Differential Mitochondrial Gene Expression in Adipose Tissue Following Weight Loss Induced by Diet or Bariatric Surgery.

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.

Plasma Proteomics Analysis Reveals Dysregulation of Complement Proteins and Inflammation in Acquired Obesity-A Study on Rare BMI-Discordant Monozygotic Twin Pairs.

PURPOSE: The purpose of this study is to elucidate the effect of excess body weight and liver fat on the plasma proteome without interference from genetic variation. EXPERIMENTAL DESIGN: The effect of excess body weight is assessed in young, healthy monozygotic twins from pairs discordant for body mass index (intrapair difference (Δ) in BMI > 3 kg m-2 , n = 26) with untargeted LC-MS proteomics quantification. The effect of liver fat is interrogated via subgroup analysis of the BMI-discordant twin cohort: liver fat discordant pairs (Δliver fat > 2%, n = 12) and liver fat concordant pairs (Δliver fat < 2%, n = 14), measured by magnetic resonance spectroscopy. RESULTS: Seventy-five proteins are differentially expressed, with significant enrichment for complement and inflammatory response pathways in the heavier co-twins. The complement dysregulation is found in obesity in both the liver fat subgroups. The complement and inflammatory proteins are significantly associated with adiposity measures, insulin resistance and impaired lipids. CONCLUSIONS AND CLINICAL RELEVANCE: The early pathophysiological mechanisms in obesity are incompletely understood. It is shown that aberrant complement regulation in plasma is present in very early stages of clinically healthy obese persons, independently of liver fat and in the absence of genetic variation that typically confounds human studies.

Upregulation of Early and Downregulation of Terminal Pathway Complement Genes in Subcutaneous Adipose Tissue and Adipocytes in Acquired Obesity.

Inflammation is an important mediator of obesity-related complications such as the metabolic syndrome but its causes and mechanisms are unknown. As the complement system is a key mediator of inflammation, we studied whether it is activated in acquired obesity in subcutaneous adipose tissue (AT) and isolated adipocytes. We used a special study design of genetically matched controls of lean and heavy groups, rare monozygotic twin pairs discordant for body mass index (BMI) [n = 26, within-pair difference (Δ) in body mass index, BMI >3 kg/m2] with as much as 18 kg mean Δweight. Additionally, 14 BMI-concordant (BMI <3 kg/m2) served as a reference group. The detailed measurements included body composition (DEXA), fat distribution (MRI), glucose, insulin, adipokines, C3a and SC5b-9 levels, and the expression of complement and insulin signaling pathway-related genes in AT and adipocytes. In both AT and isolated adipocytes, the classical and alternative pathway genes were upregulated, and the terminal pathway genes downregulated in the heavier co-twins of the BMI-discordant pairs. The upregulated genes included C1q, C1s, C2, ficolin-1, factor H, receptors for C3a and C5a (C5aR1), and the iC3b receptor (CR3). While the terminal pathway components C5 and C6 were downregulated, its inhibitor clusterin was upregulated. Complement gene upregulation in AT and adipocytes correlated positively with adiposity and hyperinsulinemia and negatively with the expression of insulin signaling-related genes. Plasma C3a, but not SC5b-9, levels were elevated in the heavier co-twins. There were no differences between the co-twins in BMI-concordant pairs. Obesity is associated with increased expression of the early, but not late, complement pathway components and of key receptors. The twins with acquired obesity have therefore an inflated inflammatory activity in the AT. The results suggest that complement is likely involved in orchestrating clearance of apoptotic debris and inflammation in the AT.

Liver Fat and Insulin Sensitivity Define Metabolite Profiles During a Glucose Tolerance Test in Young Adult Twins.

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.

Abdominal obesity and circulating metabolites: A twin study approach.

OBJECTIVE: To investigate how obesity, insulin resistance and low-grade inflammation link to circulating metabolites, and whether the connections are due to genetic or environmental factors. SUBJECTS AND METHODS: Circulating serum metabolites were determined by proton NMR spectroscopy. Data from 1368 (531 monozygotic (MZ) and 837 dizygotic (DZ)) twins were used for bivariate twin modeling to derive the genetic (rg) and environmental (re) correlations between waist circumference (WC) and serum metabolites. Detailed examination of the associations between fat distribution (DEXA) and metabolic health (HOMA-IR, CRP) was performed among 286 twins including 33 BMI-discordant MZ pairs (intrapair BMI difference ≥3 kg/m(2)). RESULTS: Fat, especially in the abdominal area (i.e. WC, android fat % and android to gynoid fat ratio), together with HOMA-IR and CRP correlated significantly with an atherogenic lipoprotein profile, higher levels of branched-chain (BCAA) and aromatic amino acids, higher levels of glycoprotein, and a more saturated fatty acid profile. In contrast, a higher proportion of gynoid to total fat associated with a favorable metabolite profile. There was a significant genetic overlap between WC and several metabolites, most strongly with phenylalanine (rg=0.40), glycoprotein (rg=0.37), serum triglycerides (rg=0.36), BCAAs (rg=0.30-0.40), HDL particle diameter (rg=-0.33) and HDL cholesterol (rg=-0.30). The effect of acquired obesity within the discordant MZ pairs was particularly strong for atherogenic lipoproteins. CONCLUSIONS: A wide range of unfavorable alterations in the serum metabolome was associated with abdominal obesity, insulin resistance and low-grade inflammation. Twin modeling and obesity-discordant twin analysis suggest that these associations are partly explained by shared genes but also reflect mechanisms independent of genetic liability.

