Body Composition And Bone Mineral Differences According to Lamin A (LMNA) Genotype in Familial Partial Lipodystrophy Type 2

Abstract Phenotypic heterogeneity is well known in Familial Partial Lipodystrophy Type 2 (FPLD2), a rare form of adipose tissue disorder caused by pathogenic mutations in LMNA gene. Animal studies from our group have identified an association between adipose tissue loss and an increase in bone mineral density (BMD) in a mouse model with adipose tissue specific knockout of LMNA gene. Aiming to translate this observation to patients with FPLD2, we analyzed body composition data obtained by dual X-ray absorptiometry from 61 patients diagnosed with FPLD2 and 61 individuals with no diagnosis of FPLD (nFPLD) matched for sex, age and body mass index. As expected, we observed lower total fat mass in FPLD2 patients compared to nFPLD (15.8±9.3 kg vs. 28.5±12.4 kg, p=0.001), as well as lower fat mass in regions of arms, legs and trunk. Interestingly, patients with FPLD2 showed lower bone mineral density (BMD) compared to nFPLD 1.0±0.2 g/cm3 vs 1.2±0.1 g/cm3, p=0.01) and lower t-score (0.2±1.8 vs.1.5±1.2). We then aimed to determine if the patients with FPLD2 displayed differences with respect to genotype. For these analyses, the FPLD2 group was divided according to the pathogenic variant; 42 with mutations on the hot spot codon of the LMNA gene (R482: 50.2 ± 164.8 years, 76% women) and 19 with non-hot spot codon mutations (nR482: 44.8 ± 12.8 years, 78% women). Patients in the R482 group were older when they were first diagnosed with lipodystrophy (39.6 ± 18.6 years vs. 36.5 ± 12.3 years, p=0.05). Also, nR482 group presented with more progeroid characteristics. Patients in n-R482 group also had lower weight compared to R482 and nFPLD groups (64.4±14.4 vs. 73.3±18.5 and 77.6±16.6 kg, p=0.01), as well as lower total fat mass (15.3±5.1 vs. 15.8±9.3 and 25.7±11.4 kg, p=0.01) and fat mass ratio (5.8±1.9 vs. 5.9±3.1 and 9.0±4.1, p= 0.01). Control group bone mass was significantly higher in arms, legs and trunk compared to the R482 and nR482 groups. Moreover, the R482 group had lower bone mass in the legs compared to nR482 (690.5±227.2 vs.703.5±95.3 g, p=0.01), while showing higher trunk bone mass (676.4±266.7 vs. 674.1±79.3, p=0.04), in addition to greater fat mass in the legs (3.3±1.6 vs. 2.6±0.7 kg, p=0.05) and trunk areas (10.3±6.1 vs. 10.0±4.2 kg, p=0.03). There were no differences in total bone mass, BMD, and t-scores, according to genotype. Our data showed more fat preservation in LMNA R482 than nR482, presumably leading to a later lipodystrophy diagnosis. Furthermore, bone mass in different regions may be affected by LMNA genotype; however, more studies are needed to define the bone phenotype and fracture risk in FPLD2 population fully.

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Bone mineral density and body composition in adolescents with failure to thrive

Einstein (São Paulo) ◽

10.1590/s1679-45082010ao1361 ◽

2010 ◽

Vol 8 (2) ◽

pp. 168-174

Author(s):

Thiago Sacchetto de Andrade ◽

Luiz Anderson Lopes ◽

Marcelo de Medeiros Pinheiro ◽

Vera Lucia Szejnfeld ◽

José Augusto de Aguiar Carrazedo Taddei

Keyword(s):

Bone Mineral Density ◽

Body Composition ◽

Bone Mass ◽

Bone Mineral ◽

Fat Mass ◽

Failure To Thrive ◽

Fat Free Mass ◽

Z Score ◽

Mineral Density ◽

Total Fat

ABSTRACT Objective To evaluate bone mineral mass in adolescents with failure to thrive in relation to body composition. Methods A case control study involving 126 adolescents (15 to 19 years), in final puberty maturation being 76 eutrophic and 50 with failure to thrive (genetic or constitutional delay of growth), of matching ages, gender and pubertal maturation. The weight, height and calculated Z score for height/age and body mass index; bone mineral content, bone mineral density and adjusted bone mineral density were established for total body, lower back and femur; total fat-free mass and height-adjusted fat-free mass index, total fat mass and height-adjusted. The statistical analyses were performed using the Student's t-test (weight, height and body composition); Mann-Whitney test (bone mass) and multiple linear regression (bone mass determinants). Results weight, height and height/age Z-score were significantly higher among eutrophic subjects. Both groups did not show statistically significant differences for fat mass, percentage of fat mass, total fat mass height adjusted and fat-free mass index height sadjusted. However, total free fat maass was smaller for the failure to thrive group. Conclusions There was no statistically significant difference for bone mass measurements among adolescents with failure to thrive; however, the factors that determine bone mass formation should be better studied due to the positive correlation with free fat mass detected in these individuals.

