Lipolysis defect in people with obesity who undergo metabolic surgery.

OBJECTIVE: Cross-sectional studies demonstrate that catecholamine stimulation of fat cell lipolysis is blunted in obesity. We investigated whether this defect persists after substantial weight loss has been induced by metabolic surgery, and whether it is related to the outcome. DESIGN/METHODS: Patients with obesity not able to successfully reduce body weight by conventional means (n = 126) were investigated before and 5 years after Roux-en-Y gastric bypass surgery (RYGB). They were compared with propensity-score matched subjects selected from a control group (n = 1017), and with the entire group after adjustment for age, sex, body mass index (BMI), fat cell volume and other clinical parameters. Catecholamine-stimulated lipolysis (glycerol release) was investigated in isolated fat cells using noradrenaline (natural hormone) or isoprenaline (synthetic beta-adrenoceptor agonist). RESULTS: Following RYGB, BMI was reduced from 39.9 (37.5-43.5) (median and interquartile range) to 29.5 (26.7-31.9) kg/m2 (p < 0.0001). The post-RYGB patients had about 50% lower lipolysis rates compared with the matched and total series of controls (p < 0.0005). Nordrenaline activation of lipolysis at baseline was associated with the RYGB effect; those with high lipolysis activation (upper tertile) lost 30%-45% more in body weight, BMI or fat mass than those with low (bottom tertile) initial lipolysis activation (p < 0.0007). CONCLUSION: Patients with obesity requiring metabolic surgery have impaired ability of catecholamines to stimulate lipolysis, which remains despite long-term normalization of body weight by RYGB. Furthermore, preoperative variations in the ability of catecholamines to activate lipolysis may predict the long-term reduction in body weight and fat mass.

Long-term improvement of adipocyte insulin action during body weight relapse after bariatric surgery: a longitudinal cohort study.

BACKGROUND: There are few long-term mechanistic studies in adipose tissue that investigate the metabolic effects of bariatric surgery. Changes in lipogenesis may be involved in long-term weight development. OBJECTIVES: To investigate the long-term effect of bariatric surgery on lipogenesis in abdominal fat cells and whether surgical treatment could induce an epigenetic memory that would maintain improved lipogenesis in spite of body weight relapse. SETTING: Karolinska University Hospital in Stockholm County, Sweden. METHODS: A total of 22 women with obesity living in the Stockholm area were examined before, 2, 5, and 10 years after bariatric surgery. Abdominal adipose tissue biopsies were obtained. Fat cells were isolated and spontaneous and insulin stimulated glucose incorporation into lipids were assayed. CpG-methylation profiling was performed on adipocytes using the Infinium EPIC BeadChips. RESULTS: Bariatric surgery was associated with improvement in adipocyte spontaneous and insulin stimulated lipogenesis, which was maintained despite some later weight regain (29 % of initial weight loss). There was also an increase in fat cell size between 2- and 10-year follow-up, albeit not to presurgery levels. There were 7729 differentially methylated CpG sites (DMS) at 2 years that showed no sign of return to baseline at either 5 or 10 years. Merging results with expression profiles identified 1259 genes with DMS which showed early response or continual change in expression in one direction after surgery. Upregulated genes with DMS were enriched in gene sets linked to cellular response to insulin stimulus (e.g., IRS1, IRS2, PDE3B, and AKT2) and regulation of lipid metabolic processes. CONCLUSION: Bariatric surgery leads to long-term improvement of lipogenesis and insulin responsiveness in subcutaneous adipocytes in women in spite of some partial body weight regain postoperatively. This may to some extent be explained by epigenetic modifications of fat cell function.

A longitudinal study of the antilipolytic effect of insulin in women following bariatric surgery.

Insulin resistance of glucose utilization is fully restored following BMI normalization after bariatric surgery. We investigated if this also pertains to insulin-induced effects on fatty acid handling. Forty-three women with obesity (OB) were investigated before and 2 years after Roux-en-Y gastric by-pass when BMI was <30 kg/m2 (PO) and compared with 26 never obese women (NO). The Adipo-IR index was used as measure of insulin antilipolytic sensitivity. Changes (delta) in circulating glycerol and fatty acid levels during hyperinsulinemic euglycemic clamp represented the insulin maximum antilipolytic effect. Overall fatty acid utilization was reflected by delta fatty acids minus 3 × delta glycerol. Adipo-IR was higher in OB than in NO and PO (p < 0.0001), the latter two groups having similar values. Insulin lowered glycerol levels by about 70% in all groups, but delta glycerol was 30% larger in PO than in NO (p = 0.04). Delta adds and adds utilization were similar in all groups. We conclude that women with obesity, whose BMI is normalized after bariatric surgery, have improved maximum in vivo antilipolytic effect of insulin above expected in absolute but not relative terms as regards glycerol changes, while the handling of circulating fatty acids is changed to the normal state.

