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Background/objectives: Different approaches are used to classify obesity severity. Beyond classical anthropometric measurements, the Edmonton Obesity Staging System (EOSS) considers medical, physical and psychological parameters. However, this method has some limitations, principally due to the absence of an objective measure for physical impairment. The aim of our study is thus to overcome this limitation suggesting a new functional parameter obtained by cardiopulmonary exercise testing (CPET), i.e., cardiorespiratory fitness (CRF), expressed as weight-adjusted peak oxygen consumption (VO 2 peak/kg)., Subjects/methods: This observational cross-sectional study conducted on a population of 843 patients affected by obesity finally enrolled 500 subjects. Every patient underwent clinical, anthropometric, biochemical assessment and CPET. First, participants have been classified according to standard EOSS in five stages. Second, patients were reclassified according to the new modified EOSS (EOSS-CRF) based on their age- and gender-appropriate VO 2 peak/kg percentiles as reported in the healthy normal-weight population of the FRIEND registry., Results: VO 2 peak/kg was significantly different between standard EOSS classes 1 and 2 and classes 1 and 3 (ANCOVA p model = 0.004), whereas patients in classes 2 and 3 showed similar CRF. The EOSS-CRF classification varied in number of patients in each class compared to EOSS, particularly with a shift from class 2 to class 3. Moreover, CRF showed that physical impairment is less addressed by EOSS when compared to EOSS-CRF., Conclusions: The integration of EOSS with CRF allowed us to assign to each patient a severity index that considers not only clinical parameters, but also their functional impairment through a quantitative and prognostically important parameter (VO 2 peak/kg). This improvement of the staging system may also provide a better approach to identify individuals at increased risk of mortality leading to targeted therapeutic management and prognostic risk stratification for patients with obesity., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Although obesity represents a risk factor for the development of type 2 diabetes mellitus (T2DM), the link between these pathological conditions is not so clear. The manner in which the different elements of adipose tissue (AT) interplay in order to grow has been suggested to have a role in the genesis of metabolic complications, but this has not yet been fully addressed in humans. Through IHC, transmission electron microscopy, cytometry, and in vitro cultures, we described the morphological and functional changes of subcutaneous and visceral AT (SAT and VAT) in normoglycemic, prediabetic and T2DM patients with obesity compared to lean subjects. In both SAT and VAT we measured a hypertrophic and hyperplastic expansion, causing similar vascular rarefaction in obese patients with different degrees of metabolic complications. Capillaries display dysfunctional basement membrane thickening only in T2DM patients evidencing VAT as a new target of T2DM microangiopathy. The largest increase in adipocyte size and decrease in adipose stem cell number and adipogenic potential occur both in T2DM and in prediabetes. We showed that SAT and VAT remodeling with stemness deficit is associated with early glucose metabolism impairment suggesting the benefit of an AT-target therapy controlling hypertrophy and hyperplasia already in prediabetic obese patients.

