F13A1 transglutaminase expression in human adipose tissue increases in acquired excess weight and associates with inflammatory status of adipocytes.

OBJECTIVE: F13A1/FXIII-A transglutaminase has been linked to adipogenesis in cells and to obesity in humans and mice, however, its role and associated molecular pathways in human acquired excess weight have not been explored. METHODS: We examined F13A1 expression and association to human weight gain in weight-discordant monozygotic twins (Heavy-Lean difference (ΔWeight, 16.8 kg ± 7.16 for n = 12). The twin pairs were examined for body composition (by dual-energy X-ray absorptiometry), abdominal body fat distribution (by magnetic resonance imaging), liver fat content (by magnetic resonance spectroscopy), circulating adipocytokines, leptin and adiponectin, as well as serum lipids. Affymetrix full transcriptome mRNA analysis was performed from adipose tissue and adipocyte-enriched fractions from subcutaneous abdominal adipose tissue biopsies. F13A1 differential expression between the heavy and lean co-twins was examined and its correlation transcriptome changes between co-twins were performed. RESULTS: F13A1 mRNA showed significant increase in adipose tissue (p < 0.0001) and an adipocyte-enriched fraction (p = 0.0012) of the heavier co-twin. F13A1 differential expression in adipose tissue (Heavy-Lean ΔF13A1) showed significant negative correlation with circulating adiponectin (p = 0.0195) and a positive correlation with ΔWeight (p = 0.034), ΔBodyFat (0.044) and ΔAdipocyte size (volume, p = 0.012;) in adipocyte-enriched fraction. A whole transcriptome-wide association study (TWAS) on ΔF13A1 vs weight-correlated ΔTranscriptome identified 182 F13A1-associated genes (r > 0.7, p = 0.05) with functions in several biological pathways including cell stress, inflammatory response, activation of cells/leukocytes, angiogenesis and extracellular matrix remodeling. F13A1 did not associate with liver fat accumulation. CONCLUSIONS: F13A1 levels in adipose tissue increase with acquired excess weight and associate with pro-inflammatory, cell stress and tissue remodeling pathways. This supports its role in expansion and inflammation of adipose tissue in obesity.

Subcutaneous adipose tissue gene expression and DNA methylation respond to both short- and long-term weight loss.

BACKGROUND: Few studies have examined both gene expression and DNA methylation profiles in subcutaneous adipose tissue (SAT) during long-term weight loss. Thus, molecular mechanisms in weight loss and regain remain elusive. PARTICIPANTS/METHODS: We performed a 1-year weight loss intervention on 19 healthy obese participants (mean body mass index (BMI) 34.6 kg m-2) and studied longitudinal gene expression (Affymetrix Human Genome U133 Plus 2.0) and DNA methylation (Infinium HumanMethylation450 BeadChip) in SAT at 0, 5 and 12 months. To examine whether weight loss and acquired obesity produce reciprocal profiles, we verified our findings in 26 BMI-discordant monozygotic twin pairs. RESULTS: We found altered expression of 69 genes from 0 to 5' months (short-term) weight loss. Sixty of these genes showed reversed expression in acquired obesity (twins). Altogether 21/69 genes showed significant expression-DNA methylation correlations. Pathway analyses revealed increased high-density lipoprotein-mediated lipid transport characteristic to short-term weight loss. After the fifth month, two groups of participants evolved: weight losers (WLs) and weight regainers (WRs). In WLs five genes were differentially expressed in 5 vs 12 months, three of which significantly correlated with methylation. Signaling by insulin receptor pathway showed increased expression. We further identified 35 genes with differential expression in WLs from 0 to 12 months (long-term) weight loss, with 20 showing opposite expression patterns in acquired obesity, and 16/35 genes with significant expression-DNA methylation correlations. Pathway analyses demonstrated changes in signal transduction, metabolism, immune system and cell cycle. Notably, seven genes (UCHL1, BAG3, TNMD, LEP, BHMT2, EPDR1 and OSTM1) were found to be downregulated during both short- and long-term weight loss. CONCLUSIONS: Our study indicates short- and long-term weight loss influences in transcription and DNA methylation in SAT of healthy participants. Moreover, we demonstrate that same genes react in an opposite manner in weight loss and acquired obesity.

Adipose tissue mitochondrial capacity associates with long-term weight loss success.

