Using a new socioepidemiological questionnaire to analyse associations between intergenerational upward social mobility and body fat distribution: a pilot study with the Oxford BioBank cohort.

BACKGROUND: As measured through body mass index (BMI), obesity is more prevalent among upwardly mobile adults than among adults born into middle-class families. Although BMI reflects general adiposity, health risks are more strongly associated with abdominal adiposity. It is therefore important to investigate associations between upward mobility and fat distribution. METHODS: A socioepidemiological questionnaire was developed, qualitatively validated and piloted with Oxford BioBank participants. Sex-specific analyses of variance (ANOVA) investigated associations between participant occupational class and adiposity, paternal occupational class and adiposity, and upward occupational mobility and adiposity. The main aim was to observe whether the expected directional effect of adiposity in relation to paternal occupational class would emerge. RESULTS: 280 participants (166 women, 114 men; age 32-67 years) completed the questionnaire. Men with fathers of occupational class 2 or 3 had higher mean BMI, total body fat percentage, android fat mass and android-to-gynoid fat mass ratio than men with fathers of occupational class 1. Women with fathers of occupational class 2 or 3 had higher mean BMI, total body fat percentage, android fat mass and gynoid fat mass than women with fathers of occupational class 1. Among men, upward mobility was not associated with adiposity. Among women, upward mobility was associated with higher total body fat percentage, android fat mass and gynoid fat mass. CONCLUSION: The expected directional effect was found, thereby supporting the questionnaire's use. Upward mobility did not appear to change associations between paternal occupational class and participant adiposity. Future research using the socioepidemiological questionnaire should investigate associations between gender, educational mobility, adiposity and health.

Comparison of regional fat measurements by dual-energy X-ray absorptiometry and conventional anthropometry and their association with markers of diabetes and cardiovascular disease risk.

BACKGROUND/OBJECTIVES: Fat distribution is a strong and independent predictor of type 2 diabetes (T2D) and cardiovascular disease (CVD) and is usually determined using conventional anthropometry in epidemiological studies. Dual-energy X-ray absorptiometry (DXA) can measure total and regional adiposity more accurately. Nonetheless, whether DXA provides more precise estimates of cardiovascular risk in relation to total and regional adiposity is not known. We determined the strength of the associations between DXA- and conventional anthropometry determined fat distribution and T2D and CVD risk markers. SUBJECTS/METHODS: Waist (WC) and hip circumference (HC) and DXA was used to measure total and regional adiposity in 4950 (2119 men) participants aged 29-55 years from the Oxford Biobank without pre-existing T2D or CVD. Cross-sectional associations were compared between WC and HC vs. DXA-determined regional adiposity (all z-score normalised) with impaired fasting glucose, hypertriglyceridemia, hypertension and insulin resistance (IR). RESULTS: Following adjustment for total adiposity, upper body adiposity measurements showed consistently increased risk of T2D and CVD risk markers except for abdominal subcutaneous fat in both sexes, and arm fat in men, which showed protective associations. Among upper adiposity depots, visceral fat mass showed stronger odds ratios (OR) ranging from 1.69 to 3.64 compared with WC 1.07-1.83. Among lower adiposity depots, HC showed modest protection for IR in both sexes (men: OR 0.80 (95% confidence interval 0.67, 0.96); women: 0.69 (0.56, 0.86)), whereas gynoid fat and in particular leg fat showed consistent and strong protective effects for all outcomes in both men and women. The differential effect of body fat distribution on CVD and T2D were more pronounced at higher levels of total adiposity. CONCLUSIONS: Compared with DXA, conventional anthropometry underestimates the associations of regional adiposity with T2D and CVD risk markers. After correcting for overall adiposity, greater subcutaneous fat mass in particular in the lower body is protective relative to greater android or visceral adipose tissue mass.

What have human experimental overfeeding studies taught us about adipose tissue expansion and susceptibility to obesity and metabolic complications?

