Peripheral Adiposity Research Articles

Neuropilin-1 expression in GnRH neurons regulates prepubertal weight gain and sexual attraction.

Hypothalamic neurons expressing gonadotropin-releasing hormone (GnRH), the "master molecule" regulating reproduction and fertility, migrate from their birthplace in the nose to their destination using a system of guidance cues, which include the semaphorins and their receptors, the neuropilins and plexins, among others. Here, we show that selectively deleting neuropilin-1 in new GnRH neurons enhances their survival and migration, resulting in excess neurons in the hypothalamus and in their unusual accumulation in the accessory olfactory bulb, as well as an acceleration of mature patterns of activity. In female mice, these alterations result in early prepubertal weight gain, premature attraction to male odors, and precocious puberty. Our findings suggest that rather than being influenced by peripheral energy state, GnRH neurons themselves, through neuropilin-semaphorin signaling, might engineer the timing of puberty by regulating peripheral adiposity and behavioral switches, thus acting as a bridge between the reproductive and metabolic axes.

The association of anthropometric parameters with markers of insulin and leptin secretion and resistance in type 2 diabetes mellitus

Abstract Aim: We evaluated the association between anthropometric parameters and markers of insulin and leptin secretion/resistance in patients with type 2 diabetes mellitus (T2DM). Material and methods: This post-hoc data analysis from a cross-sectional study included 176 T2DM patients. Laboratory tests (serum leptin, soluble form of leptin receptor (sObR), C peptide, glycemic and lipid parameters) and anthropometric parameters were obtained, adiposity indexes (including body adiposity index (BAI), visceral adiposity index (VAI)), indicators of insulin resistance, β-cell function, and leptin resistance (Free Leptin Index, FLI) were calculated. Results: The body mass index (BMI), diabetes duration, VAI and leptin correlated independently with HOMA-IR, while BMI, diabetes duration and HbA1c with HOMA-B. The total body fat mass (TBFM), C peptide, diabetes duration, BMI and BAI correlated with leptin concentrations, while the first three with FLI. VAI was an indicator of insulin resistance (β=0.166, p=0.003), while BAI of leptin secretion (β=0.260, p=0.010). TBFM strongly associated with leptin resistance and secretion (β=0.037, r=0.688, p<0.0001, and β=0.521, r=0.667, p<0.0001), and BMI correlated weakly with insulin secretion and resistance. While insulin and leptin secretion increased progressively with BMI, leptin and insulin resistance became significant only in case of obesity. The sObR was significantly associated with C peptide concentrations (β=-0.032; p=0.044), but not with HOMA-B or -IR. A strong positive correlation between the C peptide/leptin ratio and non-fat mass /TBFM ratio was noted (r=0.62 [0.52, 0.71], p<0.0001). Conclusions: Parameters of peripheral adiposity correlated better with markers of leptin system, and those of visceral adiposity with markers of insulin secretion/resistance. The sObR correlated independently and negatively with C peptide.

Association between pubertal development stages and body adiposity in children and adolescents

BackgroundThe study aimed to analyze the association between pubertal development stages and adiposity in children and adolescents.MethodsCross-sectional study conducted in 2007 in Florianópolis, Brazil, with 2339 schoolchildren 32 aged 8 to 14 years old (1107 males). The outcome (adiposity) was evaluated using Z score and 33 percentilee values > = 85 of four skinfolds (triceps, subscapular, suprailiac and calf) and waist 34 circumference. Total body adiposity (Z score of the sum of skinfolds), central adiposity (Z score 35 of waist circumference) and peripheral adiposity (Z scores of triceps and calf skinfolds) were 36 estimated. Pubertal development stages was self-assessed according to Tanner stages of development. Thirty-seven Children and adolescents were classified according to tertiles of age for each pubertal development stages 38 stage - early, normal and late. Statistical analysis was performed using univariate and 39 multivariate Poisson regression models.ResultsChildren and adolescent from both sexes with early pubertal development stages presented higher prevalence of central adiposity (waist circumference), with adjusted prevalence ratio (CI 95%) of 2.21 (1.12; 4.35) for males and 2.18 (1.04; 4.57) for females (reference group: normal pubertal development stages). Among females, there was a reduction in the prevalence of excess adiposity with decreased occurrence of early pubertal development stages. There was a strong relationship between adiposity and pubertal development stages.ConclusionsExcess adiposity was higher in both sexes for those with early pubertal development stages.