OBJECTIVES: We investigated whether (1) subcutaneous adipose tissue (SAT) mitochondrial capacity predicts weight loss success and (2) weight loss ameliorates obesity-related SAT mitochondrial abnormalities. METHODS: SAT biopsies were obtained from 19 clinically healthy obese subjects (body mass index (BMI) 34.6±2.7 kg m-2) during a weight loss intervention (0, 5 and 12 months) and from 19 lean reference subjects (BMI 22.7±1.1 kg m-2) at baseline. Based on 1-year weight loss outcome, the subjects were divided into two groups: continuous weight losers (WL, n=6) and weight regainers (WR, n=13). Main outcome measures included SAT mitochondrial pathways from transcriptomics, mitochondrial amount (mitochondrial DNA (mtDNA), Porin protein levels), mtDNA-encoded transcripts, oxidative phosphorylation (OXPHOS) proteins, and plasma metabolites of the mitochondrial branched-chain amino-acid catabolism (BCAA) pathway. SAT and visceral adipose tissue (VAT) glucose uptake was measured with positron emission tomography. RESULTS: Despite similar baseline clinical characteristics, SAT in the WL group exhibited higher gene expression level of nuclear-encoded mitochondrial pathways (P=0.0224 OXPHOS, P=0.0086 tricarboxylic acid cycle, P=0.0074 fatty acid beta-oxidation and P=0.0122 BCAA), mtDNA transcript COX1 (P=0.0229) and protein level of Porin (P=0.0462) than the WR group. Many baseline mitochondrial parameters correlated with WL success, and with SAT and VAT glucose uptake. During WL, the nuclear-encoded mitochondrial pathways were downregulated, together with increased plasma metabolite levels of BCAAs in both groups. MtDNA copy number increased in the WR group at 5 months (P=0.012), but decreased to baseline level between 5 and 12 months (P=0.015). The only significant change in the WL group for mtDNA was a reduction between 5 and 12 months (P=0.004). The levels of Porin did not change in either group upon WL. CONCLUSIONS: Higher mitochondrial capacity in SAT predicts good long-term WL success. WL does not ameliorate SAT mitochondrial downregulation and based on pathway expression, may paradoxically further reduce it.Data availability:The transcriptomics data generated in this study have been deposited to the Gene Expression Omnibus public repository, accession number GSE103769.

Physical activity, cardiorespiratory fitness, and metabolic outcomes in monozygotic twin pairs discordant for body mass index.

This study aims to investigate (i) how monozygotic (MZ) twin pairs who are discordant for body mass index (BMI) differ for objectively and subjectively measured physical activity (PA) and cardiorespiratory fitness (VO2 max) and (ii) associations of PA and VO2 max with adiposity and measures of metabolic health, in individual twins and independent of genetic and shared environmental effects within twin pairs. We examined 27 BMI-discordant and 14 BMI-concordant MZ twin pairs. Fat and fat-free mass (ffm) were measured by dual-energy X-ray absorptiometry and VO2 max by spiroergometry. PA was measured objectively by accelerometers using ActiGraph GT1M for daytime activity and Actiwatch AW7 for 24 h/d. Self-reported PA was obtained through the Baecke and IPAQ long-form questionnaires. Objectively measured moderate-to-vigorous PA (MVPA, min/d), steps/d, and VO2 max/kg were significantly lower, by 30%, 21%, and 14%, respectively, in the heavier compared with the leaner co-twins of the BMI-discordant twin pairs. There were no significant differences in self-reported PA or VO2 max/ffm. As expected, PA and VO2 max/ffm were similar in the BMI-concordant co-twins. Furthermore, the 24-h recording of activity suggested that the heavier co-twins had more restless sleep during the night, whereas the leaner co-twins were more active during the day. Within all twin pairs, higher MVPA and steps per day were associated with lower fat percentage and improved metabolic health measures. Objectively, but not subjectively measured PA is associated with lower fat percentage and better metabolic health, independent of genetic and shared environmental factors.

Gene expression profile of subcutaneous adipose tissue in BMI-discordant monozygotic twin pairs unravels molecular and clinical changes associated with sub-types of obesity.

