Association of the CPT1B Gene with Skeletal Muscle Fat Infiltration in Afro‐Caribbean Men

Skeletal muscle fat is greater in African ancestry individuals compared with whites, is associated with diabetes, and is a heritable polygenic trait. However, specific genetic factors contributing to skeletal muscle fat in humans remain to be defined. Muscle carnitine palmitoyltransferase‐1B (CPT1B) is a key enzyme in the regulation of skeletal muscle mitochondrial β‐oxidation of long‐chain fatty acids, and as such is a reasonable biological candidate gene for skeletal muscle fat accumulation. Therefore, we examined the association of three nonsynonymous coding variants in CPT1B (G531L, I66V, and S427C; a fourth, A320G, could not be genotyped) and quantitative computed tomography measured tibia skeletal muscle composition and BMI among 1,774 Afro‐Caribbean men aged ≥40, participants of the population‐based Tobago Health Study. For all variants, no significant differences were observed for BMI or total adipose tissue. Among individuals who were homozygous for the minor allele at G531L or I66V, intermuscular adipose tissue (IMAT) was 87% (P = 0.03) and 54% lower (P = 0.03), respectively. In contrast, subcutaneous adipose tissue (SAT) was 11% (P = 0.017) and 7% (P = 0.049) higher, respectively, than among individuals without these genotypes. These associations were independent of age, body size, and muscle area. Finally, no individuals with type 2 diabetes were found among those who were homozygous for the minor allele of either at G531L and I66V whereas 14–18% of men with the major alleles had type 2 diabetes (P = 0.03 and 0.007, respectively). Our results suggest a novel association between common nonsynonymous coding variants in CPT1B and ectopic skeletal muscle fat among middle‐aged and older African ancestry men.     

Skeletal muscle attenuation determined by computed tomography is associated with skeletal muscle lipid content.

The purpose of this investigation was to validate that in vivo measurement of skeletal muscle attenuation (MA) with computed tomography (CT) is associated with muscle lipid content. Single-slice CT scans performed on phantoms of varying lipid concentrations revealed good concordance between attenuation and lipid concentration (r(2) = 0.995); increasing the phantom's lipid concentration by 1 g/100 ml decreased its attenuation by approximately 1 Hounsfield unit (HU). The test-retest coefficient of variation for two CT scans performed in six volunteers was 0.51% for the midthigh and 0.85% for the midcalf, indicating that the methodological variability is low. Lean subjects had significantly higher (P < 0.01) MA values (49.2 +/- 2.8 HU) than did obese nondiabetic (39.3 +/- 7.5 HU) and obese Type 2 diabetic (33.9 +/- 4. 1 HU) subjects, whereas obese Type 2 diabetic subjects had lower MA values that were not different from obese nondiabetic subjects. There was also good concordance between MA in midthigh and midcalf (r = 0.60, P < 0.01), psoas (r = 0.65, P < 0.01), and erector spinae (r = 0.77, P < 0.01) in subsets of volunteers. In 45 men and women who ranged from lean to obese (body mass index = 18.5 to 35.9 kg/m(2)), including 10 patients with Type 2 diabetes mellitus, reduced MA was associated with increased muscle fiber lipid content determined with histological oil red O staining (P = -0.43, P < 0. 01). In a subset of these volunteers (n = 19), triglyceride content in percutaneous biopsy specimens from vastus lateralis was also associated with MA (r = -0.58, P = 0.019). We conclude that the attenuation of skeletal muscle in vivo determined by CT is related to its lipid content and that this noninvasive method may provide additional information regarding the association between muscle composition and muscle function.     

Visceral adiposity is associated with serum retinol binding protein-4 levels in healthy women