In women, central obesity predicts higher inflammation, higher serum hepcidin, lower absorption and hypoferremia

Obesity is characterized by chronic low-grade inflammation. Visceral adipose tissue (VAT) is heavily infiltrated by macrophages producing pro-inflammatory cytokines (IL-6), therefore VAT predicts greater systemic inflammation compared to peripheral fat. Thus, central adiposity may cause increased serum hepcidin (SHep) and may affect iron metabolism more than peripheral adiposity. Although increased total body fat (BF) is linked to disordered iron homeostasis, the potential effects of body fat distribution on iron metabolism have not been studied. Therefore, the aim of this study was to assess the effect of BF distribution on iron and inflammation parameters, SHep and iron metabolism.We enrolled 37 normal-weight women and 81 overweight/obese women in this cross-sectional study. Body composition was assessed using DXA and iron- and inflammation parameters and SHep were measured. The overweight/obese women were assigned to a peripheral (n = 54) and a central (n = 27) fat deposit group, according to their android fat percentage. All women received 100 mg oral iron as ferrous citrate and the change in serum iron was assessed after 2 h to determine iron absorption.The three groups differed significantly in body weight, BMI, waist circumference, android fat, gynoid fat, total fat, android/gynoid ratio and VAT (for all p < 0.001). Hemoglobin, serum ferritin, body iron stores (BIS), serum iron and transferrin saturation (TSAT) were lowest and transferrin receptor was highest in central obesity. CRP was higher in central obesity compared to both, peripheral obesity (p < 0.05) and normal-weight (p < 0.001). SHep was higher in central and peripheral obesity compared to normal-weight (both p < 0.01), with no difference between the two overweight/obese groups. Δserum iron was ≈30% and ≈20% lower in central obesity compared to normal-weight and peripheral obesity. We performed linear regression analysis on SHep, CRP, TSAT and Δserum iron: Android fat and BIS were positive predictors of SHep (p < 0.05, p < 0.001), android fat was a positive predictor of CRP (p < 0.001), BIS was a positive, android fat was a negative predictor of TSAT (p < 0.001, p < 0.05) and TSAT and android fat were both negative predictors of Δserum iron (p < 0.001, p < 0.05).Controlling for iron status, inflammation and SHep are increased in women with central obesity and predict lower iron absorption and hypoferremia compared to women with more peripheral fat distribution. Thus, women with central fat distribution may be at increased risk for iron deficiency and anemia.

Patterns of body mass index, percentage body fat, and skinfold thicknesses in 7- to 18-year-old children and adolescents from Indonesia

Background:Body mass index (BMI) and skinfold thickness are widely used to evaluate body composition. Information on patterns of skinfold thickness may help to understand changes in body composition during growth. The objectives of this study were to observe patterns of BMI, percentage body fat (%BF), and skinfold thicknesses of Indonesian children and adolescents aged 7–18 years.Methods:Weight, height, and four skinfold thicknesses were measured in 2104 school children (924 boys, 1,180 girls) aged 7–18 years from Yogyakarta between 2015 and 2018. BMI and ratios between central and peripheral skinfold thicknesses were determined. %BF was predicted using the equation of Slaughter et al. Data were analyzed using analysis variance (ANOVA), independent sample t-test, and partial correlation (SPSS version 20.0).Results:At 7–18 years, boys and girls showed a comparable gain in BMI. The comparable gain in %BF between boys and girls only occurred till age 10 and total skinfolds till age 11 years. While, %BF and skinfold thicknesses were higher in girls at 12–17 years, central to peripheral skinfold ratio were higher in boys. Partial correlation analyses showed that all skinfold thickness parameters and %BF were significantly correlated with BMI (P < 0.001; r = 0.19–0.87).Conclusions:The gain in BMI and skinfold thickness between the ages of 7 and 18 years occurred in age- and sex-specific patterns. Instead of comparable BMI, girls showed higher means of total skinfold thickness from age 12 years, while boys had higher central to peripheral adiposity ratio.

Prenatal Cadmium Exposure Is Negatively Associated With Adiposity in Girls Not Boys During Adolescence.