Weight Loss Is Associated With Increased NAD(+)/SIRT1 Expression But Reduced PARP Activity in White Adipose Tissue.

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.

Agreement of bioelectrical impedance with dual-energy X-ray absorptiometry and MRI to estimate changes in body fat, skeletal muscle and visceral fat during a 12-month weight loss intervention.

The aim of the present study was to analyse the agreement of bioelectrical impedance analysis (BIA) compared with dual-energy X-ray absorptiometry (DXA) and MRI in estimating body fat, skeletal muscle and visceral fat during a 12-month weight loss intervention. A total of nineteen obese adults (twelve females, seven males) aged 20·2-48·6 years, mean BMI 34·6 (SE 0·6) kg/m², participated in the study. Body fat, skeletal muscle and visceral fat index were measured by BIA (Omron BF-500; Omron Medizintechnik) and compared with DXA (body fat and skeletal muscle) at baseline, 5 and 12 months, and with MRI (visceral fat) at baseline and 5 months. The subjects lost 8·9 (SE 1·8) kg (9·0 (SE 1·7) %) of body weight during the 12-month intervention. BIA, as compared to DXA, accurately assessed loss of fat (7·0 (SE 1·5) v. 7·0 (SE 1·4) kg, P= 0·94) and muscle (1·0 (SE 0·2) v. 1·4 (SE 0·3) kg, P= 0·18). While body fat was similar by the two methods, skeletal muscle was underestimated by 1-2 kg using BIA at each time point. Compared to MRI, BIA overestimated visceral fat, especially in males. BIA and DXA showed high correlations for kg fat, both cross-sectionally and longitudinally (r 0·91-0·99). BIA, compared with DXA and MRI, detected kg muscle and visceral fat more accurately cross-sectionally (r 0·77-0·87 and r 0·40-0·78, respectively) than their changes longitudinally (r 0·24-0·61 and r 0·46, respectively). BIA is at its best when assessing the amount or changes in fat mass. It is a useful method for measuring skeletal muscle, but limited in its ability to measure visceral fat.

Obesity-related derangements of coagulation and fibrinolysis: a study of obesity-discordant monozygotic twin pairs.

Coagulation and fibrinolytic activities are under strong genetic control. We studied the effects of acquired obesity, independent of genetic factors on coagulation and fibrinolysis activities in obesity-discordant healthy monozygotic (MZ) twin pairs. Fourteen obesity-discordant (BMI within-pair difference >3 kg/m(2)) and 10 concordant (BMI difference <2 kg/m(2)) MZ twin pairs were identified from the nationwide FinnTwin16 study. Body composition (dual-energy x-ray absorptiometry), abdominal fat distribution (magnetic resonance imaging), liver fat (magnetic resonance spectroscopy), high sensitivity C-reactive protein, insulin sensitivity (euglycemic hyperinsulinemic clamp), and a panel of different markers of blood coagulation and fibrinolysis in the fasting state were measured. Strong resemblance was observed in most coagulation factors within all twin pairs, with the intraclass correlations ranging from 0.73 to 0.97, P < 0.03. However, the activities of fibrinogen and FIX, FXI, and FXII, and plasminogen activator inhibitor-1 (PAI-1) activities were increased in the obese co-twins (P < 0.05) and strongly correlated with the measures of adiposity, inflammation, and insulin resistance (r = 0.32-0.73, P < 0.05) among the twin individuals. Intrapair differences in fibrinogen and PAI-1 correlated with those in BMI, adiposity, and fasting insulin levels (r = 0.40-0.58, P < 0.05) indicating the independent effect of obesity. Derangements of blood coagulation and fibrinolysis are present already in early adulthood in obese subjects. Acquired obesity, independent of genetic factors, increases the activities of fibrinogen and activities of FIX, FXI, FXII, and PAI-1. This study confirms the mechanisms of simultaneous activities of intrinsic coagulation factors and impaired fibrinolysis predisposing obese subjects to thrombosis.