A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance.

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study.

OBJECTIVES: The purpose of this study was to evaluate the association between inflammation and heart failure (HF) risk in older adults. BACKGROUND: Inflammation is associated with HF risk factors and also directly affects myocardial function. METHODS: The association of baseline serum concentrations of interleukin (IL)-6, tumor necrosis factor-alpha, and C-reactive protein (CRP) with incident HF was assessed with Cox models among 2,610 older persons without prevalent HF enrolled in the Health ABC (Health, Aging, and Body Composition) study (age 73.6 +/- 2.9 years; 48.3% men; 59.6% white). RESULTS: During follow-up (median 9.4 years), HF developed in 311 (11.9%) participants. In models controlling for clinical characteristics, ankle-arm index, and incident coronary heart disease, doubling of IL-6, tumor necrosis factor-alpha, and CRP concentrations was associated with 29% (95% confidence interval: 13% to 47%; p < 0.001), 46% (95% confidence interval: 17% to 84%; p = 0.001), and 9% (95% confidence interval: -1% to 24%; p = 0.087) increase in HF risk, respectively. In models including all 3 markers, IL-6, and tumor necrosis factor-alpha, but not CRP, remained significant. These associations were similar across sex and race and persisted in models accounting for death as a competing event. Post-HF ejection fraction was available in 239 (76.8%) cases; inflammatory markers had stronger association with HF with preserved ejection fraction. Repeat IL-6 and CRP determinations at 1-year follow-up did not provide incremental information. Addition of IL-6 to the clinical Health ABC HF model improved model discrimination (C index from 0.717 to 0.734; p = 0.001) and fit (decreased Bayes information criterion by 17.8; p < 0.001). CONCLUSIONS: Inflammatory markers are associated with HF risk among older adults and may improve HF risk stratification.

Increased body fat is independently and negatively related with cardiorespiratory fitness levels in children and adolescents with normal weight.

Body mass index (BMI) is related with cardiorespiratory fitness (CRF), but less is known regarding the combined relationships between BMI and body fat (BF) on CRF. Cross-sectional study included 2361 girls and 2328 boys aged 10–18 years living in the area of Lisbon, Portugal. BMI was calculated by measuring height and weight, and obesity was assessed by international criteria. BF was assessed by bioimpedance. CRF was assessed by the 20-m shuttle run and the participants were classified as normal-to-high or low-CRF level according to Fitness gram criterion-referenced standards. The prevalence of low CRF was 47 and 39% in girls and boys, respectively. The corresponding values for the prevalence of obesity were 4.8 and 5.6% (not significant) and of excess BF of 12.1 and 25.1% (P <0.001), respectively. In both sexes, BMI and BF were inversely related with CRF: r = – 0.53 and – 0.45 for BMI and % BF, respectively, in boys and the corresponding values in girls were – 0.50 and – 0.33 (all P <0.01). When compared with a participant with normal BMI and BF, the odds ratios (95% confidence interval) for low CRF were 1.94 (1.46–2.58) for a participant with normal BMI and high BF, and 6.19 (5.02–7.63) for a participant with high BMI and high BF. The prevalence of low-CRF levels is high in Portuguese youths. BF negatively influences CRF levels among children/adolescents with normal BMI.

Male body size and breeding tubercles are both linked to intra-sexual dominance and reproductive success in the minnow

Male dominance hierarchies are usually linked to relative body size and to weapon size, that is, to determinants of fighting ability. Secondary sexual characters that are not directly used as weapons could still be linked to dominance if they reveal determination or overall health and vigour and hence, indirectly, fighting ability. We studied the mating behaviour of the minnow, Phoxinus phoxinus, a cyprinid fish in which males develop breeding tubercles during the spawning season. The function of these breeding tubercles is still not clear. Using microsatellite markers, we determined male reproductive success under controlled conditions. The minnows were territorial and quickly established a dominance hierarchy at the beginning of the spawning season. Dominance was strongly and positively linked to fertilization success. Although body size and number of breeding tubercles were not significantly correlated in our sample, both large males and males with many breeding tubercles were more dominant and achieved higher fertilization success than small males or males with few tubercles. We found multimale fertilization in most clutches, suggesting that sperm competition is important in this species. Females showed behaviour that may be linked to spawning decision, that is, male dominance might not be the only determinant of male reproductive success in minnows

Monocarboxylate transporters: new players in body weight regulation.