Overfeeding experiments, in which we impose short-term positive energy balance, help unravel the cellular, physiological and behavioural adaptations to nutrient excess. These studies mimic longer-term mismatched energy expenditure and intake. There is considerable inter-individual heterogeneity in the magnitude of weight gain when exposed to similar relative caloric excess reflecting variable activation of compensatory adaptive mechanisms. Significantly, given similar relative weight gain, individuals may be protected from/predisposed to metabolic complications (insulin resistance, dyslipidaemia, hypertension), non-alcoholic fatty liver disease and cardiovascular disease. Similar mechanistic considerations underpinning the heterogeneity of overfeeding responses are pertinent in understanding emerging metabolic phenotypes, for example, metabolically unhealthy normal weight and metabolically healthy obesity. Intrinsic and extrinsic factors modulate individuals' overfeeding response: intrinsic factors include gender/hormonal status, genetic/ethnic background, baseline metabolic health and cardiorespiratory fitness; extrinsic factors include macronutrient (fat vs carbohydrate) content, fat/carbohydrate composition and overfeeding pattern. Subcutaneous adipose tissue (SAT) analysis, coupled with metabolic assessment, with overfeeding have revealed how SAT remodels to accommodate excess nutrients. SAT remodelling occurs either by hyperplasia (increased adipocyte number) or by hypertrophy (increased adipocyte size). Biological responses of SAT also govern the extent of ectopic (visceral/liver) triglyceride deposition. Body composition analysis by DEXA/MRI (dual energy X-ray absorptiometry/magnetic resonance imaging) have determined the relative expansion of SAT (including abdominal/gluteofemoral SAT) vs ectopic fat with overfeeding. Such studies have contributed to the adipose expandability hypothesis whereby SAT has a finite capacity to expand (governed by intrinsic biological characteristics), and once capacity is exceeded ectopic triglyceride deposition occurs. The potential for SAT expandability confers protection from/predisposes to the adverse metabolic responses to overfeeding. The concept of a personal fat threshold suggests a large inter-individual variation in SAT capacity with ectopic depot expansion/metabolic decompensation once one's own threshold is exceeded. This review summarises insight gained from overfeeding studies regarding susceptibility to obesity and related complications with nutrient excess.

Inequality and childhood overweight and obesity: a commentary.

Statements on childhood overweight and obesity (COO) have focused on different avenues for prevention and treatment, critical stages of the life cycle, including pregnancy and lactation, individual, family, school and community-based interventions, multidisciplinary family programmes and multicomponent interventions. This commentary is concerned with the less-addressed relationship between COO and inequality. It describes current global patterns of inequality and COO and the ways in which those inequalities are linked to COO at micro-level, meso-level and macro-level. It then describes current programmatic approaches for COO inequality, preventive and medical, and considers important pitfalls in the framing of the problem of COO and inequality. It ends with describing how childhood and adolescent overweight and obesity prevention and treatment programmes might be formulated within broader socio-political frameworks to influence outcomes.

Regulation of human subcutaneous adipose tissue blood flow.

Subcutaneous adipose tissue represents about 85% of all body fat. Its major metabolic role is the regulated storage and mobilization of lipid energy. It stores lipid in the form of triacylglycerol (TG), which is mobilized, as required for use by other tissues, in the form of non-esterified fatty acids (NEFA). Neither TG nor NEFA are soluble to any extent in water, and their transport to and out of the tissue requires specialized transport mechanisms and adequate blood flow. Subcutaneous adipose tissue blood flow (ATBF) is therefore tightly linked to the tissue's metabolic functioning. ATBF is relatively high (in the fasting state, similar to that of resting skeletal muscle, when expressed per 100 g tissue) and changes markedly in different physiological states. Those most studied are after ingestion of a meal, when there is normally a marked rise in ATBF, and exercise, when ATBF also increases. Pharmacological studies have helped to define the physiological regulation of ATBF. Adrenergic influences predominate in most situations, but nevertheless the regulation of ATBF is complex and depends on the interplay of many different systems. ATBF is downregulated in obesity (when expressed per 100 g tissue), and its responsiveness to meal intake is reduced. However, there is little evidence that this leads to adipose tissue hypoxia in human obesity, and we suggest that, like the downregulation of catecholamine-stimulated lipolysis seen in obesity, the reduction in ATBF represents an adaptation to the increased fat mass. Most information on ATBF has been obtained from studying the subcutaneous abdominal fat depot, but more limited information on lower-body fat depots suggests some similarities, but also some differences: in particular, marked alpha-adrenergic tone, which can reduce the femoral ATBF response to adrenergic stimuli.