Background: Non-alcoholic fatty liver disease (NAFLD) has a high prevalence in obesity and its presence should be screened. Laparoscopic sleeve gastrectomy (LSG) is an effective treatment for obesity, but its effects on NAFLD are still to be firmly established. The diagnosis of non-alcoholic steatohepatitis (NASH) is currently performed by liver biopsy, a costly and invasive procedure. Squamous cell carcinoma antigen-IgM (SCCA-IgM) is a biomarker of viral hepatitis to hepatocellular carcinoma development and its role in NAFLD to NASH progression has not yet been investigated., Objective: The aim of this study was to evaluate SCCA-IgM as a non-invasive biomarker of NAFLD/NASH in patients with different degrees of metabolic-complicated obesity before and after LSG., Method: Fifty-six patients with obesity were studied before and 12 months after LSG; anthropometric, biochemical, clinical, and imaging data were collected., Results: At baseline steatosis was strongly associated with the glycaemic profile (p = 0.016) and was already present in prediabetic patients with obesity (82%). Only 3 patients had an SCCA-IgM level above the normal cut-off. SCCA-IgM titre did not change according to glycaemic profile or steatosis. Metabolic and inflammatory factors and transaminases significantly reduced after LSG-induced weight loss, except for SCCA-IgM. The ALT/AST ratio decreased post-LSG correlated with BMI (r = 0.297, p = 0.031), insulin (r = 0.354, p = 0.014), and triglycerides (r = 0.355, p = 0.009) reduction., Conclusions: Our results confirm the tight link between NAFLD and metabolic complications, suggesting prediabetes as a new risk factor of steatosis. SCCA-IgM does not seem to have a role in the identification and prognosis of NAFLD., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Insulin plays a major role in glucose metabolism and insulin-signaling defects are present in obesity and diabetes. CK2 is a pleiotropic protein kinase implicated in fundamental cellular pathways and abnormally elevated in tumors. Here we report that in human and murine adipocytes CK2-inhibition decreases the insulin-induced glucose-uptake by counteracting Akt-signaling and GLUT4-translocation to the plasma membrane. In mice CK2 acts on insulin-signaling in adipose tissue, liver and skeletal muscle and its acute inhibition impairs glucose tolerance. Notably, CK2 protein-level and activity are greatly up-regulated in white adipose tissue from ob/ob and db/db mice as well as from obese patients, regardless the severity of their insulin-resistance and the presence of pre-diabetes or overt type 2 diabetes. Weight loss obtained by both bariatric surgery or hypocaloric diet reverts CK2 hyper-activation to normal level. Our data suggest a central role of CK2 in insulin-sensitivity, glucose homeostasis and adipose tissue remodeling. CK2 up-regulation is identified as a hallmark of adipose tissue pathological expansion, suggesting a new potential therapeutic target for human obesity.

Context: Postprandial hypoglycemia (PPHG) is a recognized complication of Roux-en-Y gastric bypass (RYGB) surgery. Data on PPHG after laparoscopic sleeve gastrectomy (LSG) are scant., Objective: The objective of the study was to identify preoperative predictors of PPHG in subjects spontaneously self-reporting PPHG after RYGB or LSG. Patients, Setting, and Intervention: Nondiabetic patients spontaneously self-reporting symptoms/signs of PPHG (PPHG group, 21 RYGB and 11 LSG) were compared in a case-control design with subjects who never experienced spontaneous or oral glucose tolerance test (OGTT)-induced hypoglycemia over 24 months after surgery (No-PPHG group, 13 RYGB and 40 LSG). Paired pre- and postoperative 3-hour OGTTs were analyzed in all participants., Main Outcome Measures: Insulin sensitivity was assessed by the oral glucose insulin sensitivity index and β-cell function by mathematical modeling of the C-peptide response to glucose., Results: Before surgery, the body mass index was lower in PPHG than No-PPHG patients in the RYGB (P = .002) and trended similarly in the LSG group (P = .08). Fasting glycemia and the glucose-OGTT nadir were lower in the PPHG than the No-PPHG subjects in both surgery groups. Before surgery, insulin sensitivity was higher in PPHG than No-PPHG in the RYGB (393 ± 55 vs 325 ± 44 mL/min -1 · m -2 , P = .001) and LSG groups (380 ± 48 vs 339 ± 60 mL/min -1 · m -2 , P = .05) and improved to a similar extent in all groups after surgery. Before surgery, β-cell glucose sensitivity was higher in PPHG than No-PPHG in both RYGB (118 ± 67 vs 65 ± 24 pmol/min -1 · m 2 · mM -1 ) and LSG patients (114 ± 32 vs 86 ± 33) (both P = .02) and improved in all subjects after surgery., Conclusions: In subjects self-reporting PPHG after surgery, lower presurgery plasma glucose concentrations, higher insulin sensitivity, and better β-cell glucose sensitivity are significant predictors of PPHG after both RYGB and LSG.