Over the last two decades, several genes have been identified that appear to play a role in the regulation of energy homeostasis and body weight. For a small subset of them, a reduction or an absence of expression confers a resistance to the development of obesity. Recently, a knockin mouse for a member of the monocarboxylate transporter (MCT) family, MCT1, was demonstrated to exhibit a typical phenotype of resistance to diet-induced obesity and a protection from its associated metabolic perturbations. Such findings point out at MCTs as putatively new therapeutic targets in the context of obesity. Here, we will review what is known about MCTs and their possible metabolic roles in different organs and tissues. Based on the description of the phenotype of the MCT1 knockin mouse, we will also provide some insights about their putative roles in weight gain regulation.

Am I shrinking? On clothing size and body size.

Comment on: Hughes LA, Schouten LJ, Goldbohm RA, van den Brandt PA, Weijenberg MP. Self-reported clothing size as a proxy measure for body size. Epidemiology. 2009 Sep;20(5):673-6. PMID: 19451821

Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.

Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.

Obstructive Sleep Apnea Severity and Overnight Body Fluid Shift before and after Hemodialysis.

BACKGROUND AND OBJECTIVES: Obstructive sleep apnea is associated with significantly increased cardiovascular morbidity and mortality. Fluid overload may promote obstructive sleep apnea in patients with ESRD through an overnight fluid shift from the legs to the neck soft tissues. Body fluid shift and severity of obstructive sleep apnea before and after hemodialysis were compared in patients with ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Seventeen patients with hemodialysis and moderate to severe obstructive sleep apnea were included. Polysomnographies were performed the night before and after hemodialysis to assess obstructive sleep apnea, and bioimpedance was used to measure fluid overload and leg fluid volume. RESULTS: The mean overnight rostral fluid shift was 1.27±0.41 L prehemodialysis; it correlated positively with fluid overload volume (r=0.39; P=0.02) and was significantly lower posthemodialysis (0.78±0.38 L; P<0.001). There was no significant difference in the mean obstructive apnea-hypopnea index before and after hemodialysis (46.8±22.0 versus 42.1±18.6 per hour; P=0.21), but obstructive apnea-hypopnea index was significantly lower posthemodialysis (-10.1±10.8 per hour) in the group of 12 patients, with a concomitant reduction of fluid overload compared with participants without change in fluid overload (obstructive apnea-hypopnea index +8.2±16.1 per hour; P<0.01). A lower fluid overload after hemodialysis was significantly correlated (r=0.49; P=0.04) with a lower obstructive apnea-hypopnea index. Fluid overload-assessed by bioimpedance-was the best predictor of the change in obstructive apnea-hypopnea index observed after hemodialysis (standardized r=-0.68; P=0.01) in multivariate regression analysis. CONCLUSIONS: Fluid overload influences overnight rostral fluid shift and obstructive sleep apnea severity in patients with ESRD undergoing intermittent hemodialysis. Although no benefit of hemodialysis on obstructive sleep apnea severity was observed in the whole group, the change in obstructive apnea-hypopnea index was significantly correlated with the change in fluid overload after hemodialysis. Moreover, the subgroup with lower fluid overload posthemodialysis showed a significantly lower obstructive sleep apnea severity, which provides a strong incentive to further study whether optimizing fluid status in patients with obstructive sleep apnea and ESRD will improve the obstructive apnea-hypopnea index.

Association of PCK1 with Body Mass Index and Other Metabolic Features in Patients With Psychotropic Treatments.

