Daniel P. Andersson

Regional impact of adipose tissue morphology on the metabolic profile in morbid obesity

Aims/hypothesisThe aim of this study was to determine whether the mean size of fat cells in either visceral or subcutaneous adipose tissue has an impact on the metabolic and inflammatory profiles in morbid obesity.MethodsIn 80 morbidly obese women, mean visceral (omental) and subcutaneous fat cell sizes were related to in vivo markers of inflammation, glucose metabolism and lipid metabolism.ResultsVisceral, but not subcutaneous, adipocyte size was significantly associated with plasma apolipoprotein B, total cholesterol, LDL-cholesterol and triacylglycerols (p ranging from 0.002 to 0.015, partial r ranging from 0.3 to 0.4). Subcutaneous, but not visceral, adipocyte size was significantly associated with plasma insulin and glucose, insulin-induced glucose disposal and insulin sensitivity (p ranging from 0.002 to 0.005, partial r ranging from −0.34 to 0.35). The associations were independent of age, BMI, body fat mass or body fat distribution. Adipose tissue hyperplasia (i.e. many small adipocytes) in both regions was significantly associated with better glucose, insulin and lipid profiles compared with adipose hypertrophy (i.e. few large adipocytes) in any or both regions (p ranging from <0.0001 to 0.04). Circulating inflammatory markers were not associated with fat cell size or corresponding gene expression in the fat cell regions examined.Conclusions/interpretationIn morbidly obese women region-specific variations in mean adipocyte size are associated with metabolic complications but not systemic or adipose inflammation. Large fat cells in the visceral region are linked to dyslipidaemia, whereas large subcutaneous adipocytes are important for glucose and insulin abnormalities. Hyperplasia (many small adipocytes) in both adipose regions may be protective against lipid as well as glucose/insulin abnormalities in obesity.

Increased fat cell size: a major phenotype of subcutaneous white adipose tissue in non-obese individuals with type 2 diabetes

Aims/hypothesisWe aimed to elucidate the impact of fat cell size and inflammatory status of adipose tissue on the development of type 2 diabetes in non-obese individuals.MethodsWe characterised subcutaneous abdominal adipose tissue by examining stromal cell populations by 13 colour flow cytometry, measuring expression of adipogenesis genes in the progenitor cell fraction and determining lipolysis and adipose secretion of inflammatory proteins in 14 non-obese men with type 2 diabetes and 13 healthy controls matched for age, sex, body weight and total fat mass.ResultsIndividuals with diabetes had larger fat cells than the healthy controls but stromal cell population frequencies, adipose lipolysis and secretion of inflammatory proteins did not differ between the two groups. However, in the entire cohort fat cell size correlated positively with the ratio of M1/M2 macrophages, TNF-α secretion, lipolysis and insulin resistance. Expression of genes encoding regulators of adipogenesis and adipose morphology (BMP4, CEBPα [also known as CEBPA], PPARγ [also known as PPARG] and EBF1) correlated negatively with fat cell size.Conclusions/interpretationWe show that a major phenotype of white adipose tissue in non-obese individuals with type 2 diabetes is adipocyte hypertrophy, which may be mediated by an impaired adipogenic capacity in progenitor cells. Consequently, this could have an impact on adipose tissue inflammation, release of fatty acids, ectopic fat deposition and insulin sensitivity.

Variations in the size of the major omentum are primarily determined by fat cell number

