Modulation of Blood Pressure by Central Melanocortinergic Pathways

Jerry R. Greenfield, M.D., Ph.D., Jeffrey W. Miller, M.D., Julia M. Keogh, B.Sc., Elana Henning, B.Soc.Sc., Julie H. Satterwhite, Ph.D., Gregory S. Cameron, Ph.D., Beatrice Astruc, M.D., John P. Mayer, Ph.D., Soren Brage, Ph.D., Teik Choon See, M.D., David J. Lomas, M.D., Stephen O'Rahilly, M.D., and I. Sadaf Farooqi, M.D., Ph.D.

ABSTRACT

Background Weight gain and weight loss are associated with changes in blood pressure through unknown mechanisms. Central melanocortinergic signaling is implicated in the control of energy balance and blood pressure in rodents, but there is no information regarding such an association with blood pressure in humans.

Methods We assessed blood pressure, heart rate, and urinary catecholamines in overweight or obese subjects with a loss-of-function mutation in MC4R, the gene encoding the melanocortin 4 receptor, and in equally overweight control subjects. We also examined the effects of an MC4R agonist administered for 7 days in 28 overweight or obese volunteers.

Results The prevalence of hypertension was markedly lower in the MC4R-deficient subjects than in the control subjects (24% vs. 53%, P=0.009). After the exclusion of subjects taking antihypertensive medications, blood-pressure levels were significantly lower in MC4R-deficient subjects than in control subjects, with mean (±SE) systolic blood pressures of 123±14 mm Hg and 131±12 mm Hg, respectively (P=0.02), and mean diastolic blood pressures of 73±10 mm Hg and 79±7 mm Hg, respectively (P=0.03). As compared with control subjects, MC4R-deficient subjects had a lower increase in heart rate on waking (P=0.007), a lower heart rate during euglycemic hyperinsulinemia (P<0.001), and lower 24-hour urinary norepinephrine excretion (P=0.04). The maximum tolerated daily dose of 1.0 mg of the MC4R agonist led to significant increases of 9.3±1.9 mm Hg in systolic blood pressure and of 6.6±1.1 mm Hg in diastolic blood pressure (P<0.001> with placebo. Differences in blood pressure were not explained by changes in insulin levels; there were no significant adverse events.

Conclusions Results of our genetic and pharmacologic studies implicate melanocortinergic signaling in the control of human blood pressure through an insulin-independent mechanism.

Association between Obesity during Pregnancy and Increased Use of Health Care

Susan Y. Chu, Ph.D., M.S.P.H., Donald J. Bachman, M.S., William M. Callaghan, M.D., M.P.H., Evelyn P. Whitlock, M.D., M.P.H., Patricia M. Dietz, Dr.P.H., M.P.H., Cynthia J. Berg, M.D., M.P.H., Maureen O'Keeffe-Rosetti, M.S., F. Carol Bruce, B.S.N., M.P.H., and Mark C. Hornbrook, Ph.D.

ABSTRACT

Background In the United States, obesity during pregnancy is common and increases obstetrical risks. An estimate of the increase in use of health care services associated with obesity during pregnancy is needed.

Methods We used electronic data systems of a large U.S. group-practice health maintenance organization to identify 13,442 pregnancies among women 18 years of age or older at the time of conception that resulted in live births or stillbirths. The study period was between January 1, 2000, and December 31, 2004. We assessed associations between measures of use of health care services and body-mass index (BMI, defined as the weight in kilograms divided by the square of the height in meters) before pregnancy or in early pregnancy. The women were categorized as underweight (BMI <18.5),> to 29.9), obese (BMI 30.0 to 34.9), very obese (BMI 35.0 to 39.9), or extremely obese (BMI 40.0). The primary outcome was the mean length of hospital stay for delivery.

Results After adjustment for age, race or ethnic group, level of education, and parity, the mean (±SE) length of hospital stay for delivery was significantly (P<0.05)> women who were overweight (3.7±0.1 days), obese (4.0±0.1 days), very obese (4.1±0.1 days), and extremely obese (4.4±0.1 days) than among women with normal BMI (3.6±0.1 days). A higher-than-normal BMI was associated with significantly more prenatal fetal tests, obstetrical ultrasonographic examinations, medications dispensed from the outpatient pharmacy, telephone calls to the department of obstetrics and gynecology, and prenatal visits with physicians. A higher-than-normal BMI was also associated with significantly fewer prenatal visits with nurse practitioners and physician assistants. Most of the increase in length of stay associated with higher BMI was related to increased rates of cesarean delivery and obesity-related high-risk conditions.

Conclusions Obesity during pregnancy is associated with increased use of health care services.