A common variant in the FTO locus is associated with waist-hip ratio in Indian adolescents.

BACKGROUND: Common variants in the FTO locus, and near MC4R locus, have been shown to have a robust association with obesity in children and adults among various ethnic groups. Associations with obesity traits among Indian adolescents have not been determined. OBJECTIVE: To study the association of rs9939609 (FTO) and rs17782313 (MC4R) to obesity related anthropometric traits in Indian adolescents. METHODS: Subjects for the current study were recruited from a cross-sectional cohort of 1,230 adolescents (age mean ± SD: 17.1 ± 1.9 years) from South India. RESULTS: The variant at the FTO locus was found to be associated with waist-hip ratio (WHR) but not with overall obesity in this population. No significant association was observed for obesity-traits and Mc4R variant rs17782313. CONCLUSION: The common variant of FTO (rs9939609) is associated with body fat distribution during early growth in Indian adolescents and may predispose to obesity and metabolic consequences in adulthood.

MicroRNAs in adipose tissue: their role in adipogenesis and obesity.

MicroRNAs (miRNAs) are endogenous small RNAs that posttranscriptionally regulate gene expression and that have been shown to have important roles in numerous disease processes. There is growing evidence for an important role of miRNAs in regulating the pathways in adipose tissue that control a range of processes including adipogenesis, insulin resistance and inflammation. Several high-throughput studies have identified differentially expressed miRNAs in adipose tissue pathology and during adipogenesis and a number of these have now been characterised functionally in terms of their actions and targets. This review will summarise the current literature on miRNAs in adipose tissue, as well as discussing the methodologies used in this area of research and the potential application of miRNAs as biomarkers and as therapeutic targets.

Apolipoprotein M can discriminate HNF1A-MODY from Type 1 diabetes.

AIMS: Missed diagnosis of maturity-onset diabetes of the young (MODY) has led to an interest in biomarkers that enable efficient prioritization of patients for definitive molecular testing. Apolipoprotein M (apoM) was suggested as a biomarker for hepatocyte nuclear factor 1 alpha (HNF1A)-MODY because of its reduced expression in Hnf1a(-/-) mice. However, subsequent human studies examining apoM as a biomarker have yielded conflicting results. We aimed to evaluate apoM as a biomarker for HNF1A-MODY using a highly specific and sensitive ELISA. METHODS: ApoM concentration was measured in subjects with HNF1A-MODY (n = 69), Type 1 diabetes (n = 50), Type 2 diabetes (n = 120) and healthy control subjects (n = 100). The discriminative accuracy of apoM and of the apoM/HDL ratio for diabetes aetiology was evaluated. RESULTS: Mean (standard deviation) serum apoM concentration (µmol/l) was significantly lower for subjects with HNF1A-MODY [0.86 (0.29)], than for those with Type 1 diabetes [1.37 (0.26), P = 3.1 × 10(-18) ) and control subjects [1.34 (0.22), P = 7.2 × 10(-19) ). There was no significant difference in apoM concentration between subjects with HNF1A-MODY and Type 2 diabetes [0.89 (0.28), P = 0.13]. The C-statistic measure of discriminative accuracy for apoM was 0.91 for HNF1A-MODY vs. Type 1 diabetes, indicating high discriminative accuracy. The apoM/HDL ratio was significantly lower in HNF1A-MODY than other study groups. However, this ratio did not perform well in discriminating HNF1A-MODY from either Type 1 diabetes (C-statistic = 0.79) or Type 2 diabetes (C-statistic = 0.68). CONCLUSIONS: We confirm an earlier report that serum apoM levels are lower in HNF1A-MODY than in controls. Serum apoM provides good discrimination between HNF1A-MODY and Type 1 diabetes and warrants further investigation for clinical utility in diabetes diagnostics.

Marked resistance of femoral adipose tissue blood flow and lipolysis to adrenaline in vivo.

