Michael Freemark

Prevention and Treatment of Pediatric Obesity: An Endocrine Society Clinical Practice Guideline Based on Expert Opinion

Objective: Our objective was to formulate practice guidelines for the treatment and prevention of pediatric obesity. Conclusions: We recommend defining overweight as body mass index (BMI) in at least the 85th percentile but < the 95th percentile and obesity as BMI in at least the 95th percentile against routine endocrine studies unless the height velocity is attenuated or inappropriate for the family background or stage of puberty; referring patients to a geneticist if there is evidence of a genetic syndrome; evaluating for obesity-associated comorbidities in children with BMI in at least the 85th percentile; and prescribing and supporting intensive lifestyle (dietary, physical activity, and behavioral) modification as the prerequisite for any treatment. We suggest that pharmacotherapy (in combination with lifestyle modification) be considered in: 1) obese children only after failure of a formal program of intensive lifestyle modification; and 2) overweight children only if severe comorbidities persist despite intensive lifestyle modification, particularly in children with a strong family history of type 2 diabetes or premature cardiovascular disease. Pharmacotherapy should be provided only by clinicians who are experienced in the use of antiobesity agents and aware of the potential for adverse reactions. We suggest bariatric surgery for adolescents with BMI above 50 kg/m2, or BMI above 40 kg/m2 with severe comorbidities in whom lifestyle modifications and/or pharmacotherapy have failed. Candidates for surgery and their families must be psychologically stable and capable of adhering to lifestyle modifications. Access to experienced surgeons and sophisticated multidisciplinary teams who assess the benefits and risks of surgery is obligatory. We emphasize the prevention of obesity by recommending breast-feeding of infants for at least 6 months and advocating that schools provide for 60 min of moderate to vigorous daily exercise in all grades. We suggest that clinicians educate children and parents through anticipatory guidance about healthy dietary and activity habits, and we advocate for restricting the availability of unhealthy food choices in schools, policies to ban advertising unhealthy food choices to children, and community redesign to maximize opportunities for safe walking and bike riding to school, athletic activities, and neighborhood shopping.

The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes.

Objectives. The prevalence of type 2 diabetes in American adolescents has increased markedly during the past generation. Although the factors that contribute to the development of type 2 diabetes are complex and not wholly elucidated, the triad of severe obesity, hyperinsulinemia, and a family history of type 2 diabetes places a child at an increased risk for development of the disease. Current approaches to the prevention of type 2 diabetes, including dietary counseling and exercise, have had limited success. We reasoned that drugs that increase glucose tolerance in diabetic patients might prove useful in preventing the progression to glucose intolerance in high-risk patients. To that end, we conducted a double-blind, placebo-controlled study of the effects of metformin on body mass index (BMI), serum leptin, glucose tolerance, and serum lipids in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes. Methods. The study population consisted of 29 white and black adolescents aged 12 to 19 years. All had BMIs exceeding 30 kg/m2. Criteria for enrollment included: 1) a fasting insulin concentration exceeding 15 μU/mL; and 2) at least 1 first- or second-degree relative with type 2 diabetes. All patients had fasting plasma glucose concentrations <110 mg% and hemoglobin A1c concentrations ≤6.0%. All had normal linear growth and sexual development for age, with no marked hirsutism, severe acne, or menstrual irregularities characteristic of polycystic ovary syndrome. Eight participants had acanthosis nigricans. After baseline laboratory studies including a rapidly sampled intravenous glucose tolerance test, patients were randomized to receive metformin (500 mg twice daily) or a placebo for a total of 6 months. The effects of metformin on BMI standard deviation score, serum leptin, glucose tolerance, and serum lipids were analyzed. The study was double-blinded and included no specific dietary restrictions. Results. Metformin caused a decline of 0.12 standard deviation in BMI in study participants (−1.3% from baseline), and a 5.5% reduction in serum leptin in girls. In contrast, BMI and serum leptin rose 0.23 standard deviation (2.3%) and 16.2%, respectively, in the placebo group during the treatment period. Metformin caused a progressive decline in fasting blood glucose (from a mean of 84.9 to 75.1 mg%) and a reduction in fasting insulin levels (from 31.3 to 19.3 μU/mL). In contrast, fasting glucose levels in the placebo group rose slightly from 77.2 to 82.3 mg%, and fasting insulin levels did not change. Insulin sensitivity, as assessed by the ratio of fasting insulin to glucose concentrations and the quantitative insulin sensitivity check index (1/[log fasting insulin + log fasting glucose]) and homeostasis model assessment insulin resistance index (fasting insulin × fasting glucose/22.5) indices, increased slightly in the metformin-treated participants. However, the insulin sensitivity measured using Bergmans minimal model did not change. There were also no significant changes in glucose effectiveness, hemoglobin A1c, serum lipids, or serum lactate in the metformin or placebo groups. Metformin was tolerated well by the majority of patients. Transient abdominal discomfort or diarrhea occurred in 40% of treated participants; there were no episodes of vomiting or lactic acidosis. Conclusions. The treatment of obesity and insulin resistance in adults often proves ineffective because the vicious cycle leading to type 2 diabetes may have become entrenched and, to some extent, may be irreversible. Early detection and therapy of the obese adolescent with a family history of type 2 diabetes may interrupt the cycle of weight gain and insulin resistance that leads to glucose intolerance in adulthood. Through its ability to reduce fasting blood glucose and insulin concentrations and to moderate weight gain, metformin might complement the effects of dietary and exercise counseling and reduce the risk of type 2 diabetes in selected patients.