Human White Adipose Tissue Displays Selective Insulin Resistance in the Obese State.

Selective hepatic insulin resistance is a feature of obesity and type 2 diabetes. Whether similar mechanisms operate in white adipose tissue (WAT) of those with obesity and to what extent these are normalized by weight loss are unknown. We determined insulin sensitivity by hyperinsulinemic euglycemic clamp and insulin response in subcutaneous WAT by RNA sequencing in 23 women with obesity before and 2 years after bariatric surgery. To control for effects of surgery, women postsurgery were matched to never-obese women. Multidimensional analyses of 138 samples allowed us to classify the effects of insulin into three distinct expression responses: a common set was present in all three groups and included genes encoding several lipid/cholesterol biosynthesis enzymes; a set of obesity-attenuated genes linked to tissue remodeling and protein translation was selectively regulated in the two nonobese states; and several postobesity-enriched genes encoding proteins involved in, for example, one-carbon metabolism were only responsive to insulin in the women who had lost weight. Altogether, human WAT displays a selective insulin response in the obese state, where most genes are normalized by weight loss. This comprehensive atlas provides insights into the transcriptional effects of insulin in WAT and may identify targets to improve insulin action.

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.

Metabolic Impact of Body Fat Percentage Independent of Body Mass Index in Women with Obesity Remission After Gastric Bypass.

BACKGROUND/OBJECTIVE: Body mass index (BMI) is central when evaluating treatment effect after gastric bypass. The metabolic impact of BMI-independent differences in body fat percentage (BF%) after gastric bypass is not fully understood. We compared metabolic and adipose tissue characteristics in women with high versus low BF% independent of BMI after obesity remission following gastric bypass. SUBJECTS/METHODS: A cohort of 215 women was included at baseline. A total of 166 women were re-examined 2 years after gastric bypass, whereof 130 had obesity remission (BMI < 30 kg/m2). Anthropometric parameters, blood pressure, and lipids were measured. Total and regional body fat mass was determined by dual-energy X-ray absorptiometry. Insulin sensitivity was assessed by homeostasis model assessment of insulin resistance (HOMA-IR) and hyperinsulinemic euglycemic clamp (M value). Adipocyte size and number were determined. RESULTS: Of the 130 women with obesity remission, 64 had BF% ≥ 35 and 65 < 35. Independent of BMI, high BF% were associated with higher HOMA-IR (P = 0.021), lower M value (P = 0.0046), higher triglycerides (P = 0.013), higher visceral/total and android/gynoid fat mass ratios (P = 0.0032 and 0.0003 respectively), and larger subcutaneous fat cell volume (P < 0.0001) 2 years after gastric bypass. No differences in anthropometric measures, glucose, blood pressure, or fat cell number were observed. CONCLUSIONS: Independent of BMI, patients with higher BF% displayed lower insulin sensitivity, higher triglyceride levels, central fat distribution, and larger subcutaneous adipocytes 2 years after gastric bypass. Thus, determination of BF% provides additional information of metabolic characteristics at follow-up of non-obese patients after gastric bypass.

Body fat mass and distribution as predictors of metabolic outcome and weight loss after Roux-en-Y gastric bypass.

