Impairment of body mass reduction-associated activation of brown/beige adipose tissue in patients with type 2 diabetes mellitus.

Backgrounds/Objectives:The activity of brown/beige adipose tissue (B/BAT) is inversely proportional to body adiposity. Studies have shown that obese subjects submitted to distinct approaches aimed at reducing body mass present an increase of B/BAT activation. However, it is unknown if this beneficial effect of body mass reduction applies to patients with type 2 diabetes mellitus. In this study, we evaluated the impact of massive body mass reduction obtained as a consequence of bariatric surgery in the cold-induced activation of B/BAT in obese non-diabetic (OND) and obese diabetic (OD) subjects. SUBJECTS/METHODS: This is an observational study. Fourteen OND, 14 OD and 11 subjects were included in the study. All obese subjects were submitted to Roux-in-Y gastric bypass and measurements were performed before and 8 months after surgery. B/BAT was evaluated by (18F)-FDG-PET/CT scan and determination of signature transcript expression in specimens obtained in biopsies. RESULTS: Before surgery, mean B/BAT activity and the expression of signature transcripts were similar between OND and OD groups. Eight months after surgery, body mass reduction was similar between the obese groups. Nevertheless, the activity of B/BAT was increased in OND and unchanged in OD subjects. This effect was correlated with a more pronounced improvement of insulin resistance, as evaluated by the hyperinsulinemic, euglycemic clamp, in OND subjects as compared with OD subjects. CONCLUSIONS: Body mass reduction has a more efficient effect to induce the activation of B/BAT in non-diabetic than in diabetic subjects. This effect is accompanied by more pronounced insulin sensitivity and serine 473 phosphorylation of Akt in B/BAT of non-diabetic than in diabetic subjects.

Distinct regulation of hypothalamic and brown/beige adipose tissue activities in human obesity.

BACKGROUND/OBJECTIVES: The identification of brown/beige adipose tissue in adult humans has motivated the search for methods aimed at increasing its thermogenic activity as an approach to treat obesity. In rodents, the brown adipose tissue is under the control of sympathetic signals originating in the hypothalamus. However, the putative connection between the depots of brown/beige adipocytes and the hypothalamus in humans has never been explored. The objective of this study was to evaluate the response of the hypothalamus and brown/beige adipose tissue to cold stimulus in obese subjects undergoing body mass reduction following gastric bypass. SUBJECTS/METHODS: We evaluated twelve obese, non-diabetic subjects undergoing Roux-in-Y gastric bypass and 12 lean controls. Obese subjects were evaluated before and approximately 8 months after gastric bypass. Lean subjects were evaluated only at admission. Subjects were evaluated for hypothalamic activity in response to cold by functional magnetic resonance, whereas brown/beige adipose tissue activity was evaluated using a (F 18) fluorodeoxyglucose positron emisson tomography/computed tomography scan and real-time PCR measurement of signature genes. RESULTS: Body mass reduction resulted in a significant increase in brown/beige adipose tissue activity in response to cold; however, no change in cold-induced hypothalamic activity was observed after body mass reduction. No correlation was found between brown/beige adipose tissue activation and hypothalamus activity in obese subjects or in lean controls. CONCLUSIONS: In humans, the increase in brown/beige adipose tissue activity related to body mass reduction occurs independently of changes in hypothalamic activity as determined by functional magnetic resonance.

Cerebrospinal fluid xenin levels during body mass reduction: no evidence for obesity-associated defective transport across the blood-brain barrier.

CONTEXT: Recent studies have shown that xenin can act in the hypothalamus, reducing food intake through a leptin- and melanocortin system-independent mechanism. OBJECTIVE: To evaluate the impact of body mass reduction on the blood and cerebrospinal fluid (CSF) levels of xenin. DESIGN AND SETTING: Thirteen obese patients (11 women) selected for roux-in-Y gastric bypass surgery were evaluated before and approximately 8 months after surgery. Xenin was determined in serum and CSF by radioimmunoassay. RESULTS: As compared with lean subjects, obese patients have increased blood levels of xenin, which reduce after surgery. There are significant correlations between blood xenin and blood leptin and insulin levels. CSF concentration of xenin is ∼10-fold lower than blood levels, and is significantly higher in obese subjects as compared with lean ones, returning to normal levels after body mass reduction. There is a significant linear correlation between CSF and blood levels of xenin. CONCLUSION: Xenin is present in the human CSF in a concentration ∼10-fold lower than the blood. Both blood and CSF xenin are correlated with blood levels of important markers of adiposity, leptin and insulin. The levels of CSF xenin are linearly correlated with blood xenin, independently of patient body mass, suggesting that either its transport across the blood-brain barrier is not saturated in the concentration range detected in this study or that there is a coordinated release of xenin from the periphery and the CNS.

