Constitutional thinness: unusual human phenotype of low bone quality.

CONTEXT: Low fat mass and hormonal or nutritional deficiencies are often incriminated in bone loss related to thinness. Constitutional thinness has been described in young women with low body mass index (BMI) but close-to-normal body composition, physiological menstruation, no hormonal abnormalities, and no anorexia nervosa (AN) psychological profile. OBJECTIVE: Our objective was to determine whether constitutional thinness is associated with impaired bone quality. DESIGN, SETTING, AND PARTICIPANTS: This was an observational, cross-sectional study on 25 constitutionally thin and 44 AN young women with similar low BMI (<16.5 kg/m2) and 28 age-matched controls. MAIN OUTCOME MEASURES: Femoral and lumbar spine bone mineral density by dual-energy x-ray absorptiometry, distal tibia and radius bone architecture and breaking strength by three-dimensional peripheral quantitative computed tomography, and bone turnover markers were determined. RESULTS: Constitutionally thin subjects displayed a higher percentage of fat mass than AN subjects but had similar lumbar and femoral bone mineral density, which were significantly lower than in controls (P < 0.001). Constitutionally thin subjects displayed more markedly impaired trabecular and cortical bone parameters in the distal tibia than in the radius. AN bone structure was impaired only in subjects with a long history of disease. Calculated breaking strength was decreased in constitutional thinness and long-standing AN in both the radius and the tibia. Bone markers in constitutionally thin subjects were similar to those of controls. Osteoprotegerin to receptor activator of nuclear factor kappa B ligand ratio was higher in constitutionally thin subjects than in controls or AN women. CONCLUSIONS: Young women with constitutional thinness present an unexpectedly high prevalence of low bone mass (44%) associated with small bone size, overall diminished breaking strength, but normal bone turnover. Mechanisms related to insufficient skeletal load and/or genetics are proposed to explain this new phenotype of impaired bone quality.

Constitutional thinness and lean anorexia nervosa display opposite concentrations of peptide YY, glucagon-like peptide 1, ghrelin, and leptin.

BACKGROUND: Food intake is controlled by the arcuate nucleus through integration of peripheral hormonal signals such as leptin, ghrelin, peptide YY (PYY), and glucagon-like peptide 1 (GLP-1). The most common condition resulting in underweight young women in the developed world is restrictive anorexia nervosa (AN). However, constitutional thinness (CT) is also known to exist in the same low-weight range. Women with CT have normal menstrual periods and do not have the psychological or hormonal features of AN. Little is currently known about regulation of food intake in subjects with CT. OBJECTIVE: We tested the hypothesis that concentrations of leptin, ghrelin, PYY, and GLP-1 in persons with AN are significantly different from those in persons with CT. DESIGN: Concentrations of PYY, GLP-1, ghrelin, and leptin were measured in 3 groups of young women: normal weight (n = 7), CT (n = 10), and AN (n = 12). Samples were collected every 4 h for 24 h. RESULTS: PYY concentrations were significantly higher in CT subjects than in AN or control subjects. GLP-1 concentrations were significantly higher in AN than in CT subjects, whereas ghrelin was significantly higher in AN subjects than in control and CT subjects. CT subjects had the lowest ghrelin concentrations. Leptin concentrations were significantly lower in AN subjects. PYY and leptin circadian variations were not significantly different between CT and control subjects, whereas these profiles were blunted in AN subjects. CONCLUSIONS: Orexigenic and anorexigenic hormones in CT contrast with an adaptative profile characterizing AN. The hormones appear to be valuable biomarkers for distinguishing these 2 categories of severely underweight subjects.

Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women.

Ghrelin, a 28-amino acid octanoylated peptide, has recently been identified in rat stomach as an endogenous ligand for the GH secretagogue receptor. In addition to GH-releasing properties, exogenous ghrelin injections exert orexigenic effects in both rodents and humans. As the endogenous peptide appears directly related to feeding behavior, we assessed its plasma levels in anorexia nervosa (AN) patients before and after renutrition and in constitutionally thin subjects with body mass indexes (BMIs) equivalent to those of AN women but with no abnormal feeding behavior. The relationships between plasma ghrelin levels and other neuroendocrine and nutritional parameters, such as GH, leptin, T3, and cortisol, were also investigated. In AN patients, morning fasting plasma ghrelin levels were doubled compared with levels in controls, constitutionally thin subjects, and AN patients after renutrition. Twenty-four-hour plasma ghrelin, GH, and cortisol levels determined every 4 h were significantly increased, whereas 24-h plasma leptin levels were decreased in AN patients compared with controls and constitutionally thin subjects. Both plasma ghrelin and leptin levels returned to control values in AN patients after renutrition. Constitutionally thin subjects displayed intermediate 24-h plasma ghrelin and leptin levels, significantly different from controls and AN patients, whereas GH and cortisol were not modified. Ghrelin was negatively correlated with BMI, leptin, and T(3) in controls, constitutionally thin subjects, and AN patients, whereas no correlation was found between GH and ghrelin or between cortisol and ghrelin. Ghrelin and BMI or T3 were still correlated after renutrition, suggesting that ghrelin is also a good nutritional indicator. Basal and GHRH-stimulated GH release were significantly increased in AN patients only. In conclusion, ghrelin is increased in AN and constitutionally thin subjects who display very low BMI but different eating behaviors, suggesting that not only is ghrelin dependent on body fat mass, but it is also influenced by nutritional status. Even though endogenous ghrelin is not strictly correlated with basal GH secretion, it may be involved in the magnitude of GHRH-induced GH release in AN patients.