Introduction: Cadmium is a pervasive toxic metal that remains a public health concern and exposure in early life has been associated with growth deficits in infancy and childhood. Growth during adolescence also may be sensitive to effects of cadmium exposure, given the changes in distribution of lean and adipose tissue that vary by sex during puberty. This study examines whether prenatal and concurrent cadmium exposures are associated with adiposity measures at ages 8–15 years in a well-characterized birth cohort.Methods: The sample included 185 participants from the ELEMENT birth cohorts in Mexico City with complete data on urinary cadmium exposures, anthropometry and covariates [child age and sex, household socioeconomic status, and maternal smoking history and body mass index (BMI)]. Maternal third trimester and adolescent urines were analyzed for cadmium using an Inductively Coupled Plasma Mass Spectrometer. Trained personnel obtained anthropometry including height, weight, waist circumference and subscapular, suprailiac, and triceps skinfold thickness. BMI z-scores for age and sex were calculated using the World Health Organization's reference standard. Linear regression models were used to estimate the association of prenatal and concurrent urinary cadmium levels with adolescent anthropometry, adjusting for covariates.Results: Among 87 males and 98 females, median age was 10 years (IQR 9 –11 years). Pregnant women and children had median urinary cadmium concentrations of 0.19 μg/L (IQR 0.12– 0.27 μg/L) and 0.14 μg/L (IQR 0.11– 0.18 μg/L), respectively. Regression models showed inverse relationships between prenatal cadmium exposure and adolescent adiposity. An IQR increase in prenatal cadmium was associated with percent decreases in BMI z-score (−27%, p = 0.01), waist circumference (−3%, p = 0.01), and subscapular (−11%, p = 0.01), suprailiac (−11%, p = 0.02), and triceps (−8%, p < 0.01) skinfold thickness. When stratified by sex, these relationships remained statistically significant in females but not males.Conclusions: Prenatal cadmium exposure was negatively associated with measures of both abdominal and peripheral adiposity in girls, but not in boys. These results emphasize the sex-dependent effects of in utero cadmium exposure on adiposity in adolescence.

Body composition and blood pressure in 6-year-old singletons born after pre-implantation genetic testing for monogenic and structural chromosomal aberrations: a matched cohort study.

STUDY QUESTIONDoes Day 3 embryo biopsy for pre-implantation genetic testing for monogenic (PGT-M) and structural chromosomal aberrations (PGT-SR) affect body composition and blood pressure readings of 6-year-old singletons?SUMMARY ANSWERThis study of 87 PGT-M and PGT-SR conceived singletons showed no differences in anthropometric measurements and blood pressure readings in comparison with a matched cohort of peers born after ICSI without embryo biopsy.WHAT IS KNOWN ALREADYWhile neonatal outcomes after PGT conception have been found comparable to those after ICSI without embryo biopsy, only a few studies have reported outcomes after PGT at older ages. Moreover, embryo biopsy is also applied in couples who opt for PGT-M and PGT-SR and hence are not necessarily infertile. Health parameters and in particular body composition data in this group of children are lacking.STUDY DESIGN, SIZE, DURATIONThis single-centre matched-pair cohort study evaluated body composition of 6-year-old children born after fresh blastocyst embryo transfer with or without embryo biopsy performed at Day 3 for the purpose of PGT-M and PGT-SR. For each child born after embryo biopsy, a singleton born after transfer of a fresh ICSI embryo at the blastocyst stage and reaching the age of 6 years between May 2011 and June 2017 was matched as closely as possible for gender, age, maternal educational level and birth order.PARTICIPANTS/MATERIALS, SETTING, METHODSAnthropometry (weight, height, BMI, skinfold thickness, waist and mid-upper arm circumference) and blood pressure readings in a longitudinally followed cohort of 87 singletons conceived by PGT-M and PGT-SR and a pairwise matched sample of 87 children conceived by ICSI are described. Results are adjusted for current, neonatal and parental characteristics.MAIN RESULTS AND THE ROLE OF CHANCEFrom the 124 eligible PGT-M and PGT-SR families, 110 could be reached of whom 23 refused and 87 (87/110 = 79%) participated. All anthropometric measurements, including z-scores of BMI, waist and mid-upper arm circumference, were comparable between the PGT-M and PGT-SR (−0.23; 0.27; 0.17, respectively) and ICSI (−0.29; 0.11; 0.11, respectively) groups (all P > 0.05). Furthermore, indices of peripheral (triceps) and central (subscapular) adiposity derived from skinfold thickness were comparable (PGT-M and PGT-SR: 14.7 mm; 11.6 mm and ICSI: 15.5 mm; 11.5 mm) as well as the percentage total body fat mass derived from these (PGT-M and PGT-SR: 13.7% and ICSI: 13.9%) (all P > 0.05). Z-scores for blood pressure were also comparable between the PGT and ICSI groups (all P > 0.05). Results did not change when adjusted for neonatal (birthweight, birth order), current (age) and parental (smoking during pregnancy, parental BMI) characteristics. Hospitalization rate and surgical intervention rate were not different for PGT-M and PGT-SR children compared to matched peers born after ICSI.LIMITATIONS, REASONS FOR CAUTIONAlthough our study describes the largest cohort of singletons born after embryo biopsy worldwide, we were only able to detect moderate differences in anthropometrics and blood pressure with our sample size.WIDER IMPLICATIONS OF THE FINDINGSAlthough Day 3 embryo biopsy followed by blastocyst transfer is not associated with adverse outcomes regarding anthropometry and blood pressure, future studies should focus on outcomes in children born after trophectoderm biopsy and/or transfer of warmed embryos after vitrification.STUDY FUNDING/COMPETING INTEREST(s)This study was supported by Methusalem grants and by grants from Wetenschappelijk Fonds Willy Gepts; all issued by the Vrije Universiteit Brussel (VUB). All co-authors, except M.B. declared no conflict of interest. M.B. has received consultancy fees from MSD, Serono Symposia and Merck. The Universitair Ziekenhuis Brussel (UZ Brussel) and the Centre for Medical Genetics have received several educational grants from IBSA, Ferring, Organon, Shering-Plough, Merck for establishing the database for follow-up research and organizing the data collection.

