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Context: The neutral amino acid transporter SLC7A10/ASC-1 is an adipocyte-expressed gene with reduced expression in insulin resistance and obesity. Inhibition of SLC7A10 in adipocytes was shown to increase lipid accumulation despite decreasing insulin-stimulated uptake of glucose, a key substrate for de novo lipogenesis. These data imply that alternative lipogenic substrates to glucose fuel continued lipid accumulation during insulin resistance in obesity., Objective: We examined whether increased lipid accumulation during insulin resistance in adipocytes may involve alter flux of lipogenic amino acids dependent on SLC7A10 expression and activity, and whether this is reflected by extracellular and circulating concentrations of marker metabolites., Methods: In adipocyte cultures with impaired SLC7A10, we performed RNA sequencing and relevant functional assays. By targeted metabolite analyses (GC-MS/MS), flux of all amino acids and selected metabolites were measured in human and mouse adipose cultures. Additionally, SLC7A10 mRNA levels in human subcutaneous adipose tissue (SAT) were correlated to candidate metabolites and adiposity phenotypes in 2 independent cohorts., Results: SLC7A10 impairment altered expression of genes related to metabolic processes, including branched-chain amino acid (BCAA) catabolism, lipogenesis, and glyceroneogenesis. In 3T3-L1 adipocytes, SLC7A10 inhibition increased fatty acid uptake and cellular content of glycerol and cholesterol. SLC7A10 impairment in SAT cultures altered uptake of aspartate and glutamate, and increased net uptake of BCAAs, while increasing the net release of the valine catabolite 3- hydroxyisobutyrate (3-HIB). In human cohorts, SLC7A10 mRNA correlated inversely with total fat mass, circulating triacylglycerols, BCAAs, and 3-HIB., Conclusion: Reduced SLC7A10 activity strongly affects flux of BCAAs in adipocytes, which may fuel continued lipogenesis during insulin resistance, and be reflected in increased circulating levels of the valine-derived catabolite 3-HIB., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Mitochondria are essential for cellular energy homeostasis, yet their role in subcutaneous adipose tissue (SAT) during different types of weight-loss interventions remains unknown., Objective: To investigate how SAT mitochondria change following diet-induced and bariatric surgery-induced weight-loss interventions in 4 independent weight-loss studies., Methods: The DiOGenes study is a European multicenter dietary intervention with an 8-week low caloric diet (LCD; 800 kcal/d; n = 261) and 6-month weight-maintenance (n = 121) period. The Kuopio Obesity Surgery study (KOBS) is a Roux-en-Y gastric bypass (RYGB) surgery study (n = 172) with a 1-year follow-up. We associated weight-loss percentage with global and 2210 mitochondria-related RNA transcripts in linear regression analysis adjusted for age and sex. We repeated these analyses in 2 studies. The Finnish CRYO study has a 6-week LCD (800-1000 kcal/d; n = 19) and a 10.5-month follow-up. The Swedish DEOSH study is a RYGB surgery study with a 2-year (n = 49) and 5-year (n = 37) follow-up., Results: Diet-induced weight loss led to a significant transcriptional downregulation of oxidative phosphorylation (DiOGenes; ingenuity pathway analysis [IPA] z-scores: -8.7 following LCD, -4.4 following weight maintenance; CRYO: IPA z-score: -5.6, all P < 0.001), while upregulation followed surgery-induced weight loss (KOBS: IPA z-score: 1.8, P < 0.001; in DEOSH: IPA z-scores: 4.0 following 2 years, 0.0 following 5 years). We confirmed an upregulated oxidative phosphorylation at the proteomics level following surgery (IPA z-score: 3.2, P < 0.001)., Conclusions: Differentially regulated SAT mitochondria-related gene expressions suggest qualitative alterations between weight-loss interventions, providing insights into the potential molecular mechanistic targets for weight-loss success., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: The joint effects of cardiorespiratory fitness (CRF) and body composition on metabolic health are not well known., Objective: To examine the associations of CRF, fat-free mass index (FFMI), and fat mass index (FMI) with metabolic health in individual twins and controlling for genetic and shared environmental effects by studying monozygotic intrapair differences., Design, Setting, and Participants: Two cross-sectional samples of healthy adult monozygotic and dizygotic twins were drawn from population-based Danish and Finnish national twin registries (n = 996 and n = 309)., Main Measures: CRF was defined as VO2max divided by fat-free mass. Insulin sensitivity and acute insulin response indices were derived from an oral glucose tolerance test. A continuous metabolic syndrome score was calculated. Visceral and liver fat were measured in the Finnish sample. Associations were analyzed separately in both cohorts with multivariate linear regression and aggregated with meta-analytic methods., Results: Insulin sensitivity, acute insulin response, metabolic syndrome score, visceral, and liver fat amount had strong and statistically significant associations with FMI (|β| 0.53 to 0.79), whereas their associations with CRF and FFMI were at most weak (|β| 0.02 to 0.15). The results of the monozygotic intrapair differences analysis showed the same pattern., Conclusions: Although FMI is strongly associated with worsening of metabolic health traits, even after controlling for genetic and shared environmental factors, there was little evidence for the effects of CRF or FFMI on metabolic health. This suggests that changing FMI rather than CRF or FFMI may affect metabolic health irrespective of genetic or early environmental determinants., (Copyright © 2017 by the Endocrine Society)