BACKGROUND: Bariatric surgery such as Roux-en-Y gastric bypass (RYGB) remains the most effective treatment of obesity and associated co-morbidities. Body fat distribution associates with metabolic function. OBJECTIVE: To investigate if preoperative body fat mass and distribution measured by dual-energy x-ray absorptiometry (DXA) predict weight loss and metabolic outcome after RYGB, and to compare predictive value of DXA with simple anthropometric measures. SETTING: Four Swedish hospitals within the Stockholm area. METHODS: Two hundred fifteen women scheduled for RYGB were included. Evaluations before and 2 years after RYGB included determination of insulin sensitivity by the homeostatic model assessment of insulin resistance, blood pressure, plasma lipids, and anthropometric measures, such as waist-to-hip-ratio and fat percentage estimated by formula. Body fat mass and distribution were determined by DXA. RESULTS: Follow-up rate was 77.2% (n = 166). All clinical, anthropometric, and DXA measures were improved/reduced postsurgery (all P<.0001). Android/gynoid fat mass ratio and waist-to-hip-ratio predicted improved homeostatic model assessment of insulin resistance (P = .0028 and .0014), independently of body mass index and age. Body fat percentage, measured by DXA or estimated by formula, predicted percent weight loss (P<.0001 and .0083). Body mass index predicted percent weight loss and percent excess body mass index lost (P = .0022 and<.0001). DXA and anthropometric measures performed equally as predictors, except for DXA measured fat percentage that was slightly better than formula estimated. CONCLUSION: DXA provided predictive values similar to those by basic anthropometric measures, suggesting a limited additional value of preoperative DXA to predict metabolic improvement and weight loss after RYGB in women.

Long-Term Improvement in Aortic Pulse Wave Velocity After Weight Loss Can Be Predicted by White Adipose Tissue Factors.

BACKGROUND: Arterial stiffness, measured by pulse wave velocity (PWV), is linked to obesity, cardiovascular disease, and all-cause mortality. Short-term weight loss improves PWV, but the long-term effects are unknown. We investigated the effect of pronounced long-term weight loss on PWV and whether anthropometric/metabolic parameters and/or white adipose tissue (WAT) phenotype could predict this change in PWV. METHODS: Eighty-two obese subjects were examined before and 2 years after Roux-en-Y gastric bypass. Analyses included anthropometrics, routine clinical chemistry, and hyperinsulinemic-euglycemic clamp. Arterial stiffness was measured as aortic PWV (aPWV) using the Arteriograph device. WAT mass and distribution were assessed by dual-X-ray absorptiometry. Baseline visceral and subcutaneous WAT samples were obtained to measure adipocyte cell size. Transcriptomic profiling of subcutaneous WAT was performed in a subset of subjects (n = 30). RESULTS: At the 2-year follow-up, there were significant decreases in body mass index (39.4 ± 3.5 kg/m2 vs. 26.6 ± 3.4 kg/m2; P < 0.0001) and aPWV (7.8 ± 1.5 m/s vs. 7.2 ± 1.4 m/s; P = 0.006). Multiple regression analyses showed that baseline subcutaneous adipocyte volume was associated with a reduction in aPWV (P = 0.014), after adjusting for confounders. Expression analyses of 52 genes implicated in arterial stiffness showed that only one, COL4A1, independently predicted improvements in aPWV after adjusting for confounders (P = 0.006). CONCLUSIONS: Bariatric surgery leads to long-term reduction in aPWV. This improvement can be independently predicted by subcutaneous adipocyte volume and WAT COL4A1 expression, which suggests that subcutaneous WAT has a role in regulating aPWV. CLINICAL TRIALS REGISTRATION: Trial Number NCT01727245 (clinicaltrials.gov).

Omentectomy in Addition to Bariatric Surgery-a 5-Year Follow-up.

AIM: Omentectomy in addition to bariatric surgery has been suggested to improve metabolic outcome but short-term (6-24 months) studies have refuted this notion. We investigated whether there was any long-term impact of omentectomy. METHODS: Forty-nine obese women underwent gastric bypass surgery and were randomly assigned to omentectomy (n = 26) or not (n = 23). They were re-examined after 5 years including dual-energy X-ray absorptiometry for body composition, blood pressure and blood sampling. RESULTS: There were no significant differences between the two groups at baseline (p = 0.07-0.93) or 5 years post-operatively (p = 0.15-0.93) regarding weight, BMI, body composition, HOMA-IR, plasma cholesterol, HDL cholesterol, or triglycerides. CONCLUSION: In agreement with previous shorter studies, removal of the greater omentum in addition to GBP is not associated with metabolic benefits after long-term follow-up.

Salt-inducible kinase 2 and -3 are downregulated in adipose tissue from obese or insulin-resistant individuals: implications for insulin signalling and glucose uptake in human adipocytes.