Is local or central adiposity more strongly associated with incident knee osteoarthritis than the body mass index in men or women?

To determine whether central (abdominal) or peripheral (thigh) adiposity measures are associated with incident radiographic knee osteoarthritis (RKOA) independent of body mass index (BMI) and whether their relation to RKOA was stronger than that of BMI. 161 Osteoarthritis Initiative (OAI) participants (62% female) with incident RKOA (Kellgren/Lawrence grade 0/1at baseline, developing an osteophyte and joint space narrowing (JSN) grade ≥1 by year-4) were matched to 186 controls (58% female) without incident RKOA. Baseline waist-height-ratio (WHtR), and anatomical cross-sectional areas of thigh subcutaneous (SCF) and intermuscular fat (IMF) were measured, the latter using axial magnetic resonance images. Logistic regression assessed the relationship between each adiposity measure and incident RKOA before and after adjustment for BMI, and area under receiver operating characteristic curves (AUC) for each adiposity measure was compared to that of BMI using chi-squared tests. BMI, WHtR, subcutaneous fat (SCF) and IMF were all significantly associated with incident RKOA when analysed separately, with similar effect sizes (odds ratio range 1.30-1.53). After adjusting for BMI, odds ratios (ORs) for WHtR, SCF and IMF were attenuated and no longer statistically significant. No measure of central or peripheral adiposity was significantly more strongly associated with incident RKOA than BMI. Results were similar for men and women. Although both central (WHtR) and peripheral (SCF and IMF) adiposity were significantly associated with incident RKOA, neither was more strongly associated with incident RKOA than BMI. The simple measure of BMI appears sufficient to capture the elevated risk of RKOA associated with greater amounts of localised adiposity.

Contribution of metabolic disease to bone fragility in MAGP1-deficient mice

Microfibril-associated glycoprotein-1 (MAGP1) is an extracellular matrix protein that interacts with fibrillin and is involved in regulating the bioavailability of signaling molecules such as TGFβ. Mice with germline MAGP1 deficiency (Mfap2−/−) develop increased adiposity, hyperglycemia, insulin resistance, bone marrow adipose tissue expansion, reduced cancellous bone mass, cortical bone thinning and bone fragility. The goal of this study was to assess whether the Mfap2−/− bone phenotypes were due to loss of MAGP1 locally or secondary to a change in whole body physiology (metabolic dysfunction). To do this, mice with conditional deletion of MAGP1 in the limb skeleton were generated by crossing MAGP1-flox mice (Mfap2lox/lox) with Prx1-Cre mice. Mfap2Prx−/− mice did not show any changes in peripheral adiposity, hyperglycemia or insulin sensitivity, but did have increased bone length and cancellous bone loss that was comparable to the germline Mfap2−/− knockout. Unlike the germline knockout, marrow adiposity, cortical bone thickness and bone strength in Mfap2Prx−/− mice were normal. These findings implicate systemic metabolic dysfunction in the development of bone fragility in germline Mfap2−/− mice. An unexpected finding of this study was the detection of MAGP1 protein in the Mfap2Prx−/− hematopoietic bone marrow, despite the absence of MAGP1 protein in osseous bone matrix and absent Mfap2 transcript expression at both sites. This suggests MAGP1 from a secondary site may accumulate in the bone marrow, but not be incorporated into the bone matrix, during times of regional MAGP1 depletion.