Context: The associations of body mass index (BMI) and liver fat (LF) with circulating prandial metabolomic markers are incompletely understood., Objective: We aimed to characterize circulating metabolite excursions during an oral glucose tolerance test (OGTT) and evaluate whether the metabolomic signatures of BMI discordance coassociate with LF content., Design, Setting, and Participants: We measured 80 metabolite parameters by nuclear magnetic resonance, together with glucose and insulin, during a 2-hour OGTT in 64 monozygotic (MZ) and 73 dizygotic (DZ) twin pairs (aged 22.8 to 36.2 years). Metabolite excursions during the OGTT were compared within BMI-discordant (intrapair difference, BMI ≥ 3 kg/m2) cotwins separately within MZ and DZ pairs. Insulin-based indices were calculated from the OGTT. LF was measured by magnetic resonance spectroscopy in 25 BMI-discordant MZ pairs. Metabolite profiles were compared with respect to LF discordance (ΔLF% ≥ 2%)., Results: We replicated many previously reported OGTT-induced metabolite excursions in all 274 individuals and report novel lipoprotein excursions. The associations between some metabolite excursions and BMI differed in MZ and DZ twins. In BMI-discordant MZ pairs (mean ΔBMI = 4.9 kg/m2) who were concordant for LF (Δ0.2%), few metabolites differed between the cotwins: very-low-density lipoprotein (VLDL) cholesterol and apolipoprotein B were elevated, and high-density lipoprotein size and concentration were decreased in the cotwins with higher BMI. In contrast, in BMI-discordant MZ pairs (ΔBMI = 6.1 kg/m2) who were discordant for LF (Δ6.8%), cotwins with higher BMI exhibited lower insulin sensitivity and widespread metabolomic differences: elevations in small VLDL and low-density lipoprotein particles, fatty acids (FAs), and isoleucine. Within all 64 MZ twin pairs, lower insulin sensitivity associated with higher levels of VLDLs, triglycerides, FAs, and isoleucine., Conclusions: BMI-discordant MZ twin pairs who also are discordant for LF have more pronounced within-pair differences in metabolomics profiles during an OGTT than BMI-discordant pairs without LF discordance., (Copyright © 2017 by the Endocrine Society)

Context: Sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs) are 2 important nicotinamide adenine dinucleotide (NAD)(+)-dependent enzyme families with opposing metabolic effects. Energy shortage increases NAD(+) biosynthesis and SIRT activity but reduces PARP activity in animals. Effects of energy balance on these pathways in humans are unknown., Objective: We compared NAD(+)/SIRT pathway expressions and PARP activities in sc adipose tissue (SAT) between lean and obese subjects and investigated their change in the obese subjects during a 12-month weight loss., Design, Setting and Participants: SAT biopsies were obtained from 19 clinically healthy obese subjects (mean ± SE body mass index, 34.6 ± 2.7 kg/m(2)) during a weight-loss intervention (0, 5, and 12 mo) and from 19 lean reference subjects (body mass index, 22.7 ± 1.1 kg/m(2)) at baseline., Main Outcome Measures: SAT mRNA expressions of SIRTs 1-7 and the rate-limiting gene in NAD(+) biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT) were measured by Affymetrix, and total PARP activity by ELISA kit., Results: SIRT1, SIRT3, SIRT7, and NAMPT expressions were significantly lower, whereas total PARP activity was increased in obese compared with lean subjects. SIRT1 and NAMPT expressions increased in obese subjects between 0 and 5 months, after a mean weight loss of 11.7%. In subjects who continued to lose weight between 5 and 12 months, SIRT1 expression increased progressively, whereas in subjects with weight regain, SIRT1 reverted to baseline levels. PARP activity significantly decreased in all subjects upon weight loss., Conclusions: Calorie restriction is an attractive strategy to improve the NAD(+)/SIRT pathway and decrease PARPs in SAT in human obesity.