BACKGROUND: Subcutaneous adipose tissue (SAT) undergoes major changes in obesity, but little is known about the whole-genome scale patterns of these changes or about their variation between different obesity sub-groups. We sought to compare how transcriptomics profiles in SAT differ between monozygotic (MZ) co-twins who are discordant for body mass index (BMI), whether the profiles vary between twin pairs and whether the variation can be linked to clinical characteristics. METHODS: We analysed the transcriptomics (Affymetrix U133 Plus 2.0) patterns of SAT in young MZ twin pairs (n=26, intra-pair difference in BMI >3 kg m-2, aged 23-36), from 10 birth cohorts of adult Finnish twins. The clinical data included measurements of body composition, insulin resistance, lipids and adipokines. RESULTS: We found 2108 genes differentially expressed (false discovery rate (FDR)<0.05) in SAT of the BMI-discordant pairs. Pathway analyses of these genes revealed a significant downregulation of mitochondrial oxidative pathways (P<0.05) and upregulation of inflammation pathways (P<0.05). Hierarchical clustering of heavy/lean twin ratios, representing effects of acquired obesity in the transcriptomics data, revealed three sub-groups with different molecular profiles (FDR<0.05). Analyses comparing these sub-groups showed that, in the heavy co-twins, downregulation of the mitochondrial pathways, especially that of branched chain amino acid degradation was more evident in two clusters while and upregulation of the inflammatory response was most evident in the last, presumably the unhealthiest cluster. High-fasting insulin levels and large adipocyte diameter were the predominant clinical characteristic of the heavy co-twins in this cluster (Bonferroni-adjusted P<0.05). CONCLUSIONS: This is the first study in BMI-discordant MZ twin pairs reporting sub-types of obesity based on both SAT gene expression profiles and clinical traits. We conclude that a decrease in mitochondrial BCAA degradation and an increase in inflammation in SAT co-occur and associate with hyperinsulinemia and large adipocyte size in unhealthy obesity.

Biotin-dependent functions in adiposity: a study of monozygotic twin pairs.

BACKGROUND: Biotin acts as a coenzyme for carboxylases regulating lipid and amino-acid metabolism. We investigated alterations of the biotin-dependent functions in obesity and the downstream effects of biotin restriction in adipocytes in vitro. SUBJECTS: Twenty-four monozygotic twin pairs discordant for body mass index (BMI). Mean within-pair difference (heavy-lean co-twin, Δ) of BMI was 6.0 kg m(-2) (range 3.1-15.2 kg m(-)(2)). METHODS: Adipose tissue (AT) DNA methylation, gene expression of AT and adipocytes, and leukocytes (real-time quantitative PCR), serum biotin, C-reactive protein (CRP) and triglycerides were measured in the twins. Human adipocytes were cultured in low and control biotin concentrations and analyzed for lipid droplet content, mitochondrial morphology and mitochondrial respiration. RESULTS: The gene expression levels of carboxylases, PCCB and MCCC1, were upregulated in the heavier co-twins' leukocytes. ΔPCCB (r=0.91, P=0.0046) and ΔMCCC1 (r=0.79, P=0.036) correlated with ΔCRP within-pairs. Serum biotin levels were lower in the heavier (274 ng l(-1)) than in the lean co-twins (390 ng l(-1), P=0.034). ΔBiotin correlated negatively with Δtriglycerides (r=-0.56, P=0.045) within-pairs. In AT, HLCS and ACACB were hypermethylated and biotin cycle genes HLCS and BTD were downregulated (P<0.05). Biotin-dependent carboxylases were downregulated (ACACA, ACACB, PCCB, MCCC2 and PC; P<0.05) in both AT and adipocytes of the heavier co-twins. Adipocytes cultured in low biotin had decreased lipid accumulation, altered mitochondrial morphology and deficient mitochondrial respiration. CONCLUSIONS: Biotin-dependent functions are modified by adiposity independent of genetic effects, and correlate with inflammation and hypertriglyceridemia. Biotin restriction decreases lipid accumulation and respiration, and alters mitochondrial morphology in adipocytes.

DNA methylation and gene expression patterns in adipose tissue differ significantly within young adult monozygotic BMI-discordant twin pairs.

BACKGROUND: Little is known about epigenetic alterations associated with subcutaneous adipose tissue (SAT) in obesity. Our aim was to study genome-wide DNA methylation and gene expression differences in SAT in monozygotic (MZ) twin pairs who are discordant for body mass index (BMI). This design completely matches lean and obese groups for genetic background, age, gender and shared environment. METHODS: 14We analyzed DNA methylome and gene expression from SAT, together with body composition (magnetic resonance imaging/spectroscopy) and glucose tolerance test, lipids and C-reactive protein from 26 rare BMI-discordant (intrapair difference in BMI ⩾3 kg m(-2)) MZ twin pairs identified from 10 birth cohorts of young adult Finnish twins. RESULTS: We found 17 novel obesity-associated genes that were differentially methylated across the genome between heavy and lean co-twins. Nine of them were also differentially expressed. Pathway analyses indicated that dysregulation of SAT in obesity includes a paradoxical downregulation of lipo/adipogenesis and upregulation of inflammation and extracellular matrix remodeling. Furthermore, CpG sites whose methylation correlated with metabolically harmful fat depots (intra-abdominal and liver fat) also correlated with measures of insulin resistance, dyslipidemia and low-grade inflammation, thus suggesting that epigenetic alterations in SAT are associated with the development of unhealthy obesity. CONCLUSION: This is the first study in BMI-discordant MZ twin pairs reporting genome-wide DNA methylation and expression profiles in SAT. We found a number of novel genes and pathways whose methylation and expression patterns differ within the twin pairs, suggesting that the pathological adaptation of SAT to obesity is, at least in part, epigenetically regulated.

