Targeting SIRT1 Rescues Age- and Obesity-Induced Microvascular Dysfunction in Ex Vivo Human Vessels.

BACKGROUND: Experimental evidence suggests a key role of SIRT1 (silent information regulator 1) in age- and metabolic-related vascular dysfunction. Whether these effects hold true in the human microvasculature is unknown. We aimed to investigate the SIRT1 role in very early stages of age- and obesity-related microvascular dysfunction in humans. METHODS: Ninety-five subjects undergoing elective laparoscopic surgery were recruited and stratified based on their body mass index status (above or below 30 kg/m2) and age (above or below 40 years) in 4 groups: Young Nonobese, Young Obese, Old Nonobese, and Old Obese. We measured small resistance arteries' endothelial function by pressurized micromyography before and after incubation with a SIRT1 agonist (SRT1720) and a mitochondria reactive oxygen species (mtROS) scavenger (MitoTEMPO). We assessed vascular levels of mtROS and nitric oxide availability by confocal microscopy and vascular gene expression of SIRT1 and mitochondrial proteins by qPCR. Chromatin immunoprecipitation assay was employed to investigate SIRT1-dependent epigenetic regulation of mitochondrial proteins. RESULTS: Compared with Young Nonobese, obese and older patients showed lower vascular expression of SIRT1 and antioxidant proteins (FOXO3 [forkhead box protein O3] and SOD2) and higher expression of pro-oxidant and aging mitochondria proteins p66Shc and Arginase II. Old Obese, Young Obese and Old Nonobese groups endothelial dysfunction was rescued by SRT1720. The restoration was comparable to the one obtained with mitoTEMPO. These effects were explained by SIRT1-dependent chromatin changes leading to reduced p66Shc expression and upregulation of proteins involved in mitochondria respiratory chain. CONCLUSIONS: SIRT1 is a novel central modulator of the earliest microvascular damage induced by age and obesity. Through a complex epigenetic control mainly involving p66Shc and Arginase II, it influences mtROS levels, NO availability, and the expression of proteins of the mitochondria respiratory chain. Therapeutic modulation of SIRT1 restores obesity- and age-related endothelial dysfunction. Early targeting of SIRT1 might represent a crucial strategy to prevent age- and obesity-related microvascular dysfunction.

Morbid obesity is associated with hypertrophic outward remodeling and increased stiffness of small conduit arteries: An ultra-high frequency ultrasound study.

BACKGROUND AND AIMS: Although many studies have been published on the effect of obesity on large and small arteries, there are no data in the literature regarding the effect of obesity on medium-sized arteries, and in particular of small conduit arteries. The aim of the present study was to investigate whether patients with severe obesity presented structural or functional alterations in different arterial segments. METHODS AND RESULTS: 34 patients with severe obesity (BMI≥35 kg/m2) and 34 age-and sex-matched normal weight patients were recruited as controls. Aortic stiffness (carotid-femoral pulse wave velocity) and wave reflection (augmentation index) were recorded. Ultrasound images of common carotid, radial and interdigital arteries were acquired for the assessment of wall-to-lumen ratio, wall cross-sectional area (WCSA), compliance, distensibility coefficient (DC) and Young's elastic modulus (Einc). Insulin sensitivity was calculated by oral glucose sensitivity index (OGIS). No differences between groups in carotid artery remodeling were found, while WCSA of the radial and interdigital arteries were higher in obese group than in controls. As regard the parameters of vascular elasticity, the DC of radial and interdigital arteries were lower (p = 0.025 and p = 0.001, respectively), as well as the Einc of radial arteries was higher (p = 0.021), in subject with obesity compared to controls. All these correlations were consistent after adjustment for the main covariates. Finally, in a multiple regression analysis OGIS was and independent determinant of interdigital artery DC (R2 = 0.29, p = 0.001). CONCLUSIONS: For the first time, we describe an outward remodeling and increased stiffness in small conduit arteries in severe obesity.

Glomerular hyperfiltration in morbid obesity: Role of the inflammasome signalling.