The Roles of Placental Growth Hormone and Placental Lactogen in the Regulation of Human Fetal Growth and Development

The human growth hormone (hGH)/human placental lactogen (hPL) gene family, which consists of two GH and three PL genes, is important in the regulation of maternal and fetal metabolism and the growth and development of the fetus. During pregnancy, pituitary GH (hGH-N) expression in the mother is suppressed; and hGH-V, a GH variant expressed by the placenta, becomes the predominant GH in the mother. hPL, which is the product of the hPL-A and hPL-B genes, is secreted into both the maternal and fetal circulations after the sixth week of pregnancy. hGH-V and hPL act in concert in the mother to stimulate insulin-like growth factor (IGF) production and modulate intermediary metabolism, resulting in an increase in the availability of glucose and amino acids to the fetus. In the fetus, hPL acts via lactogenic receptors and possibly a unique PL receptor to modulate embryonic development, regulate intermediary metabolism and stimulate the production of IGFs, insulin, adrenocortical hormones and pulmonary surfactant. hGH-N, which is expressed by the fetal pituitary, has little or no physiological actions in the fetus until late in pregnancy due to the lack of functional GH receptors on fetal tissues. hGH-V, which is also a potent somatogenic hormone, is not released into the fetus. Taken together, studies of the hGH/hPL gene family during pregnancy reveal a complex interaction of the hormones with one another and with other growth factors. Additional investigations are necessary to clarify the relative roles of the family members in the regulation of fetal growth and development and the factors that modulate the expression of the genes.

Placental hormones and the control of maternal metabolism and fetal growth.

Purpose of review To examine the roles of the placental and pituitary hormones in the control of maternal metabolism and fetal growth. Recent findings In addition to promoting growth of maternal tissues, placental growth hormone (GH-V) induces maternal insulin resistance and thereby facilitates the mobilization of maternal nutrients for fetal growth. Human placental lactogen (hPL) and prolactin increase maternal food intake by induction of central leptin resistance and promote maternal beta-cell expansion and insulin production to defend against the development of gestational diabetes mellitus. The effects of the lactogens are mediated by diverse signaling pathways and are potentiated by glucose. Pathologic conditions of pregnancy are associated with dysregulation of GH-V and hPL gene expression. Summary The somatogenic and lactogenic hormones of the placenta and maternal pituitary gland integrate the metabolic adaptations of pregnancy with the demands of fetal and neonatal development. Dysregulation of placental growth hormone and/or placental lactogen in pathologic conditions of pregnancy may adversely impact fetal growth and postnatal metabolic function.

Body Weight and Fat Deposition in Prolactin Receptor-Deficient Mice1

To explore the roles of the lactogens in adipose tissue development and function, we measured body weight, abdominal fat content, and plasma leptin concentrations in a unique model of lactogen resistance: the PRL receptor (PRLR)-deficient mouse. The absence of PRLRs in knockout mice was accompanied by a small (5-12%), but progressive, reduction in body weight after 16 weeks of age. Females were affected to a greater degree than males. The reduction in weight in female PRLR-deficient mice (age 8-9 months) was associated with a 49% reduction in total abdominal fat mass and a 29% reduction in fat mass expressed as a percentage of body weight. Lesser reductions were noted in male mice. Plasma leptin concentrations were reduced in females but not in males. That the reductions in abdominal fat may reflect in part the absence of lactogen action in the adipocyte is suggested by the demonstration of PRLR messenger RNA in normal mouse white adipose tissue. Nevertheless, steady state levels of PRLR messenger RNA in mature adipocytes are very low, suggesting that the effects of lactogens might be mediated by other hormones or cellular growth factors. Our observations suggest roles for the lactogens in adipose tissue growth and metabolism in pregnancy and postnatal life.