A break in the obesity epidemic? Explained by biases or misinterpretation of the data?

Recent epidemiologic papers are presenting prevalence data suggesting breaks and decreases in obesity rates. However, before concluding that the obesity epidemic is not increasing anymore, the validity of the presented data should be discussed more thoroughly. We had a closer look into the literature presented in recent reviews to address the major potential biases and distortions, and to develop insights about how to interpret the presented suggestions for a potential break in the obesity epidemic. Decreasing participation rates, the use of reported rather than measured data and small sample sizes, or lack of representativeness, did not seem to explain presented breaks in the obesity epidemic. Further, available evidence does not suggest that stabilization of obesity rates is seen in higher socioeconomic groups only, or that urbanization could explain a potential break in the obesity epidemic. However, follow-ups of short duration may, in part, explain the apparent break or decrease in the obesity epidemic. On the other hand, a single focus on body mass index (BMI) ⩾25 or ⩾30 kg m(-)(2) is likely to mask a real increase in the obesity epidemic. And, in both children and adults, trends in waist circumferences were generally suggesting an increase, and were stronger than those reported for trends in BMI. Studies concluding that there is a recent break in the obesity epidemic need to be interpreted with caution. Reported studies presenting a break were mostly of short duration. Further, focusing on trends in waist circumference rather than BMI leads to a less optimistic conclusion: the public health problem of obesity is still increasing.

Characterising metabolically healthy obesity in weight-discordant monozygotic twins.

AIMS/HYPOTHESIS: Not all obese individuals display the metabolic disturbances commonly associated with excess fat accumulation. Mechanisms maintaining this 'metabolically healthy obesity' (MHO) are as yet unknown. We aimed to study different fat depots and transcriptional pathways in subcutaneous adipose tissue (SAT) as related to the MHO phenomenon. METHODS: Sixteen rare young adult obesity-discordant monozygotic (MZ) twin pairs (intra-pair difference (∆) in BMI ≥ 3 kg/m(2)), aged 22.8-35.8 years, were examined for detailed characteristics of metabolic health (subcutaneous, intra-abdominal and liver fat [magnetic resonance imaging/spectroscopy]), OGTT, lipids, adipokines and C-reactive protein (CRP). Affymetrix U133 Plus 2.0 chips were used to analyse transcriptomics pathways related to mitochondrial function and inflammation in SAT. RESULTS: Based on liver fat accumulation, two metabolically different subgroups emerged. In half (8/16) of the pairs (∆weight 17.1 ± 2.0 kg), the obese co-twin had significantly higher liver fat (∆718%), 78% increase in AUC insulin during OGTT and CRP, significantly more disturbance in the lipid profile and greater tendency for hypertension compared with the lean co-twin. In these obese co-twins, SAT expression of mitochondrial oxidative phosphorylation, branched-chain amino acid catabolism, fatty acid oxidation and adipocyte differentiation pathways were downregulated and chronic inflammation upregulated. In the other eight pairs (∆weight 17.4 ± 2.8 kg), the obese co-twin did not differ from the non-obese co-twin in liver fat (∆8%), insulin sensitivity, CRP, lipids, blood pressure or SAT transcriptomics. CONCLUSIONS/INTERPRETATION: Our results suggest that maintenance of high mitochondrial transcription and lack of inflammation in SAT are associated with low liver fat and MHO.

Adipocyte morphology and implications for metabolic derangements in acquired obesity.

