight in adult OF pigs was associated with increased body size and low insulin sensitivity. Sexually mature OF pigs had higher IGF-1 plasma concentrations than their lean littermates (P < 0.05). In the OF group, TGs and glucose were both decreased (P < 0.05). Muscle PPARgamma and alpha in OF pubescent pigs as compared to NF pigs were 11 times higher and 20 times lower, respectively (P < 0.01). CONCLUSION: Obesity and insulin resistance induced by overfeeding mini-pigs during development and puberty were not associated with the cluster of metabolic modifications frequently observed in their adult littermates. Increased IGF-1 concentrations and modifications of skeletal muscle PPAR (alpha and gamma) expressions may help the young obese pig to partially regulate its glycaemia and triglyceridaemia through an increase of fat mass, which maintains its high insulin sensitivity.

Acute low back pain findings and management in an academic medical center.

To compare medical records of patients treated for acute low back pain in the departments of Family Medicine, Internal Medicine, Occupational Medicine and Emergency Medicine in an academic medical center to determine if there was variation in patient population, diagnostic and treatment procedures and outcomes. Records were randomly reviewed using a standardized form for patients diagnosed with ICD 9 codes pertaining to back pain. Of the 96 patients with acute back pain seen in outpatient areas, 66 were seen by Family Medicine, 26 by Medical Group Practice (MGP), and four by Occupational Medicine. One hundred seven were seen in the Emergency Department. There was no significant difference in duration or type of pain or the type of findings or treatment. Very few had positive physical findings, (9% outpatient and 10% Emergency Department), but many more, (38% outpatient and 17% ED), had psychosocial findings (smoker, dissatisfaction with work, previous psychiatric history, psychosomatic history, or abnormal social adjustment) documented, Plain films of the lumbrosacral spine done in both practice settings did not change treatment.

1993 West Virginia family practice residents: demographics and future plans.

To call attention to the concerns of the 92 family practice residents in the five programs in West Virginia and assist with their retention, a questionnaire was mailed to these physicians. The questions asked concerned their home states, future plans, educational debts, salary expectations, recruiting preferences, and their suggestions on how to interest more medical students into this specialty. The responses to the survey provided valuable information regarding how to improve retention of family practice residents in the state, as well as increase the number of medical students entering family medicine. In addition, the survey showed the Bureau of Public Health, the Kellogg Program and the Rural Health Initiative Program are not as effective as they could be in recruiting family practice residents to practice in underserved areas of the state.

Family physicians' perceptions of health manpower needs in West Virginia.

West Virginia family physicians feel that they are able to assess the health care needs of their communities. There is a need for more physicians in all of the major specialties in West Virginia, but the largest numbers of physicians are needed in family practice and obstetrics. More registered nurses and licensed practical nurses are needed than any other health care professionals. Twenty-five percent of the respondents are actively recruiting associates, and 48 percent have seriously considered leaving, or are leaving West Virginia. The most commonly cited reasons for leaving are inadequate reimbursement, the state's economy, SB-576, lack of tort reform, and state government in general. The greatest advantage given to practicing in the state are its people, the quality of life, and home and family. In addition, the greatest problems are reimbursement, state government, the malpractice climate and the state economy. The survey shows that state government needs to show a good faith effort to enact tort reform to improve relations with physicians. The threat of losing more physicians is real and must be addressed. Improving the climate for the practice of medicine is a viable solution to West Virginia's manpower problems. There is also a need to continue all present health care professional training programs. More emphasis should be placed on recruitment and retention of nursing students. There is expressed support for nurse midwives, nurse practitioners, and physicians' assistants all working under the supervision of physicians. The finding that home and family are frequently listed as advantages to practicing here indicates recruitment and nurturing of students from underserved areas should be increased.(ABSTRACT TRUNCATED AT 250 WORDS)