Highly Active Antiretroviral Therapy-Associated Metabolic Syndrome and Lipodystrophy: Pathophysiology and Current Therapeutic Interventions

The use of highly active antiretroviral therapy (HAART) has extremely enhanced the clinical outcome of HIV disease with a decrease in mortality and morbidity. However, the inclusion of protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (tNRTIs) has strongly been linked to the development of metabolic abnormalities and lipodystrophy. Lipodystrophy is defined by the loss of peripheral subcutaneous fat and central adiposity, mainly in the abdomen, breast and dorsocervical region. These disorders are reported to be cosmetically distressing and socially stigmatizing to many patients leading to decreased adherence to antiretroviral therapy. Metabolic syndrome precedes lipodystrophy leading to increased risk of diabetes and cardiovascular diseases. With a shifted trajectory of HIV/AIDS morbidity from immunodeficiency and opportunistic infections to metabolic complications, clinical management of these patients has therefore become more complex. Currently there are no evidence-based standard guidelines for the management of HIV-associated lipodystrophy. Several pharmacological interventions such as using anti-diabetic, anti-dyslipidemic drugs or hormone replacement therapy have been tried to effectively improve metabolic syndrome and lipodystrophy but have been hampered by low efficacy, drug interactions, or unwanted side-effects. Non-pharmacological interventions including surgical manipulations, dietary and lifestyle modifications have also been tried with limited success. This review focuses on the proposed mechanisms involved in the development of metabolic syndrome and lipodystrophy, and highlights suggested potential therapeutic interventions to prevent lipodystrophy associated with HAART. J Endocrinol Metab. 2017;7(4):103-116 doi: https://doi.org/10.14740/jem364w

Lipasin/betatrophin is differentially expressed in liver and white adipose tissue without association with insulin resistance in Wistar and Goto-Kakizaki rats.

Lipasin is a recently identified lipokine expressed predominantly in liver and in adipose tissue. It was linked to insulin resistance in mice and to type 1 and type 2 diabetes (T1D, T2D) in humans. No metabolic studies concerning lipasin were performed yet in rats. Therefore, we used rat model of T2D and insulin resistance, Goto-Kakizaki (GK) rats, to determine changes of lipasin expression in liver and in white adipose tissue (WAT) over 52 weeks in the relation to glucose tolerance, peripheral tissue insulin sensitivity and adiposity. GK rats were grossly glucose intolerant since the age of 6 weeks and developed peripheral insulin resistance at the age of 20 weeks. Expression of lipasin in the liver did not differ between GK and Wistar rats, declining with age, and it was not related to hepatic triacylglycerol content. In WAT, the lipasin expression was significantly higher in Wistar rats where it correlated positively with adiposity. No such correlation was found in GK rats. In conclusion, lipasin expression was associated neither with a mild age-related insulin resistance (Wistar), nor with severe genetically-based insulin resistance (GK).

Effect of gender and adiposity on in vivo vascular function in young African Americans

The relationship between obesity and high blood pressure is not as strong among African Americans (AA) as compared to Caucasians. We designed the current study to determine the effect of adiposity on vascular endothelial function (a harbinger of hypertension) among young healthy AA without additional cardiovascular disease risk factors. A total of 108 AA subjects (46 women) between the ages of 18 and 45 years were recruited. All the subjects were normotensive, nonsmokers, and normoglycemic. Anthropometric and cardiovascular disease risk factor measurements (lipid, insulin resistance, and inflammatory markers) were obtained. Vascular endothelial function was measured by brachial artery flow-mediated dilation (FMD). Adiposity distribution was measured by using magnetic resonance imaging scan. There were no gender differences in age and levels of blood pressure, lipids, insulin resistance, and inflammatory markers. Women had higher total body fat percentage and higher peripheral adiposity compared to men. We observed that total and central adiposity did not correlate significantly with brachial artery FMD in women (r = −0.12 and r = 0.23, respectively; P = NS). However, in men, waist circumference was positively associated with FMD (r = 0.3, P ≤ .05). Hyperemic flow was negatively correlated significantly with total and central adiposity in men (r = −0.34 and r = −0.48, respectively; P < .05), but not in women (r = −0.26 and r = 0.03, respectively; P = NS). Our study suggests that increased adiposity may pose greater risk to AA men compared to AA women by adversely affecting resistance vessel function (as measured by hyperemic flow). Larger studies are necessary to validate these findings.

Highly Active Antiretroviral Therapy-Associated Metabolic Syndrome and Lipodystrophy: Pathophysiology and Current Therapeutic Interventions