Objective: Retinol binding protein‐4 (RBP4) has been reported to impair insulin sensitivity throughout the body. We investigated the relationship between serum RBP4 levels and adiposity indices as well as metabolic risk variables. Research Methods and Procedure: We recruited a total of 102 healthy women 21 to 67 years old. We assessed body composition by computed tomography and divided the study population into four groups based on body weight and visceral fat area (non‐obese without visceral adiposity, non‐obese with visceral adiposity, obese without visceral adiposity, and obese with visceral adiposity). Serum RBP4 levels were measured by radioimmunoassay. Results: Despite similar levels of total body fat, non‐obese women had lower systolic blood pressure, total cholesterol, triglyceride (TG), low‐density lipoprotein (LDL)‐cholesterol levels, insulin resistance indices, and RBP4 levels than non‐obese women with visceral adiposity and had higher high‐density lipoprotein‐cholesterol levels. Similarly, obese women without visceral adiposity had lower blood pressure, total cholesterol, TG levels, insulin resistance indices, and RBP4 levels than obese women with visceral adiposity. In addition, despite having increased body fat, obese women without visceral adiposity had lower TGs, insulin resistance indices, and serum RBP4 levels than non‐obese women with visceral adiposity. By step‐wise multiple regression analysis, visceral fat areas and LDL‐cholesterol levels independently affected RBP4 levels. Discussion: We determined that serum RBP4 levels are independently associated with visceral fat and LDL‐cholesterol levels. These results suggest that, irrespective of body weight, visceral obesity is an independent predictor of serum RBP4 levels, and RBP4 may represent a link between visceral obesity and cardiovascular disease.     

The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity

Proteins secreted from adipose tissue are increasingly recognized to play an important role in the regulation of glucose metabolism. However, much less is known about their effect on lipid metabolism. The fasting-induced adipose factor (FIAF/angiopoietin-like protein 4/peroxisome proliferator-activated receptor gamma angiopoietin-related protein) was previously identified as a target of hypolipidemic fibrate drugs and insulin-sensitizing thiazolidinediones. Using transgenic mice that mildly overexpress FIAF in peripheral tissues we show that FIAF is an extremely powerful regulator of lipid metabolism and adiposity. FIAF overexpression caused a 50% reduction in adipose tissue weight, partly by stimulating fatty acid oxidation and uncoupling in fat. In addition, FIAF overexpression increased plasma levels of triglycerides, free fatty acids, glycerol, total cholesterol, and high density lipoprotein (HDL)-cholesterol. Functional tests indicated that FIAF overexpression severely impaired plasma triglyceride clearance but had no effect on very low density lipoprotein production. The effects of FIAF overexpression were amplified by a high fat diet, resulting in markedly elevated plasma and liver triglycerides, plasma free fatty acids, and plasma glycerol levels, and impaired glucose tolerance in FIAF transgenic mice fed a high fat diet. Remarkably, in mice the full-length form of FIAF was physically associated with HDL, whereas truncated FIAF was associated with low density lipoprotein. In human both full-length and truncated FIAF were associated with HDL. The composite data suggest that via physical association with plasma lipoproteins, FIAF acts as a powerful signal from fat and other tissues to prevent fat storage and stimulate fat mobilization. Our data indicate that disturbances in FIAF signaling might be involved in dyslipidemia.     

Polymorphism of rs873308 near the transmembrane protein 57 gene is associated with serum lipid levels

SNP (single-nucleotide polymorphism) of rs10903129 near the TMEM (transmembrane protein) 57 locus has been associated with TC (total cholesterol) in a previous GWAS (genome-wide association study), but the association of TMEM57 rs873308 SNP and serum lipid levels has not been previously reported. The current study was undertaken to detect the association of the TMEM57 rs873308 SNP and several environmental factors with serum lipid profiles in the Han Chinese and Mulao populations. The genotypes of the TMEM57 rs873308 SNP in 865 individuals of Han Chinese and 902 participants of Mulao nationality were determined by PCR and RFLP (restriction-fragment-length polymorphism) combined with gel electrophoresis and then confirmed by direct sequencing. The T allele frequency of TMEM57 rs873308 SNP was not different between Han and Mulao (23.18% versus 25.72%, P>0.05), but different between males and females in the two ethnic groups (P<0.05). The T allele carriers had lower serum TC, Apo (apolipoprotein) B, HDL-C (high-density lipoprotein cholesterol) levels, ApoA1/ApoB ratio in Han; and lower TAG (triacylglycerol), LDL-C (low-density lipoprotein cholesterol), ApoA1 levels and the ApoA1/ApoB ratio and higher HDL-C levels in Mulao than the T allele non-carriers. There was also different association of the TMEM57 rs873308 SNP and serum lipid profiles between males and females in the both ethnic groups. Serum lipid parameters in the two ethnic groups were also associated with several environmental factors. The association of the TMEM57 rs873308 SNP and serum lipid levels was different in the Han Chinese and Mulao populations and between males and females in the both ethnic groups. There may be a sex-specific association of the TMEM57 rs873308 SNP and serum lipid levels in our study populations.     