Determinants of resting energy expenditure (REE) in humans are still under investigation, especially the association with insulin resistance. Brown adipose tissue (AT) regulates energy expenditure through the activity of the uncoupling protein 1 (UCP1). White AT browning is the process by which some adipocytes within AT depots acquire properties of brown adipocytes ("brite" adipocytes) and it correlates with metabolic improvement. We analyzed determinants of REE in patients with obesity and assessed UCP1 expression as a "brite" marker in abdominal subcutaneous AT (SAT) and visceral omental AT (VAT). Clinical data, REE, free fat mass (FFM), and fat mass (FM) were determined in 209 patients with obesity. UCP1 , PPARG coactivator 1 alpha (PPARGC1A), transcription factor A, mitochondrial (TFAM), T-box transcription factor 1 (TBX1), and solute carrier family 27 member 1 (SLC27A1) expression was assayed in SAT and VAT samples, obtained during sleeve gastrectomy from 62 patients with obesity. REE and body composition data were also available for a subgroup of 35 of whom. In 209 patients with obesity a multiple regression model was computed with REE as the dependent variable and sex, waist, FFM, FM, homeostasis model assessment-insulin resistance (HOMA), interleukin-6 and High Density Lipoprotein-cholesterol as the independent variables. Only FFM, FM and HOMA were independently correlated with REE (r = 0.787, AdjRsqr = 0.602). In each patient VAT displayed a higher UCP1, PPARGC1A, TFAM, TBX1 , and SLC27A1 expression than SAT and UCP1 expression in VAT (UCP1 -VAT) correlated with Body Mass Index (BMI) (r = 0.287, p < 0.05). Introducing UCP1 -VAT in the multivariate model, we showed that FFM, HOMA, interleukin-6, High Density Lipoprotein-cholesterol, and UCP1 -VAT were independent factors correlated with REE (r = 0.736, AdjRsqr = 0.612). We confirmed that REE correlates with FFM, FM and HOMA in a large cohort of patients. Our results clearly showed that UCP1 -VAT expression was significantly increased in severe human obesity (BMI > 50 kg/m2) and that it behaved as an independent predictor of REE. Lastly, we suggest that an increased REE and browning in metabolically complicated severe obesity could represent an effort to counteract further weight gain. [ABSTRACT FROM AUTHOR]

Intracellular calcium influences an array of pathways and affects cellular processes. With the rapidly progressing research investigating the molecular identity and the physiological roles of the mitochondrial calcium uniporter (MCU) complex, we now have the tools to understand the functions of mitochondrial Ca2 + in the regulation of pathophysiological processes. Herein, we describe the role of key MCU complex components in insulin resistance in mouse and human adipose tissue. Adipose tissue gene expression was analyzed from several models of obese and diabetic rodents and in 72 patients with obesity as well as in vitro insulin-resistant adipocytes. Genetic manipulation of MCU activity in 3T3-L1 adipocytes allowed the investigation of the role of mitochondrial calcium uptake. In insulin-resistant adipocytes, mitochondrial calcium uptake increased and several MCU components were upregulated. Similar results were observed in mouse and human visceral adipose tissue (VAT) during the progression of obesity and diabetes. Intriguingly, subcutaneous adipose tissue (SAT) was spared from overt MCU fluctuations. Furthermore, MCU expression returned to physiological levels in VAT of patients after weight loss by bariatric surgery. Genetic manipulation of mitochondrial calcium uptake in 3T3-L1 adipocytes demonstrated that changes in mitochondrial calcium concentration ([Ca2+]mt) can affect mitochondrial metabolism, including oxidative enzyme activity, mitochondrial respiration, membrane potential, and reactive oxygen species formation. Finally, our data suggest a strong relationship between [Ca2+]mt and the release of IL-6 and TNFa in adipocytes. Altered mitochondrial calcium flux in fat cells may play a role in obesity and diabetes and may be associated with the differential metabolic profiles of VAT and SAT. [ABSTRACT FROM AUTHOR]