The use of highly active antiretroviral therapy (HAART) has extremely enhanced the clinical outcome of HIV disease with a decrease in mortality and morbidity. However, the inclusion of protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (tNRTIs) has strongly been linked to the development of metabolic abnormalities and lipodystrophy. Lipodystrophy is defined by the loss of peripheral subcutaneous fat and central adiposity, mainly in the abdomen, breast and dorsocervical region. These disorders are reported to be cosmetically distressing and socially stigmatizing to many patients leading to decreased adherence to antiretroviral therapy. Metabolic syndrome precedes lipodystrophy leading to increased risk of diabetes and cardiovascular diseases. With a shifted trajectory of HIV/AIDS morbidity from immunodeficiency and opportunistic infections to metabolic complications, clinical management of these patients has therefore become more complex. Currently there are no evidence-based standard guidelines for the management of HIV-associated lipodystrophy. Several pharmacological interventions such as using anti-diabetic, anti-dyslipidemic drugs or hormone replacement therapy have been tried to effectively improve metabolic syndrome and lipodystrophy but have been hampered by low efficacy, drug interactions, or unwanted side-effects. Non-pharmacological interventions including surgical manipulations, dietary and lifestyle modifications have also been tried with limited success. This review focuses on the proposed mechanisms involved in the development of metabolic syndrome and lipodystrophy, and highlights suggested potential therapeutic interventions to prevent lipodystrophy associated with HAART. J Endocrinol Metab. 2017;7(4):103-116 doi: https://doi.org/10.14740/jem364w

Marrow Adipose Tissue Expansion Coincides with Insulin Resistance in MAGP1-Deficient Mice.

Marrow adipose tissue (MAT) is an endocrine organ with the potential to influence skeletal remodeling and hematopoiesis. Pathologic MAT expansion has been studied in the context of severe metabolic challenge, including caloric restriction, high fat diet feeding, and leptin deficiency. However, the rapid change in peripheral fat and glucose metabolism associated with these models impedes our ability to examine which metabolic parameters precede or coincide with MAT expansion. Microfibril-associated glycoprotein-1 (MAGP1) is a matricellular protein that influences cellular processes by tethering signaling molecules to extracellular matrix structures. MAGP1-deficient (Mfap2−/−) mice display a progressive excess adiposity phenotype, which precedes insulin resistance and occurs without changes in caloric intake or ambulation. Mfap2−/− mice were, therefore, used as a model to associate parameters of metabolic disease, bone remodeling, and hematopoiesis with MAT expansion. Marrow adiposity was normal in Mfap2−/− mice until 6 months of age; however, by 10 months, marrow fat volume had increased fivefold relative to wild-type control at the same age. Increased gonadal fat pad mass and hyperglycemia were detectable in Mfap2−/− mice by 2 months, but peaked by 6 months. The development of insulin resistance coincided with MAT expansion. Longitudinal characterization of bone mass demonstrated a disconnection in MAT volume and bone volume. Specifically, Mfap2−/− mice had reduced trabecular bone volume by 2 months, but this phenotype did not progress with age or MAT expansion. Interestingly, MAT expansion in the 10-month-old Mfap2−/− mice was associated with modest alterations in basal hematopoiesis, including a shift from granulopoiesis to B lymphopoiesis. Together, these findings indicate MAT expansion is coincident with insulin resistance, but not excess peripheral adiposity or hyperglycemia in Mfap2−/− mice; and substantial MAT accumulation does not necessitate a proportional decrease in either bone mass or bone marrow cellularity.

Relative Importance of Central and Peripheral Adiposities on Cardiometabolic Variables in Females: A Japanese Population-Based Study

In epidemiological studies, there is little evidence regarding the relative impact of central adiposity and peripheral adiposity on cardiometabolic risk factors, especially in Asian populations. This study investigated associations between central-to-peripheral fat ratios and cardiometabolic variables using data from a population-based study of Japanese women. The source population was composed of 1800 women aged 50 yr or older at the 15th- to 16th-yr follow-up survey of the Japanese Population-Based Osteoporosis Cohort Study. This study analyzed cross-sectional data from 998 women for whom complete information about body fat variables according to dual-energy X-ray absorptiometry, cardiometabolic variables, and potential confounding factors was available. Both before and after adjusting for potential confounding factors, trunk-to-appendicular fat ratios showed significant (p < 0.05) correlations with brachial–ankle pulse wave velocity, serum lipids, and hemoglobin A1c levels. Relationships between fat ratios and cardiometabolic variables were independent of relationships between fat volumes (in whole body or in trunk) and cardiometabolic variables. Furthermore, relationships between trunk-to-appendicular fat ratios and cardiometabolic variables were observed among women in the lowest tertile of total body fat (brachial–ankle pulse wave velocity, β = 0.08; high-density lipoprotein cholesterol, β = −0.32; low-density lipoprotein cholesterol, β = 0.15; and hemoglobin A1C, β = 0.16; p < 0.05, respectively). Central adiposity is more related to cardiometabolic variables than peripheral adiposity. Information on central-to-peripheral fat ratios is particularly valuable for the evaluation of relatively thin Japanese women.