AIMS/HYPOTHESIS: Fatty acid entrapment in femoral adipose tissue has been proposed to prevent ectopic fat deposition and visceral fat accumulation, resulting in protection from insulin resistance. Our objective was to test the hypothesis of femoral, compared with abdominal, adipose tissue resistance to adrenergic stimulation in vivo as a possible mechanism. METHODS: Regional fatty acid trafficking, along with the measurement of adipose tissue blood flow (ATBF) with (133)Xe washout, was studied with the arteriovenous difference technique and stable isotope tracers in healthy volunteers. Adrenergic agonists (isoprenaline, adrenaline [epinephrine]) were infused either locally by microinfusion or systemically. Local microinfusion of adrenoceptor antagonists (propranolol, phentolamine) was used to characterise specific adrenoceptor subtype effects in vivo. RESULTS: Femoral adipose tissue NEFA release and ATBF were lower during adrenaline stimulation than in abdominal tissue (p < 0.001). Mechanistically, femoral adipose tissue displayed a dominant α-adrenergic response during adrenaline stimulation. The α-adrenoceptor blocker, phentolamine, resulted in the 'disinhibition' of the femoral ATBF response to adrenaline (p < 0.001). CONCLUSIONS/INTERPRETATION: Fatty acids, once stored in femoral adipose tissue, are not readily released upon adrenergic stimulation. Femoral adipose tissue resistance to adrenaline may contribute to the prevention of ectopic fatty acid deposition.

Association of adipose tissue blood flow with fat depot sizes and adipokines in women.

OBJECTIVE: To explore possible associations between adipose tissue (AT) blood flow (ATBF), AT depot sizes and adipocyte-derived hormones (adipokines) in women. SUBJECTS: In all, 43 healthy women were divided into four groups: normal-weight (n=11) and obese (n=11) pre-menopausal women and normal-weight (n=10) and obese (n=11) post-menopausal women. METHODS: Fasting levels of adipokines were obtained, and a single-slice computed tomography scan at the level of L4-L5 was used to estimate fat depot sizes. ATBF was assessed by xenon washout while in a fasting state and after oral glucose load. We also measured glucose, insulin and non-esterified fatty acids. RESULTS: Total, subcutaneous and visceral AT areas strongly correlated with ATBF (all P<0.001). Circulating leptin levels strongly and inversely correlated with ATBF (P=0.001), but this association did not remain after adjustment for body mass index. Adiponectin was not associated with blood flow. CONCLUSION: ATBF is closely linked to subcutaneous and visceral AT size. Further analyses are needed to determine possible mediators of this association, including mechanistic studies to assess a putative role for leptin as a significant modulator of blood flow.

Failure to increase postprandial blood flow in subcutaneous adipose tissue is associated with tissue resistance to adrenergic stimulation.

AIMS: Adequate adipose tissue blood flow (ATBF) is essential for its metabolic and endocrine functions. From a metabolic point of view, sufficient increases in ATBF after meals permits full storage of excess energy into fat, thus protecting other tissues against the toxic effects of fatty acids and glucose spillover. It was previously shown that postprandial increases in ATBF are blunted in obese and insulin-resistant subjects, and that much of the postprandial ATBF response is the result of ß-adrenergic activation. Examination of previously recorded data on postprandial ATBF responses revealed an underlying heterogeneity, with postprandial ATBF being largely unresponsive to food stimuli in a substantial proportion of normal weight healthy people (low responders). Our study tests the hypothesis that this unresponsive pattern is due to resistance to ß-adrenergic stimulation in adipose tissue. METHODS: Five responders and five low responders were selected from a previously studied cohort and matched for BMI (20.5±0.7 vs 22±1 kg/m(2), respectively), gender (male/female: 2/3) and age (30±3 vs 37±6 years). Subcutaneous adipose tissue microinfusions of stepwise increasing doses of isoproterenol were performed with concomitant monitoring of blood flow, using the (133)Xenon washout technique. RESULTS: Although BMI was similar between responders and low responders, there were significant differences in fat mass (9.9±1.6 vs 14.4±1.6 kg; P<0.05) and four-point skinfold thickness (33±4 vs 52±16 mm; P<0.05). Lack of ATBF response to oral glucose was confirmed in the low responder group. In responders, ATBF was higher at baseline (5.4±1 vs 3.4±1 mL/min/100 g of tissue) and responded more distinctly to increasing isoproterenol doses (10(-8) M: 7.6±1.4 vs 4.9±1; 10(-6) M: 12.5±1.7 vs 7.5±1.6; and 10(-4) M: 20 ±1.7 vs 9±0.9 mL/min/100 g of tissue). CONCLUSION: These data suggest that the lack of glucose-stimulated ATBF is associated with resistance to sympathetic activation in adipose tissue.