OBJECTIVE Accumulation of visceral adipose tissue (VAT) is strongly linked to insulin resistance. Variations in the size of any adipose depot are determined by alterations in adipocyte volume and/or number. The individual contribution of each of the latter factors was determined in the major omentum, a fully resectable VAT depot. SUBJECTS Total removal of the major omentum (omentectomy) was performed in conjunction with bariatric surgery in 55 obese patients. Tissue weight as well as mean adipocyte size and number in the omentum were determined. In subgroups, total VAT was estimated by computerized tomography (n = 17) or dual-energy x-ray absorptiometry (n = 34). RESULTS The weight of the major omentum (on average 0.6 kg) correlated significantly with total VAT mass estimated by computerized tomography or dual-energy x-ray absorptiometry (r = 0.48-0.7; P < .01). Omental weight in relation to total body fat correlated with several features of the metabolic syndrome and inversely with serum-leptin (P < .001). Mean adipocyte size and total adipocyte number correlated strongly with omental weight (r = 0.6-0.8; P < .0001), irrespective of body mass index and total body fat mass, and accounted almost in total for interindividual variations in omental size. However, stepwise regression analysis demonstrated that adipocyte number was significantly (P < .0001) more important (62%) than adipocyte size (35%). CONCLUSION The size of the major omentum is representative for VAT mass and correlates with a pernicious metabolic profile. Variations in omental weight are primarily determined by adipocyte number and to a lesser degree by adipocyte size, suggesting that increased VAT mass in obesity is predominantly dependent on adipocyte proliferation.

Changes in Subcutaneous Fat Cell Volume and Insulin Sensitivity After Weight Loss

OBJECTIVE Large subcutaneous fat cells associate with insulin resistance and high risk of developing type 2 diabetes. We investigated if changes in fat cell volume and fat mass correlate with improvements in the metabolic risk profile after bariatric surgery in obese patients. RESEARCH DESIGN AND METHODS Fat cell volume and number were measured in abdominal subcutaneous adipose tissue in 62 obese women before and 2 years after Roux-en-Y gastric bypass (RYGB). Regional body fat mass by dual-energy X-ray absorptiometry; insulin sensitivity by hyperinsulinemic-euglycemic clamp; and plasma glucose, insulin, and lipid profile were assessed. RESULTS RYGB decreased body weight by 33%, which was accompanied by decreased adipocyte volume but not number. Fat mass in the measured regions decreased and all metabolic parameters were improved after RYGB (P < 0.0001). Whereas reduced subcutaneous fat cell size correlated strongly with improved insulin sensitivity (P = 0.0057), regional changes in fat mass did not, except for a weak correlation between changes in visceral fat mass and insulin sensitivity and triglycerides. The curve-linear relationship between fat cell size and fat mass was altered after weight loss (P = 0.03). CONCLUSIONS After bariatric surgery in obese women, a reduction in subcutaneous fat cell volume associates more strongly with improvement of insulin sensitivity than fat mass reduction per se. An altered relationship between adipocyte size and fat mass may be important for improving insulin sensitivity after weight loss. Fat cell size reduction could constitute a target to improve insulin sensitivity.

Adipose tissue and metabolic alterations: regional differences in fat cell size and number matter, but differently: a cross-sectional study.

OBJECTIVE White adipose tissue can expand by increasing the size and/or number of fat cells. Although increased sc and visceral fat cell size associates with an adverse metabolic profile, the relationship with fat cell number in either depot is unknown. We hypothesized that adipocyte number and size displayed different relationships with clinically relevant metabolic variables. METHODS This was a cross-sectional study of 204 patients scheduled for gastric bypass surgery. Fat cell size and number were determined in visceral and abdominal sc adipose tissue and related to insulin sensitivity (by hyperinsulinemic euglycemic clamp), fasting plasma levels of insulin, triglycerides and high-density lipoprotein (HDL) cholesterol. RESULTS Visceral and sc fat cell volumes were positively correlated with insulin and triglyceride levels and negatively with insulin sensitivity and HDL-cholesterol (P = .0020 or better). In contrast, although visceral fat cell number did not associate with any metabolic parameter, sc adipocyte number displayed a positive association with insulin sensitivity and HDL-cholesterol and a negative relationship with insulin and triglyceride levels (P = .0014 or better). All results were independent of body fat mass. CONCLUSIONS Variations in fat cell size and number correlate differently with metabolic parameters in obesity. Increased fat cell size in visceral and sc depots associates with a pernicious metabolic profile, whereas increased sc, but not visceral, fat cell number correlates with a more beneficial phenotype. Whether determination of sc fat cell number, in addition to adipocyte size, may have a predictive value for the risk of type 2 diabetes needs to be demonstrated in prospective or mechanistic studies.