Organic background of restrictive-type anorexia nervosa suggested by increased serotonin 1A receptor binding in right frontotemporal cortex of both lean and recovered patients: [18F]MPPF PET scan study.

BACKGROUND: Serotonin (5-HT) pathway abnormalities were demonstrated in anorexia nervosa (AN). Brain imaging studies on 5-HT receptors support this evidence. 4-(2-methoxyphenyl)-1-[2-(N-2-pyridinyl)-p-fluorobenzamido]-ethylpiperazine ([(18)F]MPPF) is a selective 5-HT(1A) receptor antagonist with an affinity close to that of endogenous 5-HT. METHODS: In 24 subjects including 8 lean restrictive-type AN patients, 9 recovered from restrictive-type AN subjects and 7 age-matched control subjects, we assessed in vivo brain [(18)F]MPPF binding by positron emission tomography and eating-related psychopathological traits. Inter-groups differences in [(18)F]MPPF binding were evaluated by voxel-based analyses. RESULTS: Restrictive AN patients presented increased [(18)F]MPPF binding in a selective area of the right cortex including part of the superior temporal gyrus, inferior frontal gyrus, parietal operculum, and temporoparietal junction. Striking regional similarities of increased [(18)F]MPPF binding were found in recovered from AN subjects. Most of the psychiatric scores were increased in restrictive AN patients, and elevated perfectionism and interpersonal distrust scores were noticed in subjects recovered from AN. CONCLUSIONS: The persistent increased 5-HT(1A) receptor binding in frontotemporal region of recovered AN concomitantly with specific psychopathological traits support the hypothesis of an organic dysfunction of this area and corroborates with previous literature reports of AN cases induced by temporal lesions.

Energy expenditure adjusted for body composition differentiates constitutional thinness from both normal subjects and anorexia nervosa.

Constitutional thinness (CT) is characterized by a low and stable body mass index (BMI) without any hormonal abnormality. To understand the weight steadiness, energetic metabolism was evaluated. Seven CT, seven controls, and six anorexia nervosa (AN) young women were compared. CT and AN had a BMI <16.5 kg/m(2). Four criteria were evaluated: 1) energy balance including diet record, resting metabolic rate (RMR) (indirect calorimetry), total energy expenditure (TEE) (doubly labeled water), physical activity; 2) body composition (dual-energy X-ray absorptiometry); 3) biological markers (leptin, IGF-I, free T3); 4) psychological profile of eating behavior. The normality of free T3 (3.7 +/- 0.5 pmol/l), IGF-I (225 +/- 93 ng/ml), and leptin (8.3 +/- 3.4 ng/ml) confirmed the absence of undernutrition in CT. Their psychological profiles revealed a weight gain desire. TEE (kJ/day) in CT (8,382 +/- 988) was not found significantly different from that of controls (8,793 +/- 845) and AN (8,001 +/- 2,152). CT food intake (7,565 +/- 908 kJ/day) was found similar to that of controls (7,961 +/- 1,452 kJ/day) and higher than in AN (4,894 +/- 703 kJ/day), thus explaining the energy metabolism balance. Fat-free mass (FFM) (kg) was similar in CT and AN (32.5 +/- 2.9 vs. 34.1 +/- 1.9) and higher in controls (37.8 +/- 1.6). While RMR absolute values (kJ/day) were lower in CT (4,839 +/- 473) than in controls (5,576 +/- 209), RMR values adjusted for FFM were the highest in CT. TEE-to-FFM ratio was also higher in CT than in controls. Energetic metabolism balance maintains a stable low weight in CT. An increased energy expenditure-to-FFM ratio differentiates CT from controls and could account for the resistance to weight gain observed in CT.

Changes in gene expression in skeletal muscle in response to fat overfeeding in lean men.

OBJECTIVE: The adaptive mechanisms in response to excess energy supply are still poorly known in humans. Our aims were to define metabolic responses and changes in gene expression in skeletal muscle of healthy volunteers during fat overfeeding. RESEARCH METHODS AND PROCEDURES: Eight lean young healthy men were given a diet rich in saturated fat with an excess of approximately 550 kcal/d for 4 weeks. Using oligonucleotide microarrays, gene expression changes in skeletal muscle were analyzed at Day 0, Day 14, and Day 28. RESULTS: Fat overfeeding led to an increase in body weight (1.0 +/- 0.3 kg) and waist circumference (2.2 +/- 0.5 cm, p = 0.005) and a significant decrease in fasting non-esterified fatty acid plasma levels (-29 +/- 5%, p = 0.028). Respiratory quotient was significantly increased (0.84 +/- 0.01 to 0.88 +/- 0.02, p = 0.034) and lipid oxidation rate tended to decrease. The expression of 55 genes was modified in skeletal muscle. The main pathways indicated a coordinated stimulation of triacylglycerol synthesis, inhibition of lipolysis, reduction of fatty acid oxidation, and development of adipocytes. Promoter analysis of the regulated genes suggests that sterol regulatory element binding proteins might be important players of the short-term adaptation to fat overfeeding in human skeletal muscle. DISCUSSION: This combined metabolic and genomic investigation shows that fat overfeeding for 28 days promotes the storage of the excess energy in lean men and demonstrates the usefulness of a transcriptomic approach to a better understanding of the metabolic adaptation to changes in nutritional behavior in human.