Gluteofemoral body fat as a determinant of metabolic health.

Body fat distribution is an important metabolic and cardiovascular risk factor, because the proportion of abdominal to gluteofemoral body fat correlates with obesity-associated diseases and mortality. Here, we review the evidence and possible mechanisms that support a specific protective role of gluteofemoral body fat. Population studies show that an increased gluteofemoral fat mass is independently associated with a protective lipid and glucose profile, as well as a decrease in cardiovascular and metabolic risk. Studies of adipose tissue physiology in vitro and in vivo confirm distinct properties of the gluteofemoral fat depot with regards to lipolysis and fatty acid uptake: in day-to-day metabolism it appears to be more passive than the abdominal depot and it exerts its protective properties by long-term fatty acid storage. Further, a beneficial adipokine profile is associated with gluteofemoral fat. Leptin and adiponectin levels are positively associated with gluteofemoral fat while the level of inflammatory cytokines is negatively associated. Finally, loss of gluteofemoral fat, as observed in Cushing's syndrome and lipodystrophy is associated with an increased metabolic and cardiovascular risk. This underlines gluteofemoral fat's role as a determinant of health by the long-term entrapment of excess fatty acids, thus protecting from the adverse effects associated with ectopic fat deposition.

Adipose tissue fatty acid metabolism in insulin-resistant men.

AIMS/HYPOTHESIS: Increased NEFA production and concentrations may underlie insulin resistance. We examined systemic and adipose tissue NEFA metabolism in insulin-resistant overweight men (BMI 25-35 kg/m2). METHODS: In a cohort study we examined NEFA concentrations in men in the upper quartile of fasting insulin (n = 124) and in men with fasting insulin below the median (n = 159). In a metabolic study we examined NEFA metabolism in the fasting and postprandial states, in ten insulin-resistant men and ten controls. RESULTS: In the cohort study, fasting NEFA concentrations were not significantly different between the two groups (median values: insulin-resistant men, 410 micromol/l; controls, 445 micromol/l). However, triacylglycerol concentrations differed markedly (1.84 vs 1.18 mmol/l respectively, p < 0.001). In the metabolic study, arterial NEFA concentrations again did not differ between groups, whereas triacylglycerol concentrations were significantly higher in insulin-resistant men. Systemic NEFA production and the release of NEFA from subcutaneous adipose tissue, expressed per unit of fat mass, were both reduced in insulin-resistant men compared with controls (fasting values by 32%, p = 0.02, and 44%, p = 0.04 respectively). 3-Hydroxybutyrate concentrations, an index of hepatic fat oxidation and ketogenesis, were lower (p = 0.03). CONCLUSIONS/INTERPRETATION: Adipose tissue NEFA output is not increased (per unit weight of tissue) in insulin resistance. On the contrary, it appears to be suppressed by high fasting insulin concentrations. Alterations in triacylglycerol metabolism are more marked than those in NEFA metabolism and are indicative of altered metabolic partitioning of fatty acids (decreased oxidation, increased esterification) in the liver.

Association of variants in the fat mass and obesity associated (FTO) gene with polycystic ovary syndrome.

AIMS/HYPOTHESIS: Variants in the fat-mass and obesity-associated gene (FTO) influence susceptibility to type 2 diabetes via an effect on adiposity/obesity. Given the important role of obesity in the aetiology of both polycystic ovary syndrome (PCOS) and type 2 diabetes mellitus, our aim was to establish whether FTO variants are also implicated in PCOS susceptibility. METHODS: We performed a genetic association study of FTO variant rs9939609 using case-control analyses, conducted in 463 PCOS patients (geometric mean BMI 27.5 kg/m(2)) and 1,336 female controls (geometric mean BMI 25.3 kg/m(2)) of UK British/Irish origin. We also sought evidence for associations between FTO variation and circulating testosterone levels in 324 UK PCOS patients and 1,000 women from the Northern Finland Birth Cohort of 1966. Outcome measures included FTO rs9939609 genotype frequencies by participant group and androgen measures (testosterone, free androgen index) by genotype. RESULTS: There was a significant association between FTO genotype and PCOS status in the UK case-control analysis, which was attenuated by adjustment for BMI (Cochran-Armitage test, odds ratio [per minor allele copy] 1.30 [95% CI 1.12, 1.51], p = 7.2 x 10(-4) [unadjusted], p = 2.9 x 10(-3) [adjusted]). This association was most evident in obese PCOS patients (PCOS patients below median BMI vs UK controls, p = 0.11; above median BMI vs controls, p = 2.9 x 10(-4)). No relationship between FTO genotype and androgen levels was seen. CONCLUSIONS/INTERPRETATION: We provide the first evidence that variants that predispose to common obesity also result in altered susceptibility to PCOS, confirming the mechanistic link between these conditions. The predominant effect of FTO variants on PCOS susceptibility is probably mediated through adiposity.