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Acute fat loss does not affect bone mass

Scientific Reports ◽

10.1038/s41598-021-93450-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Marie K. Lagerquist ◽

Karin L. Gustafsson ◽

Petra Henning ◽

Helen Farman ◽

Jianyao Wu ◽

...

Keyword(s):

Adipose Tissue ◽

Bone Mass ◽

Fat Mass ◽

Tissue Loss ◽

Obese Mice ◽

Long Term Effects ◽

High Bone Mass ◽

Age Related ◽

Total Fat ◽

Old Mice

AbstractObesity has previously been thought to protect bone since high body weight and body mass index are associated with high bone mass. However, some more recent studies suggest that increased adiposity negatively impacts bone mass. Here, we aimed to test whether acute loss of adipose tissue, via adipocyte apoptosis, alters bone mass in age-related obese mice. Adipocyte apoptosis was induced in obese male FAT-ATTAC mice through AP20187 dimerizer-mediated activation of caspase 8 selectively in adipocytes. In a short-term experiment, dimerizer was administered to 5.5 month-old mice that were terminated 2 weeks later. At termination, the total fat mass weighed 58% less in dimerizer-treated mice compared with vehicle-treated controls, but bone mass did not differ. To allow for the detection of long-term effects, we used 9-month-old mice that were terminated six weeks after dimerizer administration. In this experiment, the total fat mass weighed less (− 68%) in the dimerizer-treated mice than in the controls, yet neither bone mass nor biomechanical properties differed between groups. Our findings show that adipose tissue loss, despite the reduced mechanical loading, does not affect bone in age-related obese mice. Future studies are needed to test whether adipose tissue loss is beneficial during more severe obesity.

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Adiposity, Insulin Resistance, and Bone Mass in Children and Adolescents

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2018-00353 ◽

2018 ◽

Vol 104 (3) ◽

pp. 892-899 ◽

Cited By ~ 9

Author(s):

Joseph M Kindler ◽

Andrea J Lobene ◽

Kara A Vogel ◽

Berdine R Martin ◽

Linda D McCabe ◽

...

Keyword(s):

Bone Mineral Density ◽

Insulin Resistance ◽

Waist Circumference ◽

Bone Mass ◽

Bone Mineral ◽

Fat Mass ◽

Areal Bone Mineral Density ◽

Mineral Density ◽

Total Body ◽

The Relationship

Abstract Context Insulin resistance is an adverse health outcome that accompanies obesity. Fat mass is negatively associated with the bone mass after adjustment for confounders. Insulin resistance might be an intermediary in this relationship. Objective To determine whether insulin resistance is an intermediary in the relationship between adiposity and bone mass in adolescents. Design Cross-sectional secondary analysis of baseline data from a previous randomized trial. Setting University research facility. Participants A total of 240 adolescents (68% female), aged 7 to 15 years. Main Outcome Measures Using dual energy x-ray absorptiometry, bone mineral content (BMC), areal bone mineral density, lean mass, and fat mass were measured. Skeletal sites of interest included the total body and lumbar spine (LS). Waist circumference was measured using an anthropometric tape measure. Insulin and glucose were measured in fasting sera, and the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Path analysis was performed to determine whether the relationship between adiposity and bone was mediated through insulin resistance. Results Fat mass (r = 0.467; P < 0.001) and waist circumference (r = 0.487; P < 0.001) correlated positively with HOMA-IR. Controlling for race, sex, maturation, lean mass, and height, fat mass, waist circumference, and HOMA-IR were negatively associated with LS BMC and total body areal bone mineral density (P < 0.05 for all). Additionally, path models for fat mass (95% CI, −5.893 to −0.956) and waist circumference (95% CI, −15.473 to −2.124) showed a negative relationship with LS BMC via HOMA-IR. Conclusions These results support an intermediary role of insulin resistance in the relationship between adiposity and LS bone mass.