AIMS/HYPOTHESIS: Salt-inducible kinases (SIKs) are related to the metabolic regulator AMP-activated protein kinase (AMPK). SIK2 is abundant in adipose tissue. The aims of this study were to investigate the expression of SIKs in relation to human obesity and insulin resistance, and to evaluate whether changes in the expression of SIKs might play a causal role in the development of disturbed glucose uptake in human adipocytes. METHODS: SIK mRNA and protein was determined in human adipose tissue or adipocytes, and correlated to clinical variables. SIK2 and SIK3 expression and phosphorylation were analysed in adipocytes treated with TNF-α. Glucose uptake, GLUT protein levels and localisation, phosphorylation of protein kinase B (PKB/Akt) and the SIK substrate histone deacetylase 4 (HDAC4) were analysed after the SIKs had been silenced using small interfering RNA (siRNA) or inhibited using a pan-SIK-inhibitor (HG-9-91-01). RESULTS: We demonstrate that SIK2 and SIK3 mRNA are downregulated in adipose tissue from obese individuals and that the expression is regulated by weight change. SIK2 is also negatively associated with in vivo insulin resistance (HOMA-IR), independently of BMI and age. Moreover, SIK2 protein levels and specific kinase activity display a negative correlation to BMI in human adipocytes. Furthermore, SIK2 and SIK3 are downregulated by TNF-α in adipocytes. Silencing or inhibiting SIK1-3 in adipocytes results in reduced phosphorylation of HDAC4 and PKB/Akt, less GLUT4 at the plasma membrane, and lower basal and insulin-stimulated glucose uptake in adipocytes. CONCLUSION/INTERPRETATION: This is the first study to describe the expression and function of SIKs in human adipocytes. Our data suggest that SIKs might be protective in the development of obesity-induced insulin resistance, with implications for future treatment strategies.

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.

Circulating and Adipose Levels of Adipokines Associated With Insulin Sensitivity in Nonobese Subjects With Type 2 Diabetes.

CONTEXT: The adipokines chemerin, dipeptidyl peptidase 4, and adiponectin influence insulin sensitivity. Whether their circulating levels and adipose secretion are altered in nonobese individuals with type 2 diabetes mellitus (T2DM) is unknown. OBJECTIVE: The objective of this study was to investigate SC adipose secretion and serum levels of the three adipokines in relation to T2DM features. DESIGN: Fourteen nonobese T2DM and 13 healthy men were investigated. Insulin sensitivity and glucose control were assessed by hyperinsulinemic euglycemic clamp, homeostasis model assessment, and glycated hemoglobin. MAIN OUTCOME MEASURE: Association of circulating and adipose-secreted adipokines with fat cell volume and insulin sensitivity was measured. PARTICIPANTS: Volunteers in an outpatient academic clinic participated. RESULTS: Although adipose secretion was similar between the groups, serum chemerin was higher (70 ± 10 vs 50 ± 1 ng/ml; P = .005), adiponectin lower (4.7 ± 1.3 vs 6.8 ± 2.2 µg/ml; P = .005), and dipeptidyl peptidase 4 unaltered in T2DM. Serum adiponectin (r = 0.53; P = .005) and chemerin (r = -0.42; P = .03) correlated with adipose secreted levels. Secreted and circulating chemerin correlated positively with adipocyte volume (r > 0.40; P < .05), whereas serum adiponectin correlated negatively with this measure (r = -0.61; P = .001). Adiponectin serum half-life was decreased in T2DM (168 ± 24 vs 186 ± 18 minutes; P = .029) and correlated negatively with glycated hemoglobin (r = -0.45; P = .03) and adipocyte volume (r = -0.56; P < .003). Serum adiponectin (r = 0.57; P = .017) and chemerin (r = -0.52; P = .03) associated with clamp measures independently of T2DM diagnosis. CONCLUSIONS: In nonobese men, circulating adiponectin and chemerin levels are altered in T2DM without changes in adipose secretion. Adipocyte volume is important for variations in serum chemerin and adiponectin and for serum clearance of adiponectin. In T2DM, poor glucose control also plays a role for adiponectin clearance.

Adipose and Circulating CCL18 Levels Associate With Metabolic Risk Factors in Women.

