Obesity is among the most common and costly chronic disorders worldwide. Estimates suggest that in the United States obesity affects one-third of adults, accounts for up to one-third of total mortality, is concentrated among lower income groups, and increasingly affects children as well as adults. A lack of effective options for long-term weight reduction magnifies the enormity of this problem; individuals who successfully complete behavioral and dietary weight-loss programs eventually regain most of the lost weight. We included evidence from basic science, clinical, and epidemiological literature to assess current knowledge regarding mechanisms underlying excess body-fat accumulation, the biological defense of excess fat mass, and the tendency for lost weight to be regained. A major area of emphasis is the science of energy homeostasis, the biological process that maintains weight stability by actively matching energy intake to energy expenditure over time. Growing evidence suggests that obesity is a disorder of the energy homeostasis system, rather than simply arising from the passive accumulation of excess weight. We need to elucidate the mechanisms underlying this "upward setting" or "resetting" of the defended level of body-fat mass, whether inherited or acquired. The ongoing study of how genetic, developmental, and environmental forces affect the energy homeostasis system will help us better understand these mechanisms and are therefore a major focus of this statement. The scientific goal is to elucidate obesity pathogenesis so as to better inform treatment, public policy, advocacy, and awareness of obesity in ways that ultimately diminish its public health and economic consequences.

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.

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Two recent, large whole-genome association studies (GWAS) in European populations have associated a ϳ47-kb region that contains part of the FTO gene with high body mass index (BMI). The functions of FTO and adjacent FTM in human biology are not clear. We examined expression of these genes in organs of mice segregating for monogenic obesity mutations, exposed to underfeeding/overfeeding, and to 4°C. Fto/Ftm expression was reduced in mesenteric adipose tissue of mice segregating for the A y , Lep ob , Lepr db , Cpe fat , or tub mutations, and there was a similar trend in other tissues. These effects were not due to adiposity per se. Hypothalamic Fto and Ftm expression were decreased by fasting in lean and obese animals and by cold exposure in lean mice. The fact that responses of Fto and Ftm expression to these manipulations were almost indistinguishable suggested that the genes might be coregulated. The putative overlapping regulatory region contains at least two canonical CUTL1 binding sites. One of these nominal CUTL1 sites includes rs8050136, a SNP associated with high body mass. The A allele of rs8050136 associated with lower body mass than the C allele preferentially bound CUTL1 in human fibroblast DNA. 70% knockdown of CUTL1 expression in human fibroblasts decreased FTO and FTM expression by 90 and 65%, respectively. Animals and humans with various genetic interruptions of FTO or FTM have phenotypes reminiscent of aspects of the Bardet-Biedl obesity syndrome, a confirmed "ciliopathy." FTM has recently been shown to be a ciliary basal body protein.obesity; hypothalamus; adipose tissue; CUTL1 HERITABILITY OF ADIPOSITY, which reflects genetic contribution to the phenotype within a specific environment, is high, and it is variously estimated at 40 -60% (28, 49). The search for the underlying genes for obesity-using conventional linkage, association, and candidate gene approaches-has generated a large number of positive findings, many of which have not been replicated (e.g., 19, 25, 32, 37, 55, 67). Among the reasons for lack of consistent replication may be the relatively small population sizes, few markers genotyped, and blunt phenotypes. The recent generation of high-density single nucleotide polymorphism (SNP) and haplotype maps (International HapMap project; http://www.hapmap.org/) has revolutionized the field of human quantitative genetics. Applied to large, suitably phenotyped groups of subjects, whole-genome association studies (GWAS) are implicating novel genes not previously considered based on extant understanding of the molecular physiology of specific phenotypes. The discovery of the "Fat Mass and Obesity Associated gene" (FTO) as a potentially important contributor to human adiposity is such an example.In two GWAS involving a total of ϳ42,000 obese and nonobese subjects, dose-dependent highly significant effects of specific SNPs on chr. 16 have been associated with increased body mass index (BMI) (14, 52). In agreement with these results, Dina et al. (8) identified an association between rs1121980 ...