Ontogenesis of prolactin receptors in the human fetus in early gestation. Implications for tissue differentiation and development.

To explore potential roles for lactogenic hormones in human fetal development, we examined the distribution and ontogenesis of expression of prolactin receptors (PRLRs) in human fetal tissues at 7.5-14 wk of gestation and in tissues of the embryonic and fetal rat on days e12.5-e20.5. Histochemical analysis of PRLR immunoreactivity in the human fetus and fetal rat revealed novel and unexpected patterns of receptor expression. Most remarkable was the appearance in early fetal development of intense PRLR immunoreactivity in tissues derived from embryonic mesoderm, including the periadrenal and perinephric mesenchyme, the pulmonary and duodenal mesenchyme, the cardiac and skeletal myocytes, and the mesenchymal precartilage and maturing chondrocytes of the endochondral craniofacial and long bones, vertebrae and ribs. Striking changes in the cellular distribution and magnitude of expression of PRLRs were noted in many tissues during development. In the fetal adrenal the initial mesenchymal PRLR expression is succeeded by the emergence of PRLR immunoreactivity in deeper fetal cortical cell layers. In the fetal kidney and lung, the invagination of cortical mesenchyme is accompanied by progressive PRLR immunoreactivity in bronchial and renal tubular epithelial cells. In the pancreas, the PRLR is expressed primarily in acinar cells and ducts in early gestation; in late gestation and in the postnatal period, the PRLR is expressed predominantly in pancreatic islets, co-localizing with insulin and glucagon. Finally in fetal hepatocytes, PRLR immunoreactivity increases significantly between embryonic days e52 and e96 in the human fetus and between days e16.5 and e18.5 in the fetal rat. In addition to playing important roles in reproduction, lactation, and immune function, the lactogenic hormones likely play roles in tissue differentiation and organ development early in gestation.

Regulation of Maternal Metabolism by Pituitary and Placental Hormones: Roles in Fetal Development and Metabolic Programming

This review outlines the regulation of maternal metabolism by hormones, cytokines and growth factors, highlighting recent studies that implicate disordered somatolactogen signalling in the pathogenesis of perinatal growth failure and the development of the metabolic syndrome.

Pharmacotherapy of childhood obesity: an evidence-based, conceptual approach.

This review provides a comparative analysis of the benefits of lifestyle intervention and pharmacotherapy in adults and children using previously published meta-analyses, as well as new data published within the past 2 years. The manuscript critically summarizes the potential risks of various established (orlistat, sibutramine, and metformin) and new (rimonabant) pharmacologic agents and presents a conceptual approach to selection of patients for pharmacotherapy, tailored drug selection, and timing of intervention. Forty-five years after an amphetamine was approved for the treatment of obesity in adults, an expert in the field characterized a new therapeutic formulation as being effective and long-lasting, posing “little risk” (1). Four years later, others (2) “confirmed the weight-reducing efficacy and good tolerability” of the drug and noted that adverse effects were “generally mild and transient.” The drug in question was dexfenfluramine, which was removed from the commercial market 18 months after its subsequent U.S. Food and Drug Administration approval owing to the development of valvular heart disease and primary pulmonary hypertension in a subset of patients (3,4). This experience and many others (5) have forced us to think long and hard before making sweeping recommendations about the use of behavior-modifying drugs for the treatment of obesity. Yet, the pediatric community confronts a serious problem: the surge of metabolic complications in obese adolescents, including impaired glucose tolerance (IGT) and type 2 diabetes, hypertension, dyslipidemia, ovarian hyperandrogenism, hepatic steatosis, and sleep apnea (6). Two recent studies highlight the concern. First (7), despite regular lifestyle counseling in a university-based clinic, one-third of obese teenagers with profound insulin resistance and IGT developed type 2 diabetes during a follow-up period of 21 months. Second (8), among Pima-Indian children and adolescents with type 2 diabetes, the rate of development of end-stage renal disease was proportional to the duration of diabetes, …