BACKGROUND: Adipocyte size and number have been suggested to predict the development of metabolic complications in obesity. However, the genetic and environmental determinants behind this phenomenon remain unclear. METHODS: We studied this question in rare-weight discordant (intra-pair difference (Δ) body mass index (BMI) 3-10 kg m(-2), n=15) and concordant (ΔBMI 0-2 kg m(-)(2), n=5) young adult (22-35 years) monozygotic twin pairs identified from 10 birth cohorts of Finnish twins (n=5 500 pairs). Subcutaneous abdominal adipocyte size from surgical biopsies was measured under a light microscope. Adipocyte number was calculated from cell size and total body fat (D × A). RESULTS: The concordant pairs were remarkably similar for adipocyte size and number (intra-class correlations 0.91-0.92, P<0.01), suggesting a strong genetic control of these measures. In the discordant pairs, the obese co-twins (BMI 30.6 ± 0.9 kg m(-2)) had significantly larger adipocytes (volume 547 ± 59 pl), than the lean co-twins (24.9 ± 0.9 kg m(-)(2); 356 ± 34 pl, P<0.001). In 8/15 pairs, the obese co-twins had less adipocytes than their co-twins. These hypoplastic obese twins had significantly higher liver fat (spectroscopy), homeostatic model assessment-index, C-reactive protein and low-density lipoprotein cholesterol than their lean co-twins. Hyperplastic obesity was observed in the rest (7/15) of the pairs, obese and lean co-twins having similar metabolic measures. In all pairs, Δadipocyte volume correlated positively and Δcell number correlated negatively with Δhomeostatic model assessment-index and Δlow-density lipoprotein, independent of Δbody fat. Transcripts most significantly correlating with Δadipocyte volume were related to a reduced mitochondrial function, membrane modifications, to DNA damage and cell death. CONCLUSIONS: Together, hypertrophy and hypoplasia in acquired obesity are related to metabolic dysfunction, possibly through disturbances in mitochondrial function and increased cell death within the adipose tissue.

CB(1) blockade-induced weight loss over 48 weeks decreases liver fat in proportion to weight loss in humans.

OBJECTIVE: Studies in mice have suggested that endocannabinoid blockade using the cannabinoid receptor type 1 (CB1) blocker rimonabant prevents obesity-induced hepatic steatosis. DESIGN AND SUBJECTS: To determine effects of rimonabant on liver fat in humans, we measured liver fat content by proton magnetic resonance spectroscopy in 37 subjects who used either a CB1 blocker rimonabant or placebo in a double-blind, randomized manner. This was retrospectively compared with a historical hypocaloric diet weight loss group (n=23). RESULTS: Weight loss averaged 8.5±1.4 kg in the rimonabant, 1.7±1.0 kg in the placebo and 7.5±0.2 kg in the hypocaloric diet group (P<0.001, rimonabant vs placebo; NS, rimonabant vs hypocaloric diet). Liver fat decreased more in the rimonabant (5.9% (2.5-14.6%) vs 1.8% (0.9-3.5%), before vs after) than in the placebo group (6.8% (2.2-15.7%) vs 4.9% (1.6-7.8%), before vs after, P<0.05). The percentage change in body weight correlated closely with the percentage loss of liver fat (r=0.70, P>0.0001). The decreases in liver fat were comparable between the rimonabant and the young historical hypocaloric diet groups. CONCLUSIONS: We conclude that, unlike in mice, in humans rimonabant decreases liver fat in proportion to weight loss.

Association between habitual dietary intake and lipoprotein subclass profile in healthy young adults.

BACKGROUND AND AIMS: Nutritional epidemiology is increasingly shifting its focus from studying single nutrients to the exploration of the whole diet utilizing dietary pattern analysis. We analyzed associations between habitual diet (including macronutrients, dietary patterns, biomarker of fish intake) and lipoprotein particle subclass profile in young adults. METHODS AND RESULTS: Complete dietary data (food-frequency questionnaire) and lipoprotein subclass profile (via nuclear magnetic resonance spectroscopy) were available for 663 subjects from the population-based FinnTwin12 study (57% women, age: 21-25 y). The serum docosahexaenoic to total fatty acid ratio was used as a biomarker of habitual fish consumption. Factor analysis identified 5 dietary patterns: "Fruit and vegetables", "Meat", "Sweets and desserts", "Junk food" and "Fish". After adjustment for sex, age, body mass index, waist circumference, physical activity, smoking status and alcohol intake, the "Junk food" pattern was positively related to serum triglycerides (r = 0.12, P = 0.002), a shift in the subclass distribution of VLDL toward larger particles (r = 0.12 for VLDL size, P < 0.001) and LDL toward smaller particles (r = -0.15 for LDL size, P < 0.001). In addition, higher scores on this pattern were positively correlated with concentrations of small, dense HDL (r = 0.16, P < 0.001). Habitual fish intake associated negatively with VLDL particle diameter ("Fish" pattern and biomarker) and positively with HDL particle diameter (biomarker). CONCLUSIONS: Our results suggest that in young adults, higher habitual fish consumption is related to favorable subclass distributions of VLDL and HDL, while junk food intake is associated with unfavorable alterations in the distribution of all lipoprotein subclasses independent of adiposity and other lifestyle factors.