Adipocyte triglyceride turnover and lipolysis in lean and overweight subjects.

Human obesity is associated with decreased triglyceride turnover and impaired lipolysis in adipocytes. We determined whether such defects also occur in subjects with only moderate increase in fat mass. Human abdominal subcutaneous adipose tissue was investigated in healthy, nonobese subjects [body mass index (BMI) > 17 kg/m2 and BMI < 30 kg/m2]. Triglyceride age, reflecting lipid turnover, was examined in 41 subjects by assessing the incorporation of atmospheric 14C into adipose lipids. Adipocyte lipolysis was examined as the ability of lipolytic agents to stimulate glycerol release in 333 subjects. Adipocyte triglyceride age was markedly increased in overweight (BMI ≥ 25 kg/m2) compared with lean subjects (P = 0.017) with triglyceride T1/2 of 14 and 9 months, respectively (P = 0.04). Triglyceride age correlated positively with BMI (P = 0.002) but not with adipocyte volume (P = 0.2). Noradrenaline-, isoprenaline- or dibutyryl cyclic AMP-induced lipolysis was inversely correlated with triglyceride age (P < 0.01) and BMI (P < 0.0001) independently of basal lipolysis, gender, and nicotine use. Current, but not the highest or lowest BMI in adult life, correlated significantly (inversely) with lipolysis. In conclusion, adipocyte triglyceride turnover and lipolytic activity are decreased in overweight subjects and reflect the current BMI status. These changes may confer an increased risk for early development and/or maintenance of excess body fat.

LXR is a negative regulator of glucose uptake in human adipocytes

Aims/hypothesisObesity increases the risk of developing type 2 diabetes mellitus, characterised by impaired insulin-mediated glucose uptake in peripheral tissues. Liver X receptor (LXR) is a positive regulator of adipocyte glucose transport in murine models and a possible target for diabetes treatment. However, the levels of LXRα are increased in obese adipose tissue in humans. We aimed to investigate the transcriptome of LXR and the role of LXR in the regulation of glucose uptake in primary human adipocytes.MethodsThe insulin responsiveness of human adipocytes differentiated in vitro was characterised, adipocytes were treated with the LXR agonist GW3965 and global transcriptome profiling was determined by microarray, followed by quantitative RT-PCR (qRT-PCR), western blot and ELISA. Basal and insulin-stimulated glucose uptake was measured and the effect on plasma membrane translocation of glucose transporter 4 (GLUT4) was assayed.ResultsLXR activation resulted in transcriptional suppression of several insulin signalling genes, such as AKT2, SORBS1 and CAV1, but caused only minor changes (<15%) in microRNA expression. Activation of LXR impaired the plasma membrane translocation of GLUT4, but not the expression of its gene, SLC2A4. LXR activation also diminished insulin-stimulated glucose transport and lipogenesis in adipocytes obtained from overweight individuals. Furthermore, AKT2 expression was reduced in obese adipose tissue, and AKT2 and SORBS1 expression was inversely correlated with BMI and HOMA index.Conclusions/interpretationIn contrast to murine models, LXR downregulates insulin-stimulated glucose uptake in human adipocytes from overweight individuals. This could be due to suppression of Akt2, c-Cbl-associated protein and caveolin-1. These findings challenge the idea of LXR as a drug target in the treatment of diabetes.