Context: Sirtuins (SIRTs) regulate cellular metabolism and mitochondrial function according to the energy state of the cell reflected by NAD(+) levels., Objective: Our aim was to determine whether expressions of SIRTs and NAD(+) biosynthesis genes are affected by acquired obesity and how possible alterations are connected with metabolic dysfunction while controlling for genetic and familial factors., Design and Participants: We studied a cross-sectional sample of 40 healthy pairs of monozygotic twins, including 26 pairs who were discordant for body mass index (within-pair difference > 3 kg/m(2)), from the FinnTwin12 and FinnTwin16 cohorts., Main Outcome Measures: Subcutaneous adipose tissue (SAT) transcriptomics was analyzed by using Affymetrix U133 Plus 2.0 chips, total SAT (poly-ADP) ribose polymerase (PARP) activity by an ELISA kit, body composition by dual-energy x-ray absorptiometry and magnetic resonance imaging/spectroscopy, and insulin sensitivity by an oral glucose tolerance test., Results: SIRT1, SIRT3, SIRT5, NAMPT, NMNAT2, NMNAT3, and NRK1 expressions were significantly down-regulated and the activity of main cellular NAD(+) consumers, PARPs, trended to be higher in the SAT of heavier co-twins of body mass index-discordant pairs. Controlling for twin-shared factors, SIRT1, SIRT3, NAMPT, NMNAT3, and NRK1 were significantly negatively correlated with adiposity, SIRT1, SIRT5, NMNAT2, NMNAT3, and NRK1 were negatively correlated with inflammation, and SIRT1 and SIRT5 were positively correlated with insulin sensitivity. Expressions of genes involved in mitochondrial unfolded protein response were also significantly down-regulated in the heavier co-twins., Conclusions: Our data highlight a strong relationship of reduced NAD(+)/SIRT pathway expression with acquired obesity, inflammation, insulin resistance, and impaired mitochondrial protein homeostasis in SAT.

Context: Observations in rodents suggest that osteocalcin (OC) participates in glucose metabolism. Based on human studies, it remains unclear whether circulating OC is simply a bone turnover marker (BTM) or also a mediator in interactions between the skeleton and glucose homeostasis., Objective: The objective of the study was to determine the responses of BTMs, including OC, to oral glucose tolerance test (OGTT) in a case-control setting., Design and Patients: Thirty-four normoglycemic young adults [mean age 19 y (SD 2.3)] with severe childhood-onset obesity and their gender- and age-matched nonobese controls underwent a standard 2-hour OGTT., Main Outcome Measures: Glucose, insulin, and six BTMs including total and carboxylated OC (cOC) were determined at baseline and at 30, 60, 90, and 120 minutes during OGTT., Results: The obese and control subjects were similar in height; the mean body mass indices were 40.4 and 21.9 kg/m(2), respectively. The homeostasis model assessment index was 2.7 times greater in the obese subjects. All BTMs, except bone-specific alkaline phophatase, were lower in the obese subjects compared with the controls: the differences at baseline were 40%, 35%, 17%, 31%, and 32% for N-terminal propeptides of type I collagen, cross-linked telopeptides of type I collagen, tartrate-resistant acid phosphatase, total OC, and carboxylated OC (P < .05 for all) after adjusting for whole-body bone area. All BTMs decreased during OGTT. The relative values for the OGTT responses for total, but not for cOC (measured as area under the curve) differed between the two groups (P = .029 and P = .139, respectively): the decrease in total OC during the OGTT was less pronounced in the obese subjects. Responses in other BTMs were similar between the groups. No associations were observed between glucose metabolism and OCs during OGTT with linear regression., Conclusions: Bone turnover markers were substantially lower in obese subjects compared with controls. Total OC and cOC showed less pronounced decrease during the OGTT in obese subjects compared with controls, whereas other BTMs responded similarly in the two groups. The role of OC, if anything, in glucose homeostasis is indirect and may be mediated via other factors than glucose or insulin.