Skeletal muscle apoptosis after burns is associated with activation of proapoptotic signals

Critical illness is associated with muscle wasting and muscle weakness. Using burn injury as a model of local and systemic inflammatory response, we tested the hypothesis that thermal injury causes apoptosis in muscle. After a 40% body surface area burn to rats, abdominal muscles beneath the burn and limb muscles distant from the burn were examined for apoptosis at varying times after burn. Ladder assay, ELISA, and histological methods showed evidence of apoptosis in the abdominal muscles within 4-12 h with peak changes occurring at 3-7 days. Maximal apoptosis was also evident at distant limb muscles at 3-7 days. Investigation of proapoptotic pathways indicated mitochondrial membrane potential to be altered by 1 h after burn. Starting at 15 min after burn, cytochrome c was released from the mitochondria into the cytosol, followed by increased activity of caspase-3, starting at 6 h after burn. These studies suggest that mitochondria and caspase-mediated apoptotic pathways may be an additional mechanism of muscle weight loss in burns and may be potential therapeutic targets for prevention of muscle wasting.     

Testosterone-induced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy

Administration of replacement doses of testosterone to healthy hypogonadal men and supraphysiological doses to eugonadal men increases muscle size. To determine whether testosterone-induced increase in muscle size is due to muscle fiber hypertrophy, 61 healthy men, 18-35 yr of age, received monthly injections of a long-acting gonadotropin-releasing hormone (GnRH) agonist to suppress endogenous testosterone secretion and weekly injections of 25, 50, 125, 300, or 600 mg testosterone enanthate (TE) for 20 wk. Thigh muscle volume was measured by magnetic resonance imaging (MRI) scan, and muscle biopsies were obtained from vastus lateralis muscle in 39 men before and after 20 wk of combined treatment with GnRH agonist and testosterone. Administration of GnRH agonist plus TE resulted in mean nadir testosterone concentrations of 234, 289, 695, 1,344, and 2,435 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Graded doses of testosterone administration were associated with testosterone dose and concentration-dependent increase in muscle volume measured by MRI (changes in vastus lateralis volume, -4, +7, +15, +32, and +48 ml at 25-, 50-, 125-, 300-, and 600-mg doses, respectively). Changes in cross-sectional areas of both type I and II fibers were dependent on testosterone dose and significantly correlated with total (r = 0.35, and 0.44, P < 0.0001 for type I and II fibers, respectively) and free (r = 0.34 and 0.35, P < 0.005) testosterone concentrations during treatment. The men receiving 300 and 600 mg of TE weekly experienced significant increases from baseline in areas of type I (baseline vs. 20 wk, 3,176 +/- 186 vs. 4,201 +/- 252 microm(2), P < 0.05 at 300-mg dose, and 3,347 +/- 253 vs. 4,984 +/- 374 microm(2), P = 0.006 at 600-mg dose) muscle fibers; the men in the 600-mg group also had significant increments in cross-sectional area of type II (4,060 +/- 401 vs. 5,526 +/- 544 microm(2), P = 0.03) fibers. The relative proportions of type I and type II fibers did not change significantly after treatment in any group. The myonuclear number per fiber increased significantly in men receiving the 300- and 600-mg doses of TE and was significantly correlated with testosterone concentration and muscle fiber cross-sectional area. In conclusion, the increases in muscle volume in healthy eugonadal men treated with graded doses of testosterone are associated with concentration-dependent increases in cross-sectional areas of both type I and type II muscle fibers and myonuclear number. We conclude that the testosterone induced increase in muscle volume is due to muscle fiber hypertrophy.     