Remodeling phenotype of human subcutaneous adipose tissue macrophages.

BACKGROUND: Adipose tissue macrophages (ATMs) have become a focus of attention recently because they have been shown to accumulate with an increase in fat mass and to be involved in the genesis of insulin resistance in obese mice. However, the phenotype and functions of human ATMs are still to be defined. METHODS AND RESULTS: The present study, performed on human subcutaneous AT, showed that ATMs from lean to overweight individuals are composed of distinct macrophage subsets based on the expression of several cell surface markers: CD45, CD14, CD31, CD44, HLA-DR, CD206, and CD16, as assessed by flow cytometry. ATMs isolated by an immunoselection protocol showed a mixed expression of proinflammatory (tumor necrosis factor-alpha, interleukin-6 [IL-6], IL-23, monocyte chemoattractant protein-1, IL-8, cyclooxygenase-2) and antiinflammatory (IL-10, transforming growth factor-beta, alternative macrophage activation-associated cc chemokine-1, cyclooxygenase-1) factors. Fat mass enlargement is associated with accumulation of the CD206+/CD16- macrophage subset that exhibits an M2 remodeling phenotype characterized by decreased expression of proinflammatory IL-8 and cyclooxygenase-2 and increased expression of lymphatic vessel endothelial hyaluronan receptor-1. ATMs specifically produced and released matrix metalloproteinase-9 compared with adipocytes and capillary endothelial cells, and secretion of matrix metalloproteinase-9 from human AT in vivo, assessed by arteriovenous difference measurement, was correlated with body mass index. Finally, ATMs exerted a marked proangiogenic effect on AT-derived endothelial and progenitor cells. CONCLUSIONS: The present results showed that the ATMs that accumulate with fat mass development exhibit a particular M2 remodeling phenotype. ATMs may be active players in the process of AT development through the extension of the capillary network and in the genesis of obesity-associated cardiovascular pathologies.

Fatty acid-induced mitochondrial uncoupling in adipocytes is not a promising target for treatment of insulin resistance unless adipocyte oxidative capacity is increased.

The release of fatty acids from white adipose tissue is regulated at several levels. We have examined the suggestion that fatty acid release might be diminished by upregulation of mitochondrial fatty acid oxidation in the adipocyte, through increasing mitochondrial uncoupling. The intrinsic oxidative capacity of white adipose tissue is low, and older studies suggest that there is little fatty acid oxidation in white adipocytes, human or rodent. We have examined data on fatty acid metabolism and O(2) consumption in human white adipose tissue in vivo, and conclude that increasing fatty acid oxidation within the oxidative capacity of the tissue would produce only small changes (a few percent) in fatty acid release. The major locus of control of fatty acid release beyond the stimulation of lipolysis is the pathway of fatty acid esterification, already probably targeted by the thiazolidinedione insulin-sensitising agents. An alternative approach would be to upregulate the mitochondrial capacity of the adipocyte. We review proof-of-concept studies in which the phenotype of the white adipocyte has been changed to resemble that of the brown adipocyte by expression of peroxisome proliferator-activated receptor coactivator-1alpha. This increases oxidative capacity and also leads to fatty acid retention through upregulation of glycerol-3-phosphate production, and hence increased fatty acid re-esterification. We conclude that prevention or treatment of insulin resistance through alteration of adipocyte fatty acid handling will require more than a simple alteration of the activity of mitochondrial beta-oxidation within normal limits.

Adipose tissue: a key target for diabetes pathophysiology and treatment?