Defective regulation of adipose tissue autophagy in obesity.

OBJECTIVES: Autophagy is a highly regulated process that has an important role in the control of a wide range of cellular functions, such as organelle recycling, nutrient availability and tissue differentiation. A recent study has shown an increased autophagic activity in the adipose tissue of obese subjects, and a role for autophagy in obesity-associated insulin resistance was proposed. Body mass reduction is the most efficient approach to tackle insulin resistance in over-weight subjects; however, the impact of weight loss in adipose tissue autophagy is unknown. SUBJECTS: Adipose tissue autophagy was evaluated in mice and humans. RESULTS: First, a mouse model of diet-induced obesity and diabetes was maintained on a 15-day, 40% caloric restriction. At baseline, markers of autophagy were increased in obese mice as compared with lean controls. Upon caloric restriction, autophagy increased in the lean mice, whereas it decreased in the obese mice. The reintroduction of ad libitum feeding was sufficient to rapidly reduce autophagy in the lean mice and increase autophagy in the obese mice. In the second part of the study, autophagy was evaluated in the subcutaneous adipose tissue of nine obese-non-diabetic and six obese-diabetic subjects undergoing bariatric surgery for body mass reduction. Specimens were collected during the surgery and approximately 1 year later. Markers of systemic inflammation, such as tumor necrosis factor-1α, interleukin (IL)-6 and IL-1ß were evaluated. As in the mouse model, human obesity was associated with increased autophagy, and body mass reduction led to an attenuation of autophagy in the adipose tissue. CONCLUSION: Obesity and caloric overfeeding are associated with the defective regulation of autophagy in the adipose tissue. The studies in obese-diabetic subjects undergoing improved metabolic control following calorie restriction suggest that autophagy and inflammation are regulated independently.

PGC1α gene Gly482Ser polymorphism predicts improved metabolic, inflammatory and vascular outcomes following bariatric surgery.

AIMS/HYPOTHESIS: Bariatric surgery is currently employed as an effective approach to treat class III obesity and class II obesity with co-morbidities. Unfortunately, the general anthropometric and metabolic outcomes of the surgery are not homogeneous, and defining the eligibility criteria that allow for a more precise prediction of the outcomes of this invasive procedure will refine the selection of patients. Here we tested the hypothesis that the Gly482Ser polymorphism of the ppargc1a gene would predict different outcomes following bariatric surgery. METHODS: Fifty-five patients (26 Gly/Gly and 29 Gly/Ser+Ser/Ser) selected for the Roux-en-Y gastric bypass according to the National Institutes of Health Consensus Statement criteria were followed up for 1 year, monitoring their anthropometric, metabolic and inflammatory parameters. RESULTS: Patients with the Gly482Ser polymorphism had significantly improved reductions in the waist/hip ratio, fasting blood glucose, C-reactive protein, blood leukocyte count, serum interleukin-6 and intima-media thickness of the carotid artery, as compared with Gly/Gly patients. CONCLUSIONS/INTERPRETATION: Thus, the Gly482Ser polymorphism may predict a more favorable metabolic and inflammatory outcome for obese patients submitted to bariatric surgery, leading to a reduced atherosclerotic risk.

Correlation between levels of adipokines and inflammatory mediators with spirometric parameters in individuals with obesity and symptoms of asthma: Cross-sectional study.