Skeletal muscle fiber quality in older men and women

Wholemuscle strength and cross-sectional area (WMCSA), andcontractile properties of chemically skinned segments from single fibers of the quadriceps were studied in 7 young men (YM, 36.5 ± 3.0 yr), 12 older men (OM, 74.4 ± 5.9 yr), and 12 olderwomen (OW, 72.1 ± 4.3 yr). WMCSA was smaller in OMcompared with YM (56.1 ± 10.1 vs. 79.7 ± 13.1 cm²; P = 0.031) and in OW (44.9 ± 7.5; P < 0.003) compared with OM. Age-related, but notsex-related, differences in strength were eliminated after adjustingfor WMCSA. Maximal force was measured in 552 type I and 230 type IIAfibers. Fibers from YM (type I = 725 ± 221; type IIA = 792 ± 271 µN) were stronger (P < 0.001) thanfibers from OM (I = 505 ± 179; IIA = 577 ± 262 µN) even after correcting for size. Type IIA fibers were stronger(P < 0.005) than type I fibers in YM and OM but not inOW (I = 472 ± 154; IIA = 422 ± 97 µN).Sex-related differences in type I and IIA fibers were dependent onfiber size. In conclusion, differences in WMCSA explain age-relateddifferences in strength. An intrinsic defect in contractile proteinscould explain weakness in single fibers from OM. Sex-relateddifferences exist at the whole muscle and single fiber levels.

     

Characterization and quantification of serum lipoprotein subfractions by capillary isotachophoresis: relationships with lipid, apolipoprotein, and lipoprotein levels.

Human serum lipoproteins are currently defined according to their density as well as according to their electrophoretic mobility. They can be fractionated into discrete subspecies which exhibit variations in their structure and function. Capillary electrophoresis has been suggested to be a potential analytical strategy in understanding metabolic lipoprotein heterogeneity. In a sample of 35 normolipidemic subjects, we analyzed ceramide-labeled serum lipoproteins by capillary isotachophoresis linked to laser-induced fluorescent detection. Capillary isotachophoresis showed advantage to be an automated, rapid (6 min) and reproducible (CV < 7%) separation mode, on-line monitoring lipoprotein subfractions according to net charge. HDL were separated into three subfractions: i) the fast migrating HDL correlated positively with serum apoA-I (P < 0.05) and negatively with triglyceride (P < 0.01) concentrations, ii) the intermediate migrating HDL involved in HDL-cholesterol delivery and inversely related to LDL particles concentration (P < 0.001), and iii) the slow migrating prebeta(1)HDL. Triglyceride level was significantly associated with two fractions: i) the VLDL fraction correlated positively with apoE serum concentration (P < 0.01), and ii) the IDL fraction closely and positively associated with apoC-III-containing lipoprotein level (P < 0.001). Two LDL subfractions were positively related to LDL-cholesterol (0.05 相似文献   

Visceral obesity is associated with high levels of serum squalene

Objective: To investigate the impact of visceral obesity on cholesterol metabolism in normoglycemic offspring of patients with type 2 diabetes. Research Methods and Procedures: The proportion of intra‐abdominal fat (IAF) was measured by abdominal computer tomography, and serum cholesterol synthesis and absorption markers were determined by gas‐liquid chromatography in 109 normoglycemic offspring of patients with type 2 diabetes. Insulin action was measured with the hyperinsulinemic euglycemic clamp. The gene encoding squalene synthase (farnesyl‐diphosphate farnesyltransferase 1) was screened with the single‐strand conformation polymorphism analysis and direct sequencing. Results: Cholesterol synthesis markers correlated positively with IAF (r = 0.213 to 0.309, p ≤ 0.027) and negatively with the rates of insulin‐stimulated whole‐body glucose uptake (r = ?0.372 to ?0.248, p ≤ 0.010). However, serum squalene, the first measured precursor of cholesterol synthesis, showed a positive correlation with IAF (r = 0.309, p = 0.001) without any association with subcutaneous fat or insulin sensitivity. Variation in the farnesyl‐diphosphate farnesyltransferase 1 gene did not explain elevated serum squalene levels in viscerally obese subjects. From the cholesterol absorption markers, cholestanol was associated negatively with IAF and positively with whole‐body glucose uptake (p < 0.05). Discussion: High serum squalene levels are associated with visceral obesity but not with subcutaneous obesity. Whether this finding is causally connected to visceral obesity remains to be established.     