Visceral Fat Cell Lipolysis and Cardiovascular Risk Factors in Obesity

Visceral fat accumulation relates to cardiovascular risk factors, but the underlying mechanisms are not well understood. We investigated the role of visceral adipocyte triglyceride breakdown (lipolysis) for several risk factors of cardiovascular disease. In 73 obese women, fat mass and distribution, blood pressure, blood samples for cardiometabolic risk factors, and whole-body insulin sensitivity were determined. A subcutaneous and a visceral fat biopsy were taken. Fat cell glycerol release after stimulation with a major lipolytic hormone, noradrenaline, was measured. In simple regression analysis, visceral fat cell lipolysis, but not subcutaneous adipocyte lipolysis was related to components of the metabolic syndrome. Moreover, subjects in the highest quartile of catecholamine-induced visceral lipolysis had higher levels of systolic blood pressure, estimated liver fat, plasma levels of glucose, insulin, cholesterol, LDL-cholesterol, triglycerides and apolipoprotein B and lower whole-body insulin sensitivity than those in the lowest quartile (p=0.0004-0.048). Among subjects with the metabolic syndrome, visceral fat cell lipolysis was 40% higher than in the remaining subjects (p=0.0052). Catecholamine-activated lipolysis in visceral but not subcutaneous fat cells is associated with cardiovascular risk factors in obesity.

Association between treatment for erectile dysfunction and death or cardiovascular outcomes after myocardial infarction

Objective Erectile dysfunction (ED) is associated with an increased risk of cardiovascular disease in healthy men. However, the association between treatment for ED and death or cardiovascular outcomes after a first myocardial infarction (MI) is unknown. Methods In a Swedish nationwide cohort study all men <80 years of age without prior MI, or cardiac revascularisation, hospitalised for MI during 2007–2013 were included. Treatment for ED, defined as dispensed phosphodiesterase-5 inhibitors or alprostadil, was related to risk of death, MI, cardiac revascularisation or heart failure. Results Forty-three thousand one hundred and forty-five men with mean age 64 (±10) years were included, of whom 7.1% had ED medication dispensed during a mean 3.3 years (141 739 person-years) of follow-up. Men with, compared with those without treatment for ED, had a 33% lower mortality (adjusted HR 0.67 (95%CI 0.55 to 0.81)), and 40% lower risk of hospitalisation for heart failure (HR 0.60 (95% CI 0.44 to 0.82)). There was no association between treatment with alprostadil and mortality. The adjusted risk of death in men with 1, 2–5 and >5 dispensed prescriptions of phosphodiesterase-5 inhibitors was reduced by 34% (HR 0.66 (95% CI 0.38 to 1.15), 53% (HR 0.47 (95% CI 0.26 to 0.87) and 81% (HR 0.19 (95% CI 0.08 to 0.45), respectively, when compared with alprostadil treatment. Conclusions Treatment for ED after a first MI was associated with a reduced mortality and heart failure hospitalisation. Only men treated with phosphodiesterase-5 inhibitors had a reduced risk, which appeared to be dose-dependent.

Long-term Protective Changes in Adipose Tissue After Gastric Bypass

OBJECTIVE Although long-term weight regain may occur after bariatric surgery, many patients are protected against relapse or development of type 2 diabetes. The study objective was to investigate whether this involves beneficial changes in adipose function. RESEARCH DESIGN AND METHODS Forty-nine obese women were investigated before and 2 and 5 years after Roux-en-Y gastric bypass (RYGB). At the 5-year follow-up, 30 subjects were pairwise matched for BMI and age to 30 control women. Clinical parameters and fine-needle biopsies from subcutaneous abdominal adipose tissue were obtained; fat cell size and number, lipolysis, adiponectin, and proinflammatory protein secretion were determined. RESULTS After 2 years, BMI decreased from 43 to 29 kg/m2, which was accompanied by improvements in insulin sensitivity (HOMA of insulin resistance [HOMA-IR]), increased circulating and adipose secreted adiponectin, and decreased adipose lipolysis and fat cell size but no change in adipocyte number. Between 2 and 5 years after surgery, BMI had increased to 31 kg/m2. This was associated with slightly increased HOMA-IR and unaltered circulating or adipose secreted adiponectin but higher secretion of tumor necrosis factor-α and increased lipolysis and number of fat cells but no change in adipocyte size. All these parameters, except lipolysis, were significantly more favorable compared with those in matched control subjects. Furthermore, the relationship between HOMA-IR and circulating adiponectin was less steep than in control subjects. CONCLUSIONS RYGB improves long-term insulin sensitivity and adipose phenotypes beyond the control state despite weight regain. Postoperative beneficial alterations in adipose function may be involved in the diabetes-protective effect of bariatric surgery.