Causes and consequences of obesity: the contribution of recent twin studies.

Obesity is a genetically complex disorder that produces a myriad of health problems. Most of the recognized complications of obesity are not only strongly influenced by lifestyle factors, but also present with independent genetic predispositions that are notoriously difficult to disentangle in humans. Most studies on the causes and consequences of acquired obesity are encumbered by the incomplete ability to control for genetic influences. However, utilizing a unique experiment of nature, namely monozygotic twins (MZ) discordant for obesity as 'clonal controls' of obese and non-obese individuals has enabled the fine characterization of the effects and possible antecedents of acquired obesity while controlling for the genetic background, as well as pointed to novel obesity predisposing candidate genes. This review is a distillation of the findings from more than 10 years of research done in an exceptionally well-characterized collection of MZ and dizygotic (DZ) twins, based on the Finnish Twin Cohorts. Topics covered include the nature of development of obesity from the childhood onwards, the role of exercise in modifying the genetic susceptibility, the resulting inflammatory, prediabetic and preatherosclerotic changes in whole body and adipose tissue physiology, as well as the newest insights provided by the omics revolution.

Does dieting make you fat? A twin study.

OBJECTIVE: To investigate whether the paradoxical weight gain associated with dieting is better related to genetic propensity to weight gain than to the weight loss episodes themselves. SUBJECTS: Subjects included 4129 individual twins from the population-based FinnTwin16 study (90% of twins born in Finland 1975-1979). Weight and height were obtained from longitudinal surveys at 16, 17, 18 and 25 years, and number of lifetime intentional weight loss (IWL) episodes of more than 5 kg at 25 years. RESULTS: IWLs predicted accelerated weight gain and risk of overweight. The odds of becoming overweight (body mass index (BMI)≥ 25 kg m(-2)) by 25 years were significantly greater in subjects with one (OR 1.8, 95% CI 1.3-2.6, and OR 2.7, 1.7-4.3 in males and females, respectively), or two or more (OR 2.0, 1.3-3.3, and OR 5.2, 3.2-8.6, in males and females, respectively), IWLs compared with subjects with no IWL. In MZ pairs discordant for IWL, co-twins with at least one IWL were 0.4 kg m(-2) (P=0.041) heavier at 25 years than their non-dieting co-twins (no differences in baseline BMIs). In DZ pairs, co-twins with IWLs gained progressively more weight than non-dieting co-twins (BMI difference 1.7 kg m(-2) at 16 years and 2.2 kg m(-2) at 25 years, P<0.001). CONCLUSION: Our results suggest that frequent IWLs reflect susceptibility to weight gain, rendering dieters prone to future weight gain. The results from the MZ pairs discordant for IWLs suggest that dieting itself may induce a small subsequent weight gain, independent of genetic factors.

Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide.

OBJECTIVE: Having demonstrated short-term weight loss with liraglutide in this group of obese adults, we now evaluate safety/tolerability (primary outcome) and long-term efficacy for sustaining weight loss (secondary outcome) over 2 years. DESIGN: A randomized, double-blind, placebo-controlled 20-week study with 2-year extension (sponsor unblinded at 20 weeks, participants/investigators at 1 year) in 19 European clinical research centers. SUBJECTS: A total of 564 adults (n=90-98 per group; body mass index 30-40 kg m(-2)) enrolled, 398 entered the extension and 268 completed the 2-year trial. Participants received diet (500 kcal deficit per day) and exercise counseling during 2-week run-in, before being randomly assigned (with a telephone or web-based system) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg, n=90-95), placebo (n=98) or open-label orlistat (120 mg × 3, n=95). After 1 year, liraglutide/placebo recipients switched to liraglutide 2.4 mg, then 3.0 mg (based on 20-week and 1-year results, respectively). The trial ran from January 2007-April 2009 and is registered with Clinicaltrials.gov, number NCT00480909. RESULTS: From randomization to year 1, liraglutide 3.0 mg recipients lost 5.8 kg (95% confidence interval 3.7-8.0) more weight than those on placebo and 3.8 kg (1.6-6.0) more than those on orlistat (P0.0001; intention-to-treat, last-observation-carried-forward). At year 2, participants on liraglutide 2.4/3.0 mg for the full 2 years (pooled group, n=184) lost 3.0 kg (1.3-4.7) more weight than those on orlistat (n=95; P<0.001). Completers on liraglutide 2.4/3.0 mg (n=92) maintained a 2-year weight loss of 7.8 kg from screening. With liraglutide 3.0 mg, 20-week body fat decreased by 15.4% and lean tissue by 2.0%. The most frequent drug-related side effects were mild to moderate, transient nausea and vomiting. With liraglutide 2.4/3.0 mg, the 2-year prevalence of prediabetes and metabolic syndrome decreased by 52 and 59%, with improvements in blood pressure and lipids. CONCLUSION: Liraglutide is well tolerated, sustains weight loss over 2 years and improves cardiovascular risk factors.