Telling facial metrics: facial width is associated with testosterone levels in men

High facial width-to-height ratio (fWHR) has been associated with a cluster of behavioural traits in men, including aggression and status-striving. This association between face structure and behaviour may be caused by testosterone. Here we investigated the relationship of both baseline and reactive testosterone levels to fWHR. In addition, we investigated the link between testosterone and three well-characterised sexually dimorphic facial metrics. Testosterone was measured in one sample of males (n = 185) before and after a speed-dating event. An additional sample provided only baseline testosterone measures (n = 92). fWHR was positively associated with testosterone reactions to potential mate exposure and marginally associated with baseline testosterone in Sample 1. We found a positive association with baseline testosterone and fWHR in Sample 2. In addition, face-width-to-lower-height ratio was positively associated with testosterone in both samples, suggesting that, in particular, facial width (scaled by two measures of facial height) is associated with testosterone. Importantly, our results also indicate that there is no association between adult testosterone and the sexual dimorphism of face shape. Thus, while our findings question the status of sexual dimorphism as a proxy measure of testosterone, they do provide evidence that testosterone is linked to fWHR and might underlie the relationship between fWHR and behaviour.     

Intestinal permeability is associated with visceral adiposity in healthy women

Increased visceral fat, as opposed to subcutaneous/gluteal, most strongly relates to key metabolic dysfunctions including insulin resistance, hepatic steatosis, and inflammation. Mesenteric fat hypertrophy in patients with Crohn's disease and in experimental rodent models of gut inflammation suggest that impaired gut barrier function with increased leakage of gut-derived antigens may drive visceral lipid deposition. The aim of this study was to determine whether increased intestinal permeability is associated with visceral adiposity in healthy humans. Normal to overweight female subjects were recruited from a population-based cohort. Intestinal permeability was assessed using the ratio of urinary excretion of orally ingested sucralose to mannitol (S/M). In study 1 (n = 67), we found a positive correlation between waist circumference and S/M excretion within a time frame of urine collection consistent with permeability of the lower gastrointestinal tract (6-9 hours post-ingestion; P = 0.022). These results were followed up in study 2 (n = 55) in which we used computed tomography and dual energy X-ray absorptiometry to measure visceral and subcutaneous fat areas of the abdomen, liver fat content, and total body fat of the same women. The S/M ratio from the 6-12 h urine sample correlated with visceral fat area (P = 0.0003) and liver fat content (P = 0.004), but not with subcutaneous or total body fat. This novel finding of an association between intestinal permeability and visceral adiposity and liver fat content in healthy humans suggests that impaired gut barrier function should be further explored as a possible mediator of excess visceral fat accumulation and metabolic dysfunction.     

Ethnic-specific differences in vitamin d status is associated with adiposity

Background

Low circulating 25 hydroxyvitamin D [25(OH)D] concentrations are common in obesity (BMI ≥30 kg/m²) and a negative relationship with body fat distribution has recently been reported. Ethnic-specific differences in body fat distribution have been described with South Asians are reported to have greater visceral adipose tissue (VAT), which could influence circulating 25(OH)D concentrations. The objective of this study is to investigate the relationship between plasma 25(OH)D, adiposity, and body fat distribution in Europeans and South Asians.

Methods/Principal Findings

187 Europeans and 192 South Asians were assessed for demographics, anthropometrics, and plasma 25(OH)D concentrations. Subcutaneous adipose tissue (SAT) and VAT were quantified by CT scan, and percent body fat by DEXA. Data were assessed by general linear models. South Asians had lower (P<0.001) plasma 25(OH)D concentrations and higher VAT (P = 0.04) than Europeans. Plasma 25(OH)D concentrations were negatively (P<0.05) associated with BMI, waist circumference, percent body fat, total adipose tissue, VAT, and SAT in unadjusted models and negatively (P<0.05) associated with VAT, SAT, and percent body fat after adjusting for BMI, ethnicity, age, and season of blood collection in males and females. When percent body fat, VAT, and SAT were included in the same model, only VAT remained negatively (P<0.05) associated with plasma 25(OH)D concentrations. Ethnicity remained significant in all models (P<0.001).

Conclusion

Compared to other adipose tissue compartments, VAT may have a distinct role in determining plasma 25(OH)D concentrations, which may account for the lower levels in South Asians.     