CONTEXT: Cardiometabolic complications in obesity may be linked to white adipose tissue (WAT) dysfunction. Transcriptomic studies of Sc WAT have reported that CCL18, encoding the CC chemokine ligand 18 (CCL18), is increased in obesity/insulin resistance but its functional role is unknown. OBJECTIVE: Our objectives were to determine if CCL18 is secreted from Sc WAT and if secreted and/or serum levels associate with metabolic phenotypes. We also planned to define the primary cellular source and if CCL18 exerts effects on adipocytes. DESIGN: This is a cohort study. SETTING: The study took place in an outpatient academic clinic. PARTICIPANTS: A total of 130 obese women scheduled for bariatric surgery and 35 nonobese controls were included. METHODS: Insulin sensitivity was assessed by hyperinsulinemic euglycemic clamp or homeostasis model assessment. CCL18 was analyzed in serum/WAT incubates by ELISA. Effects of recombinant CCL18 was determined in cultures of primary human adipocytes and the monocyte cell line THP-1 differentiated into M0/M1/M2 macrophages. MAIN OUTCOME MEASURE: Association with metabolic risk factors was measured. RESULTS: CCL18 was secreted from WAT and the levels correlated positively with insulin resistance, Adult Treatment Panel III risk score and plasma triglycerides, independent of body mass index and better than other established adipocytokines. In 80 obese women, S-CCL18 levels were significantly higher in insulin resistant compared with insulin sensitive subjects. In WAT CCL18 mRNA was expressed in macrophages and correlated positively with immune-related genes, particularly those enriched in M2 macrophages. While CCL18 increased cyto-/chemokine expression in M0/M2-THP-1 cells, human adipocytes showed no responses in vitro. CONCLUSIONS: Circulating and WAT-secreted CCL18 correlates with insulin resistance and metabolic risk score. Because CCL18 is macrophage-specific and associates with adipose immune gene expression, it may constitute a marker of WAT inflammation.

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

AIMS/HYPOTHESIS: We 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. METHODS: We 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. RESULTS: Individuals 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/INTERPRETATION: We 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.

Transplanted Bone Marrow-Derived Cells Contribute to Human Adipogenesis.

Because human white adipocytes display a high turnover throughout adulthood, a continuous supply of precursor cells is required to maintain adipogenesis. Bone marrow (BM)-derived progenitor cells may contribute to mammalian adipogenesis; however, results in animal models are conflicting. Here we demonstrate in 65 subjects who underwent allogeneic BM or peripheral blood stem cell (PBSC) transplantation that, over the entire lifespan, BM/PBSC-derived progenitor cells contribute ∼10% to the subcutaneous adipocyte population. While this is independent of gender, age, and different transplantation-related parameters, body fat mass exerts a strong influence, with up to 2.5-fold increased donor cell contribution in obese individuals. Exome and whole-genome sequencing of single adipocytes suggests that BM/PBSC-derived progenitors contribute to adipose tissue via both differentiation and cell fusion. Thus, at least in the setting of transplantation, BM serves as a reservoir for adipocyte progenitors, particularly in obese subjects.

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.

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.

Omentectomy in addition to gastric bypass surgery and influence on insulin sensitivity: a randomized double blind controlled trial.

BACKGROUND & AIMS: Accumulation of visceral adipose tissue is associated with insulin resistance and cardio-vascular disease. The aim of this study was to elucidate whether removal of a large amount of visceral fat by omentectomy in conjunction with Roux en-Y gastric bypass operation (RYGB) results in enhanced improvement of insulin sensitivity compared to gastric bypass surgery alone. METHODS: Eighty-one obese women scheduled for RYGB were included in the study. They were randomized to RYGB or RYGB in conjunction with omentectomy. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp before operation and sixty-two women were also reexamined 2 years post-operatively. The primary outcome measure was insulin sensitivity and secondary outcome measures included cardio-metabolic risk factors. RESULTS: Two-year weight loss was profound but unaffected by omentectomy. Before intervention, there were no clinical or metabolic differences between the two groups. The difference in primary outcome measure, insulin sensitivity, was not significant between the non-omentectomy (6.7 ± 1.6 mg/kg body weight/minute) and omentectomy groups (6.6 ± 1.5 mg/kg body weight/minute) after 2 years. Nor did any of the cardio-metabolic risk factors that were secondary outcome measures differ significantly. CONCLUSION: Addition of omentectomy to gastric bypass operation does not give an incremental effect on long term insulin sensitivity or cardio-metabolic risk factors. The clinical usefulness of omentectomy in addition to gastric bypass operation is highly questionable. CLINICAL TRIAL REGISTRATION NUMBER: NCT01785134.