Context: Obesity is associated with increased circulating 17β-estradiol (E₂), but less is known about E₂ concentrations in adipose tissue. In addition to E₂, adipose tissue synthesizes E₂ fatty acyl esters (E₂-FAE)., Objective: The aim was to compare estrogen concentrations and expression of estrogen-converting enzymes in adipose tissue between severely obese men and women., Design and Setting: Tissue samples were obtained during elective surgery in University Central Hospital in the years 2008 through 2011., Patients: We studied 14 men and 22 premenopausal women undergoing bariatric surgery and 10 control women operated for nonmalignant reasons., Interventions: Paired samples were taken from abdominal sc and visceral adipose tissue and serum and analyzed for E₂ and E₂-FAE by fluoroimmunoassay and liquid chromatography-tandem mass spectrometry. mRNA expression of genes was analyzed by quantitative PCR., Results: Compared with men, E₂ levels in sc adipose tissue in obese women were higher, along with higher relative mRNA expression of steroid sulfatase and 17β-hydroxysteroid dehydrogenases 1, 7, and 12. In men, E₂-FAE concentrations in adipose tissue were similar to E₂ but in women significantly lower compared with E₂. Adipose tissue E₂-FAE and serum E₂-FAE levels correlated positively in obese subjects. Serum E₂ did not significantly correlate with E₂ concentration or mRNA expression of genes in adipose tissue in obese men or women., Conclusions: The production of E₂ by the large adipose mass was not reflected by increased circulating E₂ concentrations in severely obese men or women. However, adipose tissue may contribute to concentrations of serum E₂-FAE.

Context: The determinants of serum anti-Müllerian hormone (AMH) levels in adult men remain unclear., Objective: The objective of the study was to investigate the genetic and environmental components in determining postpubertal AMH levels in healthy men., Design and Participants: Serum AMH levels, body mass index (BMI), and fat mass (dual energy x-ray absorptiometry) were measured in 64 healthy male (23 monozygotic and 41 dizygotic) twin pairs., Results: Postpubertal AMH levels were highly genetically determined (broad sense heritability 0.92, 95% confidence interval 0.83-0.96). AMH correlated negatively with BMI (r = -0.26, P = 0.030) and fat mass (r = -0.23, P = 0.048). As AMH, BMI had a high heritability (0.68, 95% confidence interval 0.39-0.83), but no genetic correlation was observed between them., Conclusions: AMH levels in men after puberty are under a strong genetic influence. Twin modeling suggests that AMH and BMI are influenced by different sets of genes.

Context: Emerging as an important metabolic regulator, fibroblast growth factor 21 (FGF21) has gained considerable interest in diabetes and obesity research. The circulating FGF21 concentration is fairly low in normal individuals, but elevated hormone levels may associate with obesity. The determining factors of FGF21 levels in humans are not clear., Objective: Our objective was to study the influence of genetic and acquired components to serum FGF21 variability in healthy young adult twins., Design and Participants: Fasting serum FGF21, lipids, body fat, and oral glucose tolerance test were investigated in 46 monozygotic (MZ) and 75 dizygotic twin pairs aged 22.8-33.1 yr. Subcutaneous, intraabdominal, and liver fat content were measured by magnetic resonance imaging/spectroscopy in a subsample of 24 MZ pairs., Results: Genetic factors contributed moderately (heritability 40%) to circulating serum FGF21 levels. Subjects with high FGF21 concentrations (≥ 250 pg/ml, n = 30) had higher fasting triglycerides, insulin, homeostasis model assessment index, and area under the curve glucose and lower high-density lipoprotein cholesterol but similar measures of overall adiposity (body mass index, body fat percent) than subjects with lower FGF21 (<100 pg/ml, n = 148). Importantly, in the MZ subsample, higher liver fat but not sc or intraabdominal fat content was found in subjects with high FGF21. Furthermore, in analyses controlling for genetic/familial effects in twin pairs, within-pair differences in liver fat (MZ) and triglycerides (dizygotic pairs) were the major acquired factors that correlated with differences in FGF21 concentrations., Conclusions: Genetic factors influence serum FGF21 levels. Of the acquired components, high liver fat and triglycerides rather than overall adiposity associate with high FGF21 levels.

Background: The liver, once fatty, overproduces components of the metabolic syndrome, such as glucose and lipids. The amount of liver fat in subjects with and without the metabolic syndrome has not been determined. It is unknown which clinically available markers best reflect liver fat content., Measurements: Components of the metabolic syndrome as defined by the International Diabetes Federation and liver fat content by proton magnetic resonance spectroscopy were measured in 271 nondiabetic subjects (162 women, 109 men). In addition, other features of insulin resistance (serum insulin, C-peptide), intraabdominal and sc fat by magnetic resonance imaging, and liver enzymes (serum alanine aminotransferase and serum aspartate aminotransferase) were measured., Results: Liver fat was 4-fold higher in subjects with [n = 116; median 8.2% (interquartile range 3.2-18.7%)] than without [n = 155; 2.0% (1.0-5.0%); P < 0.0001] the metabolic syndrome. This increase in liver fat remained significant after adjusting for age, gender, and body mass index. All components of the metabolic syndrome correlated with liver fat content. The best correlate was waist in both women (r = 0.59, P < 0.0001) and men (r = 0.56, P < 0.0001). Liver fat correlated significantly with serum alanine aminotransferase (r = 0.39, P < 0.0001 for women; r = 0.44, P < 0.0001 for men) and aspartate aminotransferase (r = 0.27, P = 0.0005 for women; r = 0.31, P = 0.0012 for men) concentrations. The best correlates of liver fat were fasting serum insulin (r = 0.61; P < 0.0001 for both women and men) and C-peptide (r = 0.62; P < 0.0001 for both women and men)., Conclusions: Liver fat content is significantly increased in subjects with the metabolic syndrome as compared with those without the syndrome, independently of age, gender, and body mass index. Of other markers, serum C-peptide is the strongest correlate of liver fat.