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Fat Mass Exerts a Greater Effect on Cortical Bone Mass in Girls than Boys

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-1907 ◽

2010 ◽

Vol 95 (2) ◽

pp. 699-706 ◽

Cited By ~ 53

Author(s):

Adrian Sayers ◽

Jonathan H. Tobias

Keyword(s):

Bone Mineral Density ◽

Bone Mass ◽

Cortical Bone ◽

Bone Mineral ◽

Fat Mass ◽

Quantitative Computed Tomography ◽

Positive Association ◽

Mineral Density ◽

Cortical Bone Mineral Density ◽

Cortical Bone Mass

Abstract Context: It is unclear whether fat mass (FM) and lean mass (LM) differ in the way they influence cortical bone development in boys and girls. Objective: The aim of the study was to investigate the contributions of total body FM and LM to parameters related to cortical bone mass and geometry. Design/Setting: We conducted a longitudinal birth cohort study, the Avon Longitudinal Study of Parents and Children. Participants: A total of 4005 boys and girls (mean age, 15.5 yr) participated in the study. Outcome Measures: We measured cortical bone mass, cortical bone mineral content (BMCC), cortical bone mineral density, periosteal circumference (PC), and endosteal circumference by tibial peripheral quantitative computed tomography. Results: LM had a similar positive association with BMCC in boys and girls [regression coefficients with 95% confidence interval (CI); P for gender interactions: boys/girls, 0.952 (0.908, 0.997); P = 0.85]. However, the mechanisms by which LM influenced bone mass differed according to gender because LM was positively associated with PC more strongly in girls [boys, 0.579 (0.522, 0.635); girls, 0.799 (0.722, 0.875); P < 0.0001], but was only associated with cortical bone mineral density in boys [boys, 0.443 (0.382, 0.505); girls, 0.014 (−0.070, 0.097); P < 0.0001]. There was a stronger positive association between FM and BMCC in girls [boys, 0.227 (0.185, 0.269); girls, 0.355 (0.319, 0.392); P < 0.0001]. This reflected both a greater positive association of FM with PC in girls [boys, 0.213 (0.174, 0.253); girls, 0.312 (0.278, 0.347); P = 0.0002], and a stronger negative association with endosteal circumferencePC [boys, −0.059 (−0.096, 0.021); girls, −0.181 (−0.215, −0.146); P < 0.0001]. Conclusions: Whereas LM stimulates the accrual of cortical bone mass to a similar extent in boys and girls, FM is a stronger stimulus for accrual of cortical bone mass in girls, reflecting a greater tendency in females for FM to stimulate periosteal growth and suppress endosteal expansion.

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Inhibition of Angiopoietin-Like 3 (ANGPTL3) Reduces Adipose Tissue Insulin Resistance in Patients With Familial Partial Lipodystrophy

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.100 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A50-A51

Author(s):

Maria Cristina Foss de Freitas ◽

Baris Akinci ◽

Adam Neidert ◽

Rita Hench ◽

Elif A Oral

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Body Fat ◽

Fat Mass ◽

Subcutaneous Fat ◽

Hormonal Changes ◽

Loss Of Function ◽

Partial Lipodystrophy ◽

Number Of Patients ◽

Familial Partial Lipodystrophy

Abstract Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat, usually affecting the trunk and limbs, but preservation in other areas, such as the face and neck. It is usually associated with dyslipidemia and diabetes mellitus, and currently, there are no approved specific therapies for this disease in the US. Reductions in circulating levels of ANGPTL3 either by homologous loss-of-function mutations in humans or by pharmacological inhibition in rodents are associated with reductions in triglyceride (and other atherogenic lipid) levels and protect from atherosclerosis, making it an attractive target for patients with FPLD and metabolic dyslipidemia. We performed a proof-of-concept study to assess the early efficacy and safety of targeting ANGPTL3 via antisense oligonucleotide ISIS-703802 (vupanorsen) in a small number of patients with FPLD. Four patients with FPLD (3F/1M; age range: 39–48; 1 with LMNA R482Q, 1 with LMNA R584H, and 2 with no causative genetic variant), diabetes (HbA1c>6.5%) and hypertriglyceridemia (>250 mg/dL at screening) were included. Patients received the study drug at a subcutaneous dose of 20 mg weekly for 26 weeks. The primary endpoint was the change in triglycerides at week 27. Other end-points of interest measured at the same time points included insulin secretion, sensitivity, lipid and hormonal changes in response to a 5 hour long mixed meal test and body composition measured by dual energy absorptiometry (DEXA). Treatment resulted in a 59.9±26.3 (mean±SD) % of reduction in triglycerides, 54.7±9.8% of reduction in serum ANGPTL3 levels and 50.8±27.4% of reduction in ApoCIII. Treatment with vupanorsen led to a reduction of 209.3±120.4 in adipose tissue insulin resistance (ADIPO-IR) from a baseline of 470.3±114.3 and the area under the curve (AUC) for circulating free fatty acid levels were decreased by 32.1±21.4 mmol/L/min from a baseline of 215.8±55.2 mmol/L/min. Glucose AUC and triglyceride AUC also decreased after treatment (-14.0±5.2 and -60.1±26.5 mg/dL/min, respectively). Analyzing body fat distribution using DEXA, we observed that the fat mass index (FMI) and trunk mass index (TMI) did not change from baseline, but the ratio of total fat mass/ fat mass from limbs decreased by 10.7±12.2. These data show a tendency for redistribution of central body fat to limbs. There were numerous adverse events observed that were related to common serious complications associated with diabetes and FPLD. Although limited, these results suggest that targeting ANGPTL3 with vupanorsen in patients with FPLD may have a therapeutic role by addressing multiple problems.

