Bone has recently emerged as a pleiotropic endocrine organ that secretes at least two hormones, FGF23 and osteocalcin, which regulate kidney function and glucose homeostasis, respectively. These findings have raised the question of whether other bone-derived hormones exist and what their potential functions are. Here we identify, through molecular and genetic analyses in mice, lipocalin 2 (LCN2) as an osteoblast-enriched, secreted protein. Loss- and gain-of-function experiments in mice demonstrate that osteoblast-derived LCN2 maintains glucose homeostasis by inducing insulin secretion and improves glucose tolerance and insulin sensitivity. In addition, osteoblast-derived LCN2 inhibits food intake. LCN2 crosses the blood–brain barrier, binds to the melanocortin 4 receptor (MC4R) in the paraventricular and ventromedial neurons of the hypothalamus and activates an MC4R-dependent anorexigenic (appetite-suppressing) pathway. These results identify LCN2 as a bone-derived hormone with metabolic regulatory effects, which suppresses appetite in a MC4R-dependent manner, and show that the control of appetite is an endocrine function of bone.

Animal studies show that CD36, a fatty acid translocase, is involved in fat detection and preference, but these findings have not been reported in humans. The objective of this study was to determine whether human genetic variation in 5 common CD36 polymorphisms is associated with oral fat perception of Italian salad dressings, self-reported acceptance of high-fat foods and obesity in African-American adults (n = 317). Ratings of perceived oiliness, fat content, and creaminess were assessed on a 170-mm visual analogue scale (VAS) in response to salad dressings that were 5%, 35%, and 55% fat-by-weight content. Acceptance of added fats and oils and high-fat foods was self-reported and anthropometric measures were taken in the laboratory. DNA was isolated from saliva and genotyped at 5 CD36 polymorphisms. Three polymorphisms, rs1761667, rs3840546, and rs1527483 were associated with the outcomes. Participants with the A/A genotype at rs1761667 reported greater perceived creaminess, regardless of the fat concentration of the salad dressings (P < 0.01) and higher mean acceptance of added fats and oils (P = 0.02) compared to those with other genotypes at this site. Individuals who had C/T or T/T genotypes at rs1527483 also perceived greater fat content in the salad dressings, independent of fat concentration (P = 0.03). BMI and waist circumference were higher in participants who were homozygous for a deletion (D/D) at rs3840546, compared to I/D or D/D individuals (P < 0.001), but only 2 D/D individuals were tested, so this finding needs replication. This is the first study to demonstrate an association between common variants in CD36 and fat ingestive behaviors in humans.

Epigenetic mechanisms may moderate genetic and environmental risk (G × E) for mood disorders. We used an experimental rhesus macaque model of early life stress to test whether epigenetic regulation of serotonin transporter (5-HTT) may contribute to G × E interactions that influence behavior and emotion. We hypothesized that peripheral blood mononuclear cell (PBMC) DNA methylation within an 800 bp cytosine-phosphate-guanosine (CpG) island that overlaps with the 5-HTT transcription initiation start site, a hypothesized model of the same genomic region in brain tissue, would mediate or moderate the effects of early life stress and a functional 5-HTT promoter polymorphism (rh5-HTTLPR) on two outcomes: PBMC 5-HTT expression and behavioral stress reactivity. Eighty-seven infant rhesus macaques (3-4 months of age) were either mother reared in large social groups (n = 70) or nursery reared (n = 17). During a maternal/social separation, infants' blood was sampled and behavioral stress reactivity recorded. PBMC DNA and RNA samples were used to determine rh5-HTTLPR genotype, 5-HTT mRNA expression using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and 5-HTT CpG methylation status using sodium bisulfite pyrosequencing. Consistent with human data, carriers of the low-expressing rh5-HTTLPR alleles exhibited higher mean 5-HTT CpG methylation, which was associated with lower PBMC 5-HTT expression. Higher 5-HTT CpG methylation, but not rh5-HTTLPR genotype, exacerbated the effects of early life stress on behavioral stress reactivity in infants. 5-HTT CpG methylation may be an important regulator of 5-HTT expression early in development and may contribute to the risk for mood disorders observed in 'high-risk' 5-HTTLPR carriers.

The relationships between the Expanded Hammersmith Functional Motor Scale (HFMSE) and genotype and motor and respiratory outcomes were examined in patients with spinal muscular atrophy types II and III (n = 70). The correlation between the HFMSE and Gross Motor Function Measure was r = 0.98. Correlations between HFMSE and forced vital capacity (percentage of predicted normal) (n = 56) and a functional rating (n = 57) were r = 0.87 and r = 0.92, respectively. Correlations with strength were as follows: knee extension, r = 0.74 (n = 60); elbow flexion, r = 0.77 (n = 61); and knee flexion, r = 0.74 (n = 58). The HFMSE differentiated patients by SMN2 copy number (P = .0007); bi-level positive airway pressure use, <8 versus ≥8 hours/day (P < .0001); ambulatory status (P < .0001); and spinal muscular atrophy type (P < .0001). The HFMSE demonstrates significant associations with established measures of function, strength, and genotype, and discriminates patients based on function, diagnostic category, and bi-level positive airway pressure need. Time of administration averaged 12 minutes. The HFMSE is a valid, time-efficient outcome measure for clinical trials in spinal muscular atrophy types II and III.