Effect of anti-IL-1ß antibody (canakinumab) on insulin secretion rates in impaired glucose tolerance or type 2 diabetes: results of a randomized, placebo-controlled trial.

AIMS: Evaluate anti-interleukin-1ß (IL-1ß) antibody, canakinumab, in patients with type 2 diabetes and impaired glucose tolerance (IGT) in whom hyperglycaemia may trigger IL-1ß-associated inflammation leading to suppressed insulin secretion and ß-cell dysfunction. METHODS: This 4-week, parallel-group study randomized 190 patients with type 2 diabetes 2 : 1, canakinumab versus placebo, into the following treatment arms: metformin monotherapy, metformin + sulfonylurea, metformin + sulfonylurea + thiazolidinedione or insulin ± metformin. IGT population (n = 54) was randomized 1 : 1, canakinumab versus placebo. Primary efficacy assessment was change from baseline in insulin secretion rate (ISR) relative to glucose 0-2 h. RESULTS: Mean changes from baseline to week 4 in ISR relative to glucose at 0-2 h or other time points were not statistically significant for canakinumab versus placebo across groups. ISR (relative to glucose) at 0-0.5 h (first-phase insulin secretion) numerically favoured canakinumab versus placebo in insulin-treated patients {difference in mean change from baseline [point estimate (PE)] 3.81 pmol/min/m(2)/mmol/l; p = 0.0525} and in the IGT group (PE 3.92 pmol/min/m(2)/mmol/l; p = 0.1729). Mean change from baseline in fasting plasma glucose favoured canakinumab in the type 2 diabetes/metformin group and the IGT group; however, differences were not statistically significant. Mean change from baseline in peak insulin level and insulin AUC 0-4 h were statistically significantly higher in the canakinumab group in IGT patients. Canakinumab was well tolerated and consistent with known safety experience. CONCLUSIONS: The trend towards improving ISR relative to glucose 0-0.5 h in patients treated with insulin supports the hypothesis that insulin secretion can be improved by blocking IL-1ß.

Association of a leucine(7)-to-proline(7) polymorphism in the signal peptide of neuropeptide Y with high serum cholesterol and LDL cholesterol levels.

High serum levels of total and LDL cholesterol are important risk factors in the development of atherosclerotic coronary artery disease. Cholesterol metabolism is affected by nutritional, environmental and genetic factors. Neuropeptide Y (NPY), which is widely expressed in both the central and peripheral nervous systems, has an important role in the hypothalamic regulation of energy balance by stimulating food intake and favoring energy storage through increased lipoprotein lipase activity in white adipose tissue. As a part of ongoing study of the genetic basis of obesity, we screened the NPY gene for sequence variants. We report here the identification of a common Leu(7)-to-Pro(7) polymorphism in the signal peptide of NPY. Presence of this Pro(7) in NPY was associated with higher serum levels of total and LDL cholesterol in obese subjects participating in two independent Finnish and Dutch studies. Furthermore, normal-weight Finns with Pro(7) also had higher serum levels of total and LDL cholesterol than did subjects with Leu(7)/Leu(7), as analyzed in three subsequent determinations at 5-year intervals during a 10-year follow-up period. The NPY polymorphism was not associated with higher cholesterol levels in normal-weight Dutch. Our study provides evidence that NPY is linked to cholesterol metabolism and that the polymorphism producing Pro(7) in NPY is one of the strongest genetic factors identified thus far affecting serum cholesterol, particularly in obese subjects.

Inaccuracies in food and physical activity diaries of obese subjects: complementary evidence from doubly labeled water and co-twin assessments.