Increased Gs Signaling in Osteoblasts Reduces Bone Marrow and Whole-Body Adiposity in Male Mice.

Bone is increasingly recognized as an endocrine organ that can regulate systemic hormones and metabolism through secreted factors. Although bone loss and increased adiposity appear to be linked clinically, whether conditions of increased bone formation can also change systemic metabolism remains unclear. In this study, we examined how increased osteogenesis affects metabolism by using an engineered G protein-coupled receptor, Rs1, to activate Gs signaling in osteoblastic cells in ColI(2.3)(+)/Rs1(+) transgenic mice. We previously showed that these mice have dramatically increased bone formation resembling fibrous dysplasia of the bone. We found that total body fat was significantly reduced starting at 3 weeks of age. Furthermore, ColI(2.3)(+)/Rs1(+) mice showed reduced O2 consumption and respiratory quotient measures without effects on food intake and energy expenditure. The mice had significantly decreased serum triacylglycerides, leptin, and adiponectin. Resting glucose and insulin levels were unchanged; however, glucose and insulin tolerance tests revealed increased sensitivity to insulin. The mice showed resistance to fat accumulation from a high-fat diet. Furthermore, ColI(2.3)(+)/Rs1(+) mouse bones had dramatically reduced mature adipocyte differentiation, increased Wingless/Int-1 (Wnt) signaling, and higher osteoblastic glucose utilization than controls. These findings suggest that osteoblasts can influence both local and peripheral adiposity in conditions of increased bone formation and suggest a role for osteoblasts in the regulation of whole-body adiposity and metabolic homeostasis.

The Apparent Relation between Plasma 25-Hydroxyvitamin D and Insulin Resistance Is Largely Attributable to Central Adiposity in Overweight and Obese Adults

Background: Research indicates that plasma 25-hydroxyvitamin D [25(OH)D] is associated with insulin resistance, but whether regional adiposity confounds this association is unclear.Objective: This study assessed the potential influence of adiposity and its anatomical distribution on the relation between plasma 25(OH)D and insulin resistance.Methods: A secondary analysis of data from middle-aged overweight and obese healthy adults [n = 336: 213 women and 123 men; mean ± SD (range); age: 48 ± 8 y (35–65 y); body mass index (BMI; in kg/m2): 30.3 ± 2.7 (26–35)] from West Lafayette, Indiana (40.4°N), were used for this cross-sectional analysis. Multiple linear regression analyses that controlled for multiple covariates were used as the primary statistical model.Results: Of all participants, 8.6% and 20.5% displayed moderate [20.1–37.5 nmol/L plasma 25(OH)D] to mild (37.6–49.9 nmol/L) vitamin D insufficiency, respectively. A regression analysis controlling for age, sex, race, plasma parathyroid hormone concentration, season of year, and supplement use showed that 25(OH)D was negatively associated with fasting insulin (P = 0.021). Additional regression analyses showed that total and central adiposity but not peripheral adiposity predicted low plasma 25(OH)D [total fat mass index (FMI): P = 0.018; android FMI: P = 0.052; gynoid FMI: P = 0.15; appendicular FMI: P = 0.07) and insulin resistance (homeostasis model assessment of insulin resistance: total and android FMI, P <0.0001; gynoid FMI, P = 0.94; appendicular FMI, P = 0.86). The associations of total and central adiposity with insulin resistance remained significant after adjusting for plasma 25(OH)D. However, adjusting for central adiposity but not other anatomical measures of fat distribution eliminated the association between plasma 25(OH)D and insulin resistance.Conclusion: Central adiposity drives the association between plasma 25(OH)D and insulin resistance in overweight and obese adults. The trial was registered at clinicaltrials.gov as NCT00812409.

Antibody-Mediated Inhibition of the FGFR1c Isoform Induces a Catabolic Lean State in Siberian Hamsters

Hypothalamic tanycytes are considered to function as sensors of peripheral metabolism. To facilitate this role, they express a wide range of receptors, including fibroblast growth factor receptor 1 (FGFR1). Using a monoclonal antibody (IMC-H7) that selectively antagonizes the FGFR1c isoform, we investigated possible actions of FGFR1c in a natural animal model of adiposity, the Siberian hamster. Infusion of IMC-H7 into the third ventricle suppressed appetite and increased energy expenditure. Likewise, peripheral treatment with IMC-H7 decreased appetite and body weight and increased energy expenditure and fat oxidation. A greater reduction in body weight and caloric intake was observed in response to IMC-H7 during the long-day fat state as compared to the short-day lean state. This enhanced response to IMC-H7 was also observed in calorically restricted hamsters maintained in long days, suggesting that it is the central photoperiodic state rather than the peripheral adiposity that determines the response to FGFR1c antagonism. Hypothalamic thyroid hormone availability is controlled by deiodinase enzymes (DIO2 and DIO3) expressed in tanycytes and is the key regulator of seasonal cycles of energy balance. Therefore, we determined the effect of IMC-H7 on hypothalamic expression of these deiodinase enzymes. The reductions in food intake and body weight were always associated with decreased expression of DIO2 in the hypothalamic ependymal cell layer containing tanycytes. These data provide further support for the notion the tanycytes are an important component of the mechanism by which the hypothalamus integrates central and peripheral signals to regulate energy intake and expenditure.

