Ruth Loos and colleagues report results of a large genome-wide association study for body mass index. They identify 18 new loci associated with this trait, some of which map near key hypothalamic regulators of energy balance. Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Puberty, a complex biologic process involving sexual development, accelerated linear growth, and adrenal maturation, is initiated when gonadotropin-releasing hormone begins to be secreted by the hypothalamus. We conducted studies in humans and mice to identify the genetic factors that determine the onset of puberty.

Severely obese (ob/ob) mice are deficient in the adipocyte-derived hormone leptin, which acts on the hypothalamus to control appetite and energy expenditure.¹ The administration of leptin to these mice corrects their obesity by reducing their food intake and increasing their energy expenditure.^2-4 These mice also have hyperinsulinemia, corticosterone excess, and infertility, which also are reversed by treatment with leptin.⁵ In humans, serum leptin concentrations, in general, correlate positively with indexes of obesity.^6,7 We previously described two cousins with severe, early-onset obesity and undetectable serum leptin concentrations who were homozygous for a frame-shift mutation in the leptin gene.⁸ In this report, we describe the results of a trial of therapy with recombinant human leptin in the older of these children, a nine-year-old girl.

Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form of obesity. However, the clinical spectrum and mode of inheritance have not been defined, pathophysiological mechanisms leading to obesity are poorly understood, and there is little information regarding genotype–phenotype correlations.

Variants in theFTO(fat mass and obesity associated) gene are associated with increased body mass index in humans. Here, we show by bioinformatics analysis that FTO shares sequence motifs with Fe(II)- and 2-oxoglutarate–dependent oxygenases. We find that recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, with concomitant production of succinate, formaldehyde, and carbon dioxide. Consistent with a potential role in nucleic acid demethylation, Fto localizes to the nucleus in transfected cells. Studies of wild-type mice indicate thatFtomessenger RNA (mRNA) is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and thatFtomRNA levels in the arcuate nucleus are regulated by feeding and fasting. Studies can now be directed toward determining the physiologically relevant FTO substrate and how nucleic acid methylation status is linked to increased fat mass.