OBJECTIVE: To study whether eating or physical-activity (PA) habits differ between obese and non-obese monozygotic (MZ) co-twins independent of genetic effects. METHODS: Rare MZ pairs discordant for obesity (n=14, body mass index difference 5.2+/-1.8 kg m(-2)) and weight-concordant control pairs (n=10, 1.0+/-0.7 kg m(-2)), identified through a population-based registry of 24-28-year-old twins (n=658 MZ pairs), completed 3-day food and PA diaries and eating behavior questionnaires. Each twin was asked to compare his/her own eating and PA patterns with the co-twin's behavior by structured questionnaires. Accuracy of energy intake was validated by doubly labeled water. RESULTS: Non-obese co-twins consistently reported that their obese twin siblings ate more food overall, consumed less healthy foods and exercised less than the non-obese co-twins do. However, no differences in energy intake (9.6+/-1.0 MJ per day vs 9.8+/-1.1 MJ per day, respectively) in the food diaries or in the mean PA level (1.74+/-0.02 vs 1.79+/-0.04, respectively) in the PA diaries were found between obese and non-obese co-twins. A considerable underreporting of energy intake (3.2+/-1.1 MJ per day, P=0.036) and overreporting of PA (1.8+/-0.8 MJ per day, P=0.049) was observed in the obese, but not in the non-obese co-twins. CONCLUSIONS: On the basis of rare MZ twin pairs discordant for obesity, the co-twin assessments confirmed substantial differences in eating and PA behavior between obese and non-obese persons. These may be overlooked in population studies using food and PA diaries because of considerable misreporting by the obese.

A clinical trial assessing the safety and efficacy of the CB1R inverse agonist taranabant in obese and overweight patients: low-dose study.

OBJECTIVE: To evaluate the weight loss efficacy, safety and tolerability of taranabant, a CB1R inverse agonist, in obese and overweight patients. DESIGN: Multicenter, double-blind, randomized, placebo-controlled study. SUBJECTS: Patients >or=18 years old, BMI 27-43 kg m(-2), were randomized to placebo (n=209) or taranabant 0.5 mg (n=207), 1 mg (n=208) or 2 mg given orally once daily (n=417) for 52 weeks. MEASUREMENTS: Key efficacy measurements included body weight (BW), waist circumference (WC), lipid endpoints and glycemic endpoints. RESULTS: Based on a last observation carried forward analysis of the all-patients-treated population, mean change in BW for taranabant 0.5, 1, and 2 mg and placebo was -5.4, -5.3, -6.7 and -1.7 kg, respectively (P<0.001 for all doses vs placebo). The proportions of patients who lost at least 5 and 10% of their baseline BW at week 52 were significantly higher for all taranabant doses vs placebo (P<0.001 for all doses). Reductions in WC, percentage of body fat, and triglycerides were significant for taranabant 2 mg and in triglycerides for taranabant 1 mg vs placebo. There was no effect of taranabant vs placebo on other lipid or glucose-related endpoints. Incidences of adverse experiences classified in the gastrointestinal (diarrhea and nausea), nervous system (dizziness/dizziness postural), psychiatric-related (irritability and anger/aggression) and vascular (flushing/hot flush) organ systems were higher and statistically significant in the taranabant 2-mg group compared with the placebo group. Irritability was higher and statistically significant in all taranabant groups compared with the placebo group. CONCLUSION: All three doses of taranabant-induced clinically meaningful and statistically significant weight loss. Incidences of adverse experiences in organ systems known to express CB1R were higher in taranabant groups.

Take action to prevent diabetes--the IMAGE toolkit for the prevention of type 2 diabetes in Europe.

When we ask people what they value most, health is usually top of the list. While effective care is available for many chronic diseases, the fact remains that for the patient, the tax payer and the whole of society: prevention is better than cure. Diabetes and its complications are a serious threat to the survival and well-being of an increasing number of people. It is predicted that one in ten Europeans aged 20-79 will have developed diabetes by 2030. Once a disease of old age, diabetes is now common among adults of all ages and is beginning to affect adolescents and even children. Diabetes accounts for up to 18 % of total healthcare expenditure in Europe. The good news is that diabetes is preventable. Compelling evidence shows that the onset of diabetes can be prevented or delayed greatly in individuals at high risk (people with impaired glucose regulation). Clinical research has shown a reduction in risk of developing diabetes of over 50 % following relatively modest changes in lifestyle that include adopting a healthy diet, increasing physical activity, and maintaining a healthy body weight. These results have since been reproduced in real-world prevention programmes. Even a delay of a few years in the progression to diabetes is expected to reduce diabetes-related complications, such as heart, kidney and eye disease and, consequently, to reduce the cost to society. A comprehensive approach to diabetes prevention should combine population based primary prevention with programmes targeted at those who are at high risk. This approach should take account of the local circumstances and diversity within modern society (e.g. social inequalities). The challenge goes beyond the healthcare system. We need to encourage collaboration across many different sectors: education providers, non-governmental organisations, the food industry, the media, urban planners and politicians all have a very important role to play. Small changes in lifestyle will bring big changes in health. Through joint efforts, more people will be reached. The time to act is now.