Weight Loss with a Low-Carbohydrate, Mediterranean, or Low-Fat Diet

Iris Shai, R.D., Ph.D., Dan Schwarzfuchs, M.D., Yaakov Henkin, M.D., Danit R. Shahar, R.D., Ph.D., Shula Witkow, R.D., M.P.H., Ilana Greenberg, R.D., M.P.H., Rachel Golan, R.D., M.P.H., Drora Fraser, Ph.D., Arkady Bolotin, Ph.D., Hilel Vardi, M.Sc., Osnat Tangi-Rozental, B.A., Rachel Zuk-Ramot, R.N., Benjamin Sarusi, M.Sc., Dov Brickner, M.D., Ziva Schwartz, M.D., Einat Sheiner, M.D., Rachel Marko, M.Sc., Esther Katorza, M.Sc., Joachim Thiery, M.D., Georg Martin Fiedler, M.D., Matthias Blüher, M.D., Michael Stumvoll, M.D., Meir J. Stampfer, M.D., Dr.P.H., for the Dietary Intervention Randomized Controlled Trial (DIRECT) Group

ABSTRACT

Background Trials comparing the effectiveness and safety of weight-loss diets are frequently limited by short follow-up times and high dropout rates.

Methods In this 2-year trial, we randomly assigned 322 moderately obese subjects (mean age, 52 years; mean body-mass index [the weight in kilograms divided by the square of the height in meters], 31; male sex, 86%) to one of three diets: low-fat, restricted-calorie; Mediterranean, restricted-calorie; or low-carbohydrate, non–restricted-calorie.

Results The rate of adherence to a study diet was 95.4% at 1 year and 84.6% at 2 years. The Mediterranean-diet group consumed the largest amounts of dietary fiber and had the highest ratio of monounsaturated to saturated fat (P<0.05> among treatment groups). The low-carbohydrate group consumed the smallest amount of carbohydrates and the largest amounts of fat, protein, and cholesterol and had the highest percentage of participants with detectable urinary ketones (P<0.05> all comparisons among treatment groups). The mean weight loss was 2.9 kg for the low-fat group, 4.4 kg for the Mediterranean-diet group, and 4.7 kg for the low-carbohydrate group (P<0.001 for the interaction between diet group and time); among the 272 participants who completed the intervention, the mean weight losses were 3.3 kg, 4.6 kg, and 5.5 kg, respectively. The relative reduction in the ratio of total cholesterol to high-density lipoprotein cholesterol was 20% in the low-carbohydrate group and 12% in the low-fat group (P=0.01). Among the 36 subjects with diabetes, changes in fasting plasma glucose and insulin levels were more favorable among those assigned to the Mediterranean diet than among those assigned to the low-fat diet (P<0.001 for the interaction among diabetes and Mediterranean diet and time with respect to fasting glucose levels).

Conclusions Mediterranean and low-carbohydrate diets may be effective alternatives to low-fat diets. The more favorable effects on lipids (with the low-carbohydrate diet) and on glycemic control (with the Mediterranean diet) suggest that personal preferences and metabolic considerations might inform individualized tailoring of dietary interventions. (ClinicalTrials.gov number, NCT00160108 [ClinicalTrials.gov] .)

Brain-Derived Neurotrophic Factor and Obesity in the WAGR Syndrome

Joan C. Han, M.D., Qing-Rong Liu, Ph.D., MaryPat Jones, M.S., Rebecca L. Levinn, B.A., Carolyn M. Menzie, B.S., Kyra S. Jefferson-George, Diane C. Adler-Wailes, M.S., Ethan L. Sanford, B.A., Felicitas L. Lacbawan, M.D., George R. Uhl, M.D., Ph.D., Owen M. Rennert, M.D., and Jack A. Yanovski, M.D., Ph.D.

ABSTRACT

Background Brain-derived neurotrophic factor (BDNF) has been found to be important in energy homeostasis in animal models, but little is known about its role in energy balance in humans. Heterozygous, variably sized, contiguous gene deletions causing haploinsufficiency of the WT1 and PAX6 genes on chromosome 11p13, approximately 4 Mb centromeric to BDNF (11p14.1), result in the Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome. Hyperphagia and obesity were observed in a subgroup of patients with the WAGR syndrome. We hypothesized that the subphenotype of obesity in the WAGR syndrome is attributable to deletions that induce haploinsufficiency of BDNF.

Methods We studied the relationship between genotype and body-mass index (BMI) in 33 patients with the WAGR syndrome who were recruited through the International WAGR Syndrome Association. The extent of each deletion was determined with the use of oligonucleotide comparative genomic hybridization.

Results Deletions of chromosome 11p in the patients studied ranged from 1.0 to 26.5 Mb; 58% of the patients had heterozygous BDNF deletions. These patients had significantly higher BMI z scores throughout childhood than did patients with intact BDNF (mean [±SD] z score at 8 to 10 years of age, 2.08±0.45 in patients with heterozygous BDNF deletions vs. 0.88±1.28 in patients without BDNF deletions; P=0.03). By 10 years of age, 100% of the patients with heterozygous BDNF deletions (95% confidence interval [CI], 77 to 100) were obese (BMI 95th percentile for age and sex) as compared with 20% of persons without BDNF deletions (95% CI, 3 to 56; P<0.001).> for childhood-onset obesity in the WAGR syndrome was located within 80 kb of exon 1 of BDNF. Serum BDNF concentrations were approximately 50% lower among the patients with heterozygous BDNF deletions (P=0.001).

Conclusions Among persons with the WAGR syndrome, BDNF haploinsufficiency is associated with lower levels of serum BDNF and with childhood-onset obesity; thus, BDNF may be important for energy homeostasis in humans.