Severe Acute Malnutrition in Childhood: Hormonal and Metabolic Status at Presentation, Response to Treatment, and Predictors of Mortality

OBJECTIVE Malnutrition is a major cause of childhood morbidity and mortality. To identify and target those at highest risk, there is a critical need to characterize biomarkers that predict complications prior to and during treatment. METHODS We used targeted and nontargeted metabolomic analysis to characterize changes in a broad array of hormones, cytokines, growth factors, and metabolites during treatment of severe childhood malnutrition. Children aged 6 months to 5 years were studied at presentation to Mulago Hospital and during inpatient therapy with milk-based formulas and outpatient supplementation with ready-to-use food. We assessed the relationship between baseline hormone and metabolite levels and subsequent mortality. RESULTS Seventy-seven patients were enrolled in the study; a subset was followed up from inpatient treatment to the outpatient clinic. Inpatient and outpatient therapies increased weight/height z scores and induced striking changes in the levels of fatty acids, amino acids, acylcarnitines, inflammatory cytokines, and various hormones including leptin, insulin, GH, ghrelin, cortisol, IGF-I, glucagon-like peptide-1, and peptide YY. A total of 12.2% of the patients died during hospitalization; the major biochemical factor predicting mortality was a low level of leptin (P = .0002), a marker of adipose tissue reserve and a critical modulator of immune function. CONCLUSIONS We have used metabolomic analysis to provide a comprehensive hormonal and metabolic profile of severely malnourished children at presentation and during nutritional rehabilitation. Our findings suggest that fatty acid metabolism plays a central role in the adaptation to acute malnutrition and that low levels of the adipose tissue hormone leptin associate with, and may predict, mortality prior to and during treatment.

Growth hormone and prolactin receptors in adipogenesis : STAT-5 activation, suppressors of cytokine signaling, and regulation of insulin-like growth factor I

Growth hormone (GH) stimulates lipolysis in mature adipocytes and primary preadipocytes but promotes adipogenesis in preadipocyte cell lines. The lactogenic hormones (prolactin [PRL] and placental lactogen) also stimulate adipogenesis in preadipocyte cell lines but have variable lipolytic and lipogenic effects in mature adipose tissue. We hypothesized that differences in expression of GH receptors (GHR) and PRL receptors (PRLR) during adipocyte development might explain some of the differential effects of the somatogens and lactogens on fat metabolism. To that end, we compared: (a) the expression of GHR and PRLR mRNAs in 3T3-L1 preadipocytes during the course of adipocyte differentiation; (b) the induction of STAT-5 activity by GH and PRL during adipogenesis; and (c) the acute effects of GH and PRL on the suppressors of cytokine signaling (SOCS-1–3 and cytokine-inducible SH2-domain-containing protein [CIS]) and IGF-I. In confluent, undifferentiated 3T3-L1 cells, the levels of GHR mRNA were ∼250-fold higher than the levels of PRLR mRNA. Following induction of adipocyte differentiation the levels of PRLR mRNA rose 90-fold but GHR mRNA increased only 0.8-fold. Expression of both full-length (long) and truncated (short) isoforms of the PRLR increased during differentiation but the long isoform predominated at all time points. Mouse GH (mGH) stimulated increases in STAT-5a and 5b activity in undifferentiated as well as differentiating 3T3-L1 cells; mouse PRL (mPRL) had little or no effect on STAT-5 activity in undifferentiated cells but stimulated increases in STAT-5a and 5b activity in differentiating cells. mGH stimulated increases in SOCS-2 and SOCS-3 mRNAs in undifferentiated cells and SOCS-1–3 and CIS mRNAs in differentiating cells; mPRL induced CIS in differentiating cells but had no effect on SOCS-1–3. mPRL and mGH stimulated increases in IGF-I mRNA in differentiating cells but not in undifferentiated cells; the potency of mGH (3–6-fold increase, p < 0.01) exceeded that of mPRL (40–90% increase, p < 0.05). Our findings reveal disparities in the expression of PRLR and GHR during adipocyte development and differential effects of the hormones on STAT-5, the SOCS proteins, CIS, and IGF-I. These observations suggest that somatogens and lactogens regulate adipocyte development and fat metabolism through distinct but overlapping cellular mechanisms.