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Thin healthy women have a similar low bone mass to women with anorexia nervosa

British Journal Of Nutrition ◽

10.1017/s0007114509274733 ◽

2009 ◽

Vol 102 (5) ◽

pp. 709-714 ◽

Cited By ~ 14

Author(s):

D. Fernández-García ◽

M. Rodríguez ◽

J. García Alemán ◽

J. M. García-Almeida ◽

M. J. Picón ◽

...

Keyword(s):

Bone Mass ◽

Bone Mineral ◽

Fat Mass ◽

Minimum Weight ◽

Normal Weight ◽

Control Group ◽

Low Bone Mass ◽

Mineral Density ◽

Anthropometric Parameters ◽

Healthy Women

An association between anorexia nerviosa (AN) and low bone mass has been demonstrated. Bone loss associated with AN involves hormonal and nutritional impairments, though their exact contribution is not clearly established. We compared bone mass in AN patients with women of similar weight with no criteria for AN, and a third group of healthy, normal-weight, age-matched women. The study included forty-eight patients with AN, twenty-two healthy eumenorrhoeic women with low weight (LW group; BMI < 18·5 kg/m2) and twenty healthy women with BMI >18·5 kg/m2 (control group), all of similar age. We measured lean body mass, percentage fat mass, total bone mineral content (BMC) and bone mineral density in lumbar spine (BMD LS) and in total (tBMD). We measured anthropometric parameters, leptin and growth hormone. The control group had greater tBMD and BMD LS than the other groups, with no differences between the AN and LW groups. No differences were found in tBMD, BMD LS and total BMC between the restrictive (n 25) and binge–purge type (n 23) in AN patients. In AN, minimum weight (P = 0·002) and percentage fat mass (P = 0·02) explained BMD LS variation (r2 0·48) and minimum weight (r2 0·42; P = 0·002) for tBMD in stepwise regression analyses. In the LW group, BMI explained BMD LS (r2 0·72; P = 0·01) and tBMD (r2 0·57; P = 0·04). We concluded that patients with AN had similar BMD to healthy thin women. Anthropometric parameters could contribute more significantly than oestrogen deficiency in the achievement of peak bone mass in AN patients.

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Bone Mineral Density in Adults With Cerebral Palsy

Frontiers in Neurology ◽

10.3389/fneur.2021.733322 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jun Hee Won ◽

Se Hee Jung

Keyword(s):