Body Fat Patterning, Hepatic Fat and Pancreatic Volume of Non-Obese Asian Indians with Type 2 Diabetes in North India: A Case-Control Study.

ObjectiveTo evaluate body fat patterning and phenotype including hepatic fat and pancreatic volume of non-obese (BMI: < 25 kg/m2) Asian Indians with type 2 diabetes residing in North India.MethodsNon-obese patients with type 2 diabetes (n = 93) and non-obese, normo-glycemic subjects (n = 40) were recruited. BMI, waist & hip circumferences, skinfold thickness at 8 sites, body fat, lean mass and detailed abdominal fat evaluation [total abdominal fat, total subcutaneous fat (superficial, deep, anterior, and posterior), total intra-abdominal fat (intra-peritoneal, retroperitoneal)], liver span, grades of fatty liver and pancreatic volume were compared.ResultsWaist circumference, subscapular skinfolds and total truncal fat (on DEXA) were higher whereas calf, total peripheral skinfolds and total leg fat (on DEXA) lower in patients. Specifically, the following volumes were higher in cases as compared to controls; total abdominal fat (19.4%), total intra-abdominal fat (49.7%), intra-peritoneal fat (47.7%), retroperitoneal fat (70.7%), pancreatic volume (26.6%), pancreatic volume index (21.3%) and liver span (10.8%). In cases, significant positive correlations were observed for pancreatic volume with BMI, waist and hip circumferences, W-HR, subscapular, abdominal and total truncal skinfolds, truncal, total subcutaneous, total intra-abdominal, intra-peritoneal, retroperitoneal fat depots, liver span and fatty liver.ConclusionsIn non-obese Asian Indians with type 2 diabetes, subcutaneous and intra-abdominal obesity, including fatty liver, and pancreatic volume were higher and peripheral subcutaneous adiposity was lower than BMI matched non-diabetic subjects. Importantly, increased pancreatic volume in patients was highly correlated with multiple measures of abdominal obesity and liver fat.

Adiponectin Levels Differentiate Metabolically Healthy vs Unhealthy Among Obese and Nonobese White Individuals.

Adiponectin levels (ADPN) are lower in individuals with central obesity and cardiometabolic diseases. Conversely, studies have shown paradoxical hyperadiponectinemia (HA) in metabolically healthy obese (MHO) individuals of non-European descent. Moreover, individuals with higher sc to visceral adipose tissue (ie, higher peripheral adiposity) distribution have higher ADPNs. However, it is not known whether metabolically healthy individuals have predominantly peripheral adiposity along with higher ADPNs. This study aimed to evaluate the association of ADPN and adiposity distribution with metabolic health in white individuals. This was a cross-sectional study of members of "Take Off Pounds Sensibly" weight loss club and their relatives. We recruited 2486 (72% women, 61% obese) individuals. They were defined as metabolically healthy by absence of hypertension, diabetes, and dyslipidemia; and they were further classified into metabolically healthy nonobese (MHNO), metabolically unhealthy nonobese (MUNO), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO). Waist-to-hip ratios (WHRs) were used as markers of adiposity distribution. Insulin resistance was measured using homeostasis model assessment. Among the four groups, MHNO had the lowest WHRs (higher peripheral adiposity) and highest ADPN, and MUO had highest WHRs (higher central adiposity) and lowest ADPN (P < .001). Among both nonobese and obese, metabolically healthy individuals had higher ADPN than metabolically unhealthy individuals (P < .05) after adjustment for age, sex, and body mass index. MHNO also had lower WHRs compared with MUNO (P < .01). Although WHRs were lower among MHO compared with MUO, the difference was not significant. In addition, nonobese and obese individuals with HA (defined using sex-specific cutoffs) had lower homeostasis model assessment and dyslipidemia compared with individuals without HA. Higher ADPN and lower WHRs (higher peripheral adiposity) are associated with better metabolic health in both nonobese and obese white individuals. These results suggest that ADPN and peripheral adiposity play a key role in determining the metabolic health independent of body mass index.