Context: Both acquired and genetic factors regulate adipose tissue function., Objective: We determined whether adipose tissue mRNA expression is regulated by obesity, independently of genetic effects, by studying monozygotic (MZ) twins., Design: Seventeen healthy pairs of MZ twins aged 24-27 yr (body mass index 20.0-33.9 kg/m(2), intrapair differences in body weight 0.1-24.7 kg), were identified from the population-based FinnTwin16 cohort. Body fat percent was determined by dual-energy x-ray absorptiometry, sc and intraabdominal fat by magnetic resonance imaging, liver fat by proton spectroscopy, and insulin sensitivity by using the euglycemic insulin clamp technique. Adipocyte cell size and expression of 10 genes (real-time PCR) were determined in sc adipose tissue biopsies. Serum levels of some of the genes were measured using ELISA., Results: Within MZ twin pairs, acquired obesity was significantly related to increased adipocyte size and increased adipose tissue mRNA expressions of leptin, TNFalpha and the macrophage marker CD68, and decreased mRNA expressions of adiponectin and peroxisome proliferator-activated receptor-gamma. Intrapair differences in liver fat correlated directly with those in leptin and CD68 expression. CD68 expression and serum TNFalpha concentrations were correlated with insulin resistance., Conclusions: Acquired obesity independent of genetic influences is able to increase expression of macrophage and inflammatory markers and decrease adiponectin expression in adipose tissue.

11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) catalyzes the interconversion of inactive cortisone to active cortisol. Overexpression of 11beta-HSD-1 in murine adipose tissue results in glucocorticoid receptor (GR)alpha overexpression, central obesity, and insulin resistance. It is controversial whether 11beta-HSD-1 or GRalpha expression are increased in human adipose tissue in obesity. We studied effects of acquired obesity on 11beta-HSD-1 gene (real-time PCR) and protein (Western blotting) expression in sc adipose tissue in 17 monozygotic twin pairs aged 24-27 yr with a mean intrapair difference in body mass index (BMI) of 3.8 kg/m(2) (range 0.4-10.1 kg/m(2)). Intrapair correlations were calculated to study effects of acquired obesity on 11beta-HSD-1 expression. Western blot analysis of adipose tissue homogenates identified approximately 50- and approximately 68-kDa proteins specific for 11beta-HSD-1. Both structural forms correlated positively with 11beta-HSD-1 mRNA concentrations. Intrapair differences in 11beta-HSD-1 mRNA, and the 50- and 68-kDa proteins in sc adipose tissue correlated positively with those in BMI (kilograms per square meter) (r = 0.78 for 11beta-HSD-1 mRNA, P = 0.0002; r = 0.87 for the 11beta-HSD-1 50-kDa protein, P = 0.0003; and r = 0.62 for the 11beta-HSD-1 68-kDa protein, P = 0.033), total body fat (percent) (r = 0.65, P = 0.005; r = 0.83, P = 0.001; and r = 0.69, P = 0.013, respectively) and sc fat (cubed centimeters) (r = 0.66, P = 0.004; r = 0.94, P = 0.0001; and r = 0.71, P = 0.009, respectively). Furthermore, 11beta-HSD-1 mRNA and 50-kDa protein expression, but not 68-kDa protein expression, correlated positively with intrapair differences in intraabdominal fat mass (cubed centimeters) (r = 0.62, P = 0.008; r = 0.69, P = 0.013; r = 0.48, P = 0.112) and serum fasting insulin concentration (milliunits per liter) (r = 0.76, P = 0.0004; r = 0.60, P = 0.037; and r = 0.43, P = 0.160, respectively). Intrapair differences in GRalpha expression were significantly inversely correlated with those in BMI and total and sc fat mass. In conclusion, expression of 11beta-HSD-1 in sc adipose tissue is increased in human acquired obesity and is closely related to accumulation of sc and intraabdominal fat and features of insulin resistance.