Bone Mineral Density ◽

Cerebral Palsy ◽

Lumbar Spine ◽

Femoral Neck ◽

Motor Function ◽

Bone Mineral ◽

Fat Mass ◽

Mineral Density ◽

Male Sex ◽

Total Fat

Low bone mineral density (BMD) is an emerging health issue in adults with cerebral palsy (CP). This cross-sectional study aimed to describe the characteristics of BMD in adults with CP, and to elucidate the risk factors for low BMD in this population. People aged ≥20 years and diagnosed with CP were recruited from February 2014 to November 2014. We assessed BMD using dual-energy X-ray absorptiometry (DXA) for the lumbar spine, femoral neck, and total femur. Moreover, the body composition was assessed using DXA. We included a total of 87 adults with CP (mean age 42.01 years; 52 men). The prevalence of low BMD was 25.3%. Male sex and age were associated with lower BMD. BMD was significantly lower in the non-ambulatory group than that in the ambulatory group for both lumbar spine and femoral neck. The total fat mass demonstrated a positive correlation with the Z-score and BMD for the femur neck and total femur. Body mass index (BMI) and total fat mass were positively correlated with BMD in the lumbar spine, femoral neck, and total femur. However, the Gross Motor Function Classification Scale levels were negatively correlated with BMD at the aforementioned three sites. In conclusion, adults with CP revealed decreased BMD, which was associated with male sex, age, decreased gross motor function, loss of ambulatory function, low BMI, decreased total fat mass, and decreased total fat-free mass.

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Reduced Bone Density and Cortical Bone Indices in Female Adiponectin-Knockout Mice

Endocrinology ◽

10.1210/en.2016-1059 ◽

2016 ◽

Vol 157 (9) ◽

pp. 3550-3561 ◽

Cited By ~ 18

Author(s):

Dorit Naot ◽

Maureen Watson ◽

Karen E. Callon ◽

Donna Tuari ◽

David S. Musson ◽

...

Keyword(s):

Bone Mineral Density ◽

Bone Density ◽

Bone Mass ◽

Bone Tissue ◽

Bone Mineral ◽

Fat Mass ◽

Microcomputed Tomography ◽

Bending Test ◽

Mineral Density ◽

Circulating Levels

A positive association between fat and bone mass is maintained through a network of signaling molecules. Clinical studies found that the circulating levels of adiponectin, a peptide secreted from adipocytes, are inversely related to visceral fat mass and bone mineral density, and it has been suggested that adiponectin contributes to the coupling between fat and bone. Our study tested the hypothesis that adiponectin affects bone tissue by comparing the bone phenotype of wild-type and adiponectin-knockout (APN-KO) female mice between the ages of 8–37 weeks. Using a longitudinal study design, we determined body composition and bone density using dual energy x-ray absorptiometry. In parallel, groups of animals were killed at different ages and bone properties were analyzed by microcomputed tomography, dynamic histomorphometry, 3-point bending test, nanoindentation, and computational modelling. APN-KO mice had reduced body fat and decreased whole-skeleton bone mineral density. Microcomputed tomography analysis identified reduced cortical area fraction and average cortical thickness in APN-KO mice in all the age groups and reduced trabecular bone volume fraction only in young APN-KO mice. There were no major differences in bone strength and material properties between the 2 groups. Taken together, our results demonstrate a positive effect of adiponectin on bone geometry and density in our mouse model. Assuming adiponectin has similar effects in humans, the low circulating levels of adiponectin associated with increased fat mass are unlikely to contribute to the parallel increase in bone mass. Therefore, adiponectin does not appear to play a role in the coupling between fat and bone tissue.

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Association between Serum Leptin Concentrations and Bone Mineral Density, and Biochemical Markers of Bone Turnover in Adult Men

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.11.8020 ◽

2001 ◽

Vol 86 (11) ◽

pp. 5273-5276 ◽

Cited By ~ 53

Author(s):

Mayumi Sato ◽

Noriyuki Takeda ◽

Hiroshi Sarui ◽

Rieko Takami ◽

Kazuhisa Takami ◽

...

Keyword(s):

Bone Mineral Density ◽

Bone Formation ◽

Bone Mineral ◽

Fat Mass ◽

Single Photon ◽

Mineral Density ◽

Serum Leptin ◽

Adult Men ◽

Total Fat

Leptin, the product of the ob gene, has been shown to inhibit bone formation in mice. We addressed whether leptin has any role in the regulation of bone mineral density (BMD) in humans. Subjects were 221 adult men with a mean (±sd) age and body mass index of 52.1 ± 8.7 yr and 23.6 ± 2.8 kg/m2. Serum leptin, carboxyterminal propeptide of type 1 procollagen (PICP; a marker of bone formation), and cross-linked carboxyterminal teleopeptide of type 1 collagen (a marker of bone resorption) were measured by RIA. BMD was assessed by single photon absorptiometry, and total fat mass was determined by bioimpedance analysis. BMD was inversely associated with serum leptin concentrations and total fat mass after adjustment for body weight. PICP, but not cross-linked carboxyterminal teleopeptide of type 1 collagen, was inversely correlated with serum leptin. These results may suggest that an increase in serum leptin reduces bone formation and decreases BMD in adult men. Leptin may be a regulator of BMD in humans.

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