Weight gain is a major health problem among psychiatric populations. It implicates several receptors and hormones involved in energy balance and metabolism. Phosphoenolpyruvate carboxykinase 1 is a rate-controlling enzyme involved in gluconeogenesis, glyceroneogenesis and cataplerosis and has been related to obesity and diabetes phenotypes in animals and humans. The aim of this study was to investigate the association of phosphoenolpyruvate carboxykinase 1 polymorphisms with metabolic traits in psychiatric patients treated with psychotropic drugs inducing weight gain and in general population samples. One polymorphism (rs11552145G > A) significantly associated with body mass index in the psychiatric discovery sample (n = 478) was replicated in 2 other psychiatric samples (n1 = 168, n2 = 188), with AA-genotype carriers having lower body mass index as compared to G-allele carriers. Stronger associations were found among women younger than 45 years carrying AA-genotype as compared to G-allele carriers (-2.25 kg/m, n = 151, P = 0.009) and in the discovery sample (-2.20 kg/m, n = 423, P = 0.0004). In the discovery sample for which metabolic parameters were available, AA-genotype showed lower waist circumference (-6.86 cm, P = 0.008) and triglycerides levels (-5.58 mg/100 mL, P < 0.002) when compared to G-allele carriers. Finally, waist-to-hip ratio was associated with rs6070157 (proxy of rs11552145, r = 0.99) in a population-based sample (N = 123,865, P = 0.022). Our results suggest an association of rs11552145G > A polymorphism with metabolic-related traits, especially in psychiatric populations and in women younger than 45 years.

Evidence for hypothalamic ketone body sensing: impact on food intake and peripheral metabolic responses in mice.

Monocarboxylates have been implicated in the control of energy homeostasis. Among them, the putative role of ketone bodies produced notably during high-fat diet (HFD) has not been thoroughly explored. In this study, we aimed to determine the impact of a specific rise in cerebral ketone bodies on food intake and energy homeostasis regulation. A carotid infusion of ketone bodies was performed on mice to stimulate sensitive brain areas for 6 or 12 h. At each time point, food intake and different markers of energy homeostasis were analyzed to reveal the consequences of cerebral increase in ketone body level detection. First, an increase in food intake appeared over a 12-h period of brain ketone body perfusion. This stimulated food intake was associated with an increased expression of the hypothalamic neuropeptides NPY and AgRP as well as phosphorylated AMPK and is due to ketone bodies sensed by the brain, as blood ketone body levels did not change at that time. In parallel, gluconeogenesis and insulin sensitivity were transiently altered. Indeed, a dysregulation of glucose production and insulin secretion was observed after 6 h of ketone body perfusion, which reversed to normal at 12 h of perfusion. Altogether, these results suggest that an increase in brain ketone body concentration leads to hyperphagia and a transient perturbation of peripheral metabolic homeostasis.

Ideal Body Size as a Mediator for the Gender-Specific Association Between Socioeconomic Status and Body Mass Index: Evidence From an Upper-Middle-Income Country in the African Region.

While obesity continues to rise globally, the associations between body size, gender, and socioeconomic status (SES) seem to vary in different populations, and little is known on the contribution of perceived ideal body size in the social disparity of obesity in African countries. We examined the gender and socioeconomic patterns of body mass index (BMI) and perceived ideal body size in the Seychelles, a middle-income small island state in the African region. We also assessed the potential role of perceived ideal body size as a mediator for the gender-specific association between SES and BMI. A population-based survey of 1,240 adults aged 25 to 64 years conducted in December 2013. Participants' BMI was calculated based on measured weight and height; ideal body size was assessed using a nine-silhouette instrument. Three SES indicators were considered: income, education, and occupation. BMI and perceived ideal body size were both higher among men of higher versus lower SES (p< .001) but lower among women of higher versus lower SES (p< .001), irrespective of the SES indicator used. Multivariate analysis showed a strong and direct association between perceived ideal body size and BMI in both men and women (p< .001) and was consistent with a potential mediating role of perceived ideal body size in the gender-specific associations between SES and BMI. Our study emphasizes the importance of gender and socioeconomic differences in BMI and ideal body size and suggests that public health interventions that promote perception of healthy weight could help mitigate SES-related disparities in BMI.