To address the expression and function of Hoxb13, the 5' most Hox gene in the HoxB cluster, we have generated mice with loss-of-function and beta-galactosidase reporter insertion alleles of this gene. Mice homozygous for Hoxb13 loss-of-function mutations show overgrowth in all major structures derived from the tail bud, including the developing secondary neural tube (SNT), the caudal spinal ganglia, and the caudal vertebrae. Using the beta-galactosidase reporter allele of Hoxb13, also a loss-of-function allele, we found that the expression patterns of Hoxb13 in the developing spinal cord and caudal mesoderm are closely associated with overgrowth phenotypes in the tails of homozygous mutant animals. These phenotypes can be explained by the observed increased cell proliferation and decreased levels of apoptosis within the tail of homozygous mutant mice. This analysis of Hoxb13 function suggests that this 5' Hox gene may act as an inhibitor of neuronal cell proliferation, an activator of apoptotic pathways in the SNT, and as a general repressor of growth in the caudal vertebrae.

Biosynthesis of insulin – critical to metabolic homeostasis – begins with folding of the proinsulin precursor, including formation of three evolutionarily conserved intramolecular disulfide bonds. Remarkably, normal pancreatic islets contain a subset of proinsulin molecules bearing at least one free cysteine thiol. In human (or rodent) islets with a perturbed endoplasmic reticulum folding environment, non-native proinsulin enters intermolecular disulfide-linked complexes. In genetically obese mice with otherwise wild-type islets, disulfide-linked complexes of proinsulin are more abundant, and leptin receptor-deficient mice, the further increase of such complexes tracks with the onset of islet insulin deficiency and diabetes. Proinsulin-Cys(B19) and Cys(A20) are necessary and sufficient for the formation of proinsulin disulfide-linked complexes; indeed, proinsulin Cys(B19)-Cys(B19) covalent homodimers resist reductive dissociation, highlighting a structural basis for aberrant proinsulin complex formation. We conclude that increased proinsulin misfolding via disulfide-linked complexes is an early event associated with prediabetes that worsens with ß-cell dysfunction in type two diabetes.

The diencephalon comprises three functionally distinct regions: synencephalon, dorsal thalamus, and ventral thalamus. Patterning of the diencephalon has been proposed to involve subdivision of its anteroposterior axis into segments, neuromeres or prosomeres (Bergquist and Kallen, 1954;Vaage, 1969;Figdor and Stern, 1993;Rubenstein et al., 1994;Redies et al., 2000;Yoon et al., 2000). However, the number and sequence of diencephalic neuromeres, or even their existence, are uncertain. We have examined the proposed subdivisions by morphology, gene expression, acquisition of boundary-specific phenotypes, and cell lineage restriction. We find that at stage 16 in chick the diencephalon is divided into synencephalon and parencephalon. The synencephalon exhibits neuromeric morphology, expresses Prox, and acquires neuromere boundary properties at its interface with both the midbrain and the parencephalon. Although the mesencephalic/synencephalic boundary restricts cell mixing, the synencephalic/parencephalic boundary does not. Similarly, there is no lineage restriction between the parencephalon and the more rostral forebrain (secondary prosencephalon). Subdivision of the parencephalon into ventral and dorsal thalamus involves the formation of a narrow intraparencephalic territory, the zona limitans intrathalamica (zli). This is correlated with the acquisition of cell lineage restriction at both anterior and posterior borders of the zli, the appearance of boundary-specific properties, and Gbx2 and Dlx2 expression in dorsal thalamic and ventral thalamic territories, respectively. At stage 22, the synencephalon is divided into two domains, distinguished by differential gene expression and tissue morphology, but associated with neither a boundary phenotype nor cell lineage restriction. Our results suggest that the diencephalon does not have an overt segmental pattern.

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