Excess adipose tissue brings with it a number of adverse consequences, many of which may stem from the development of insulin resistance. An emerging view is that inflammatory changes occurring in expanding adipose tissue are associated with the secretion of peptide and other factors that can adversely affect metabolic processes in other key insulin-target tissues, especially liver and skeletal muscle. However, there is still a commonly-expressed view that the adverse changes in other tissues are ultimately due to an excess of fatty acids, liberated by a metabolically-challenged adipose tissue. Our own studies of adipose tissue metabolism and physiological function (especially blood flow) IN VIVO suggest that these two views of adipose tissue function may be closely linked. Enlarged adipocytes are less dynamic in their responses, just as 'enlarged adipose tissue' is less dynamic in blood flow regulation. Adipocytes seem to be able to sense the appropriate level of fat storage. If the normal mechanisms regulating adipocyte fat storage are interfered with (either in genetically-modified animals or by increasing the size of the adipocytes), then perhaps some sort of cellular stress sets in, leading to the inflammatory and endocrine changes. Some evidence for this comes from the effects of the thiazolidinediones, which improve adipose tissue function and in parallel reduce inflammatory changes.

Removal of triacylglycerols from chylomicrons and VLDL by capillary beds: the basis of lipoprotein remnant formation.

The triacylglycerol content of chylomicrons and VLDL (very-low-density lipoprotein) compete for the same lipolytic pathway in the capillary beds. Although chylomicron triacylglycerols appear to be the favoured substrate for lipoprotein lipase, VLDL particles compete in numbers. Methods to quantify the specific triacylglycerol removal from VLDL and chylomicrons may involve endogenous labelling of the triacylglycerol substrate with stable isotopes in combination with arteriovenous blood sampling in humans. Arteriovenous quantification of remnant lipoproteins suggests that adipose tissue with its high lipoprotein lipase activity is a principal site for generation of remnant lipoproteins. Under circumstances of reduced efficiency in the removal of triacylglycerols from lipoproteins, there is accumulation of remnant lipoproteins, which are potentially atherogenic.

Acute and selective regulation of glyceroneogenesis and cytosolic phosphoenolpyruvate carboxykinase in adipose tissue by thiazolidinediones in type 2 diabetes.

AIMS/HYPOTHESIS: Regulation of glyceroneogenesis and its key enzyme cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) plays a major role in the control of fatty acid release from adipose tissue. Here we investigate the effect of rosiglitazone on the expression of genes involved in fatty acid metabolism and the resulting metabolic consequences. MATERIALS AND METHODS: Rosiglitazone was administered to Zucker fa/fa rats for 4 days and to 24 diabetic patients for 12 weeks, then mRNA expression for the genes encoding PEPCK-C, mitochondrial PEPCK, adipocyte lipid-binding protein, glycerol kinase, lipoprotein lipase and glycerol-3-phosphate dehydrogenase was examined in s.c. adipose tissue by real-time RT-PCR. Glyceroneogenesis was determined using [1-(14)C]pyruvate incorporation into lipids. Cultured adipose tissue explants from overweight women undergoing plastic surgery were incubated with rosiglitazone for various times before mRNA determination and analysis of PEPCK-C protein, activity and glyceroneogenesis. RESULTS: Rosiglitazone administration to rats induced the expression of the gene encoding PEPCK-C mRNA (PCK1) and PEPCK-C activity in adipose tissue with a resulting 2.5-fold increase in glyceroneogenesis. This was accompanied by an improvement in dyslipidaemia as demonstrated by the decrease in plasma NEFAs and triacylglycerol. In rosiglitazone-treated diabetic patients, PCK1 mRNA was raised 2.5-fold in s.c. adipose tissue. Rosiglitazone treatment of adipose tissue explants from overweight women caused a selective augmentation in PCK1 mRNA which reached a maximum of 9-fold at 14 h, while mRNA for other genes remained unaffected. Experiments with inhibitors showed a direct and transcription-only effect, which was followed by an increase in PEPCK-C protein, enzyme activity and glyceroneogenesis. CONCLUSIONS/INTERPRETATION: These results favour adipocyte glyceroneogenesis as the initial thiazolidinedione-responsive pathway leading to improvement in dyslipidaemia.