INTRODUCTION: The adipose tissue secretes adipokines and influences the release of inflammatory mediators contributing to a state of low-grade systemic inflammation that may change lung function. OBJECTIVE: To correlate levels of adipokines and inflammatory mediators with lung function in individuals with obesity and bronchial asthma symptoms. MATERIALS AND METHODS: A cross-sectional study, including women with obesity (grade II and III) with symptoms and clinical diagnosis of asthma. Anthropometric measurements (weight, height, BMI), pulmonary function test (spirometry), asthma control test questionnaire, collection of systemic inflammatory markers (blood collection) and pulmonary markers (sputum collection) were collected and were analyzed: IL-6, IL-8, TNF-α, adiponectin, resistin, leptin and C-reactive protein (CRP). The patients were stratified into two groups according to asthma control. RESULTS: 80 women were analyzed and 40% had an ACT score greater than or equal to 18 and were classified as "controlled asthma". More than half of the patients of ACT<18 score obtaining measures of FEV1, PEF and FEF25-75% below and 80% of predicted. There was a significant and negative correlation between IL-6 in the sputum with FVC and FEF25-75% in the group ACT<18 and with FVC and FEV1 in the group ACT≥18. CONCLUSIONS: Therefore, we concluded that the increase of interleukin-6 in the sputum is related to worse pulmonary function even in patients with controlled asthma, especially in the translate airway permeability measures.

Erectile dysfunction and hormonal imbalance in morbidly obese male is reversed after gastric bypass surgery: a prospective randomized controlled trial.

The effects of weight loss on erectile function and hormones have not been well studied. The aim of this study was to measure the degree to which sexual function and in particular erectile function and hormonal environment change after substantial weight loss, surgically and non-surgically induced in the morbidly obese male in a prospective randomized long-term controlled trial. Furthermore, how surgery makes a difference when treating morbidly obese men was envisaged in this context. We prospectively studied 20 morbidly obese men for 24 months, divided into two groups: group A included 10 patients who underwent life style modifications (exercise and diet) for 4 months and subsequently gastric bypass, and another 10 patients in group B were kept on weekly follow-up. None of the men were taking phosphodiesterase type-5 inhibitors. All patients underwent International Index of Erectile Function (IIEF)-5 questionnaire, serum oestradiol, prolactin (PRL), luteinizing (LH) and follicle-stimulating (FSH) hormones, free and total testosterone (FT and TT) at baseline (time 0), surgery - 4 months latter baseline (time 1) and final evaluation - 24 months (time 2). From times 0 to 1, group A presented a mean body mass index (BMI) reduction of 12.6 (p < 0.0001), whereas group B, 2.1 (p > 0.05). The BMI reductions between times 0 and 2 were 24.7 (p < 0.0001) and 0.7 (p > 0.05) for groups A and B respectively. BMI average between the two groups was similar at time 0 (p = 0.2142), and different at times 1 (p = 0.0033) and 2 (p < 0.0006). Increase in IIEF-5 score (p = 0.0469), TT (p = 0.0349) and FSH levels (p = 0.0025), and reduction in PRL level (p < 0.0001) were observed in group A from times 0 to 2 and 1 to 2. There were no changes from times 0 to 1. Comparing groups A and B at time 2, IIEF-5, TT and FT increased significantly in group A (p = 0.0224, 0.0043 and 0.0149 respectively). Surgery-induced weight loss increased erectile function quality measured by IIEF-5 questionnaire, increased TT, FT and FSH and reduced PRL levels. The hormonal impact verified could justify the improvement in erectile function. Lifestyle modifications impacted BMI without hormonal or sexual impact in morbidly obese. New studies are warranted in the field to support our data.

Surgical treatment of type 2 diabetes in subjects with mild obesity: mechanisms underlying metabolic improvements.