Adropin deficiency is associated with increased adiposity and insulin resistance

Adropin is a secreted peptide that improves hepatic steatosis and glucose homeostasis when administered to diet-induced obese mice. It is not clear if adropin is a peptide hormone regulated by signals of metabolic state. Moreover, the significance of a decline in adropin expression with obesity with respect to metabolic disease is also not clear. We investigated the regulation of serum adropin by metabolic status and diet. Serum adropin levels were high in chow-fed conditions and were suppressed by fasting and diet-induced obesity (DIO). High adropin levels were observed in mice fed a high-fat low carbohydrate diet, whereas lower levels were observed in mice fed a low-fat high carbohydrate diet. To investigate the role of adropin deficiency in metabolic homeostasis, we generated adropin knockout mice (AdrKO) on the C57BL/6J background. AdrKO displayed a 50%-increase in increase in adiposity, although food intake and energy expenditure were normal. AdrKO also exhibited dyslipidemia and impaired suppression of endogenous glucose production (EndoR(a)) in hyperinsulinemic-euglycemic clamp conditions, suggesting insulin resistance. While homo- and heterozygous carriers of the null adropin allele exhibited normal DIO relative to controls, impaired glucose tolerance associated with weight gain was more severe in both groups. In summary, adropin is a peptide hormone regulated by fasting and feeding. In fed conditions, adropin levels are regulated dietary macronutrients, and increase with dietary fat content. Adropin is not required for regulating food intake, however, its functions impact on adiposity and are involved in preventing insulin resistance, dyslipidemia, and impaired glucose tolerance.     

Cholesterol ester transfer protein gene is associated with high-density lipoprotein cholesterol levels in Korean population

High-density lipoprotein (HDL) cholesterol levels are associated with decreased risk of coronary artery disease. Several genome-wide association studies (GWAS) for HDL cholesterol levels have implicated cholesterol ester transfer protein (CETP) as possibly causal. We tested for the association between single nucleotide polymorphisms (SNPs) in CETP gene and HDL cholesterol levels in Korean population. A total of 979 subjects in Seoul City were genotyped using a genome-wide marker panel for a discovery study. Another 2,277 subjects in Bundang-Gu in Korea were used for a replication study with selected markers. In the discovery phase, the top SNP associated with mean HDL cholesterol levels was rs6499861 in the CETP gene on chromosome 16 (p=1.18×10^?6 in the Seoul City sample, p=8.91×10^?3 in the Bundang-Gu sample). Another SNP (rs6499863) in the CETP gene was also among the top five SNPs associated with HDL cholesterol levels (p=3.83×10^?5 in the Seoul City sample, p=3.29×10^?3 in the Bundang-Gu sample). SNP rs1800775 was also associated with HDL cholesterol levels (p=4.86×10^?4 in meta-analysis results of 3256 samples). This study clearly demonstrates that genetic variants in CETP influence HDL cholesterol levels in Korean adults.     

Lipoprotein lipase gene variation is associated with adipose tissue lipoprotein lipase activity, and lipoprotein lipid and glucose concentrations in overweight postmenopausal women

Adipose tissue lipoprotein lipase (LPL) activity is under strong genetic control in both mice and humans. This study determines whether common DNA variation in the LPL gene (PvuII and HindIII polymorphisms) is associated with adipose tissue LPL activity and metabolic risk factors in a homogeneous population of 75 overweight postmenopausal women (body mass index >25 kg/m2; age: 51-69 years old). The allele frequencies for the presence of the cut-sites for LPL HindIII and PvuII were 0.71 and 0.49, respectively. There were no associations between the HindIII polymorphism and any of the measured variables. Age, body mass index, percent body fat, waist-hip ratio, visceral and subcutaneous fat area, and gluteal (GLT) and abdominal (ABD) adipocyte size did not differ by LPL PvuII genotype. However, adipose tissue LPL activity at both GLT and ABD sites was higher in women without the LPL PvuII cut-site (-/-) compared with women who were heterozygous (+/-) or homozygous (+/+) for the cut-site (P<0.05). Total and LDL cholesterol were lower in women without the LPL PvuII cut-site (-/-) compared with women who were heterozygous or homozygous for the cut-site (P<0.05), whereas triglyceride and HDL levels were similar between LPL PvuII genotypes. Fasting glucose, but not insulin, was lower in women without the LPL PvuII cut-site (-/-). These data suggest that the LPL PvuII polymorphism is a possible marker for a functional mutation that is found in the LPL gene and that alters LPL activity in older overweight women.