BACKGROUND: This study aims to assess the clinical and physiological effects of Roux-en-Y gastric bypass (RYGBP) on type 2 diabetes associated with mild obesity (body mass index [BMI] 30-34.9 kg/m(2)) over 24 months postsurgery. METHODS: In this prospective trial, 36 mildly obese subjects (19 males) with type 2 diabetes using oral antidiabetic drugs with (n = 24) or without insulin (n = 12) underwent RYGBP. Follow-up was conducted at baseline and 3, 6, 12, and 24 months postsurgery. The following endpoints were considered: changes in HbA1c, fasting glucose and insulin, antidiabetic therapy, BMI, oral glucose insulin sensitivity [OGIS, from meal tolerance test (MTT)], beta-cell secretory function [ΔCP(0-30)/ΔGlu(0-30) (ΔC-peptide/Δglucose ratio, MTT 0-30 min), disposition index (DI = OGIS [Symbol: see text] ΔCP(0-30)/ΔGlu(0-30)], glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) [incremental area under the curve (AUCi)], adiponectin, C-reactive protein, and lipids. RESULTS: All subjects achieved normal-to-overweight BMI after 3 months. Over 24 months, 31/36 (86 %) subjects presented HbA1c <7 % [complete and partial remission of diabetes in 9/36 (22 %) and 1/36 (3 %), respectively]. Since 3 months postsurgery, improvements were observed in OGIS [290 (174) to 373 (77) ml/min/m(2), P = 0.009], ΔCP(0-30)/ΔGlu(0-30) [0.24 (0.19) to 0.52 (0.34) ng/mg, P = 0.001], DI [7.16 (8.53) to 19.8 (15.4) (ng/mg) (ml/min/m(2)), P = 0.001], GLP-1 AUCi [0.56 (0.64) to 3.97 (3.86) ng/dl [Symbol: see text] 10 min [Symbol: see text] 103, P = 0.000], and GIP AUCi [30.2 (12.6) to 27.0 (20.2) ng/dl [Symbol: see text] 10 min [Symbol: see text] 103, P = 0.004]. At baseline and after 12 months, subjects with diabetes nonremission had longer diabetes duration, higher HbA1c, lower beta-cell secretory function, and higher first 30-min GIP AUCi, compared with those with remission. CONCLUSIONS: RYGBP improves the glucose metabolism in subjects with type 2 diabetes and mild obesity. This effect is associated with improvement of insulin sensitivity, beta-cell secretory function, and incretin secretion.

The effect of electroconvulsive therapy (ECT) on implicit memory: skill learning and perceptual priming in patients with major depression.

While explicit memory in amnesics is impaired, their implicit memory remains preserved. Memory impairment is one of the side effects of electroconvulsive therapy (ECT). ECT patients are expected to show impairment on explicit but not implicit tasks. The present study examined 17 normal controls and 17 patients with severe major depressive disorder who underwent right unilateral ECT. Patients were tested in three sessions: 24-48 hours prior to, 24-48 hours following the first ECT, and 24-48 hours following the eighth ECT. The controls were tested in three sessions, at time intervals that paralleled those of the patients. Implicit memory was tested by the perceptual priming task - Partial Picture-Identification (PPI). The skill learning task used entailed solving the Tower of Hanoi puzzle (TOHP). Explicit memory was tested by picture recall from the PPI task, verbal recall of information regarding the TOHP, and by the Visual Paired Association (VPA) test. Results showed that explicit questions about the implicit tasks were impaired following ECT treatment. Patients' learning ability, as measured by the VPA task, was only impaired in the first testing session, prior to ECT treatment, reflecting the effect of depression. In addition, groups only differed in the first session on the learning rate of the skill learning task. Perceptual priming was preserved in the patients' group in all sessions, indicating that it is resilient to the effect of depression and ECT. The results are interpreted in terms of the differential effect of depression and ECT on explicit and implicit memory.

Restored insulin inhibition on insulin secretion in nondiabetic severely obese patients after weight loss induced by bariatric surgery.

OBJECTIVE: To examine the impact of important weight loss on insulin inhibition of its own secretion during experimentally induced hyperinsulinemia under euglycemic conditions. DESIGN: Longitudinal, clinical intervention study--bariatric surgery (vertical banded gastroplasty--gastric bypass--Capella technique), re-evaluation after 4 and 14 months. SUBJECTS: Nine obese patients class III (BMI=54.6+/-2.6 kg/m2) and nine lean subjects (BMI=22.7+/-0.7 kg/m2). MEASUREMENTS: Euglycemic hyperinsulinemic clamp (insulin infusion: 40 mU/min m2), C-peptide plasma levels, electrical bioimpedance methodology, and oral glucose tolerance test (OGTT). RESULTS: BMI was reduced in the follow-up: 44.5+/-2.2 and 33.9+/-1.5 kg/m2 at 4 and 14 months. Insulin-induced glucose uptake was markedly reduced in obese patients (19.5+/-1.9 micromol/min kg FFM) and improved with weight loss, but in the third study, it was still lower than that observed in controls (35.9+/-4.0 vs 52.9+/-2.2 micromol/min kg FFM). Insulin-induced inhibition of its own secretion was blunted in obese patients (19.9+/-5.7%, relative to fasting values), and completely reversed to values similar to that of lean ones in the second and third studies (-60.8+/-4.2 and -54.0+/-6.1%, respectively). CONCLUSION: Weight loss in severe obesity improved insulin-induced glucose uptake, and completely normalized the insulin inhibition on its own secretion.