AIM: Obesity is associated with glomerular hyperfiltration which may precede the development of overt renal damage. Few studies evaluated the link between inflammasome signalling and hyperfiltration. The aim is to evaluate the relationship between IL1-ß/Caspase-1, insulin sensitivity and hyperfiltration in subjects with severe obesity, before and after weight loss. METHODS: Forty-six patients with BMI > 35 kg/m2 , without type-2-diabetes or hypertension, were evaluated at baseline and 6 months after bariatric surgery with oral glucose tollerance test, bioimpedance analysis and blood tests. The eGFR was calculated according to EPIcr-cys formula and insulin sensitivity by Oral Glucose Insulin Sensitivity. IL-1ß/Caspase-1 were measured with the ELISA-kit. HF was defined as eGFR ≥ 140 ml/min (non-indexed for BSA). RESULTS: Sixteen subjects at baseline had hyperfiltration, with a higher insulin resistance, BMI, lean mass and plasma levels of IL-1ß/Caspase-1. After surgery, there was a reduction in BMI and improvement in insulin resistance in all patients. However, in 8 of 16 patients hyperfiltration persisted and IL-1ß/Caspase-1 levels did not decrease (3.22 ± 0.79 vs. 3.13 ± 1.03 and 23.7 ± 12.1 vs. 20.6 ± 9.1, pre vs. post, pg/ml), while cytokines normalized in all the other patients in parallel with the eGFR. In a logistic regression model, correcting for the main covariates, lean mass and IL-1ß before surgery (p = .01 and p = .03, respectively), were the only predictors of hyperfiltration. CONCLUSION: Weight loss is effective in reducing hyperfiltration in most, but not all patients. Hyperfiltration remains unchanged in subjects who do not have a reduction in IL-1ß/Caspase-1, suggesting a pathogenetic role of the inflammasome signalling in the early stages of nephropathy.

Evidence of a Gastro-Duodenal Effect on Adipose Tissue and Brain Metabolism, Potentially Mediated by Gut-Liver Inflammation: A Study with Positron Emission Tomography and Oral 18FDG in Mice.

Interventions affecting gastrointestinal (GI) physiology suggest that the GI tract plays an important role in modulating the uptake of ingested glucose by body tissues. We aimed at validating the use of positron emission tomography (PET) with oral 18FDG administration in mice, and to examine GI effects on glucose metabolism in adipose tissues, brain, heart, muscle, and liver, and interfering actions of oral lipid co-administration. We performed sequential whole-body PET studies in 3 groups of 10 mice, receiving i.p. glucose and 18FDG or oral glucose and 18FDG ± lipids, to measure tissue glucose uptake (GU) and GI transit, and compute the absorption lumped constant (LCa) as ratio of oral 18FDG-to-glucose incremental blood levels. GI and liver histology and circulating hormones were tested to generate explanatory hypothesis. Median LCa was 1.18, constant over time and not significantly affected by lipid co-ingestion. Compared to the i.p. route, the oral route (GI effect) resulted in lower GU rates in adipose tissues and brain, and a greater steatohepatitis score (+17%, p = 0.03). Lipid co-administration accelerated GI transit, in relation to the suppression in GIP, GLP1, glucagon, PP, and PYY (GI motility regulators), abolishing GI effects on subcutaneous fat GU. Duodenal crypt size, gastric wall 18FDG uptake, and macro-vesicular steatosis were inversely related to adipose tissue GU, and positively associated with liver GU. We conclude that 18FDG-PET is a suitable tool to examine the role of the GI tract on glucose transit, absorption, and bio-distribution. The GI effect consists in the suppression of glucose metabolism selectively in organs responsible for energy intake and storage, and is blunted by lipid ingestion. Modulation of gut and liver inflammation, as reflected by high GU, may be involved in the acute signalling of the energy status.

Postprandial hypoglycaemia after Roux-en-Y gastric bypass in individuals with type 2 diabetes.

AIMS/HYPOTHESIS: Postprandial hypoglycaemia (PPHG) is a complication of Roux-en-Y gastric bypass (RYGB) surgery in normoglycaemic individuals. In type 2 diabetes, RYGB improves glucose metabolism, but whether this improvement is related to the later development of PPHG is not known. We investigated the presence and mechanisms of PPHG in individuals with type 2 diabetes undergoing RYGB. METHODS: A total of 35 obese individuals with type 2 diabetes underwent an OGTT before and 24 months after surgery. PPHG was defined as a plasma glucose level of ≤3.3 mmol/l when not taking glucose-lowering agents. Insulin sensitivity was assessed by oral glucose insulin sensitivity index and beta-cell function by mathematical modelling of the plasma glucose, insulin and C-peptide concentrations. RESULTS: After surgery, PPHG occurred in 11 of 35 individuals who underwent RYGB. Before surgery, BMI was lower, glycaemic control less good and time of glucose peak earlier in the PPHG vs No PPHG group, and the duration of diabetes was shorter with PPHG (all p ≤ 0.05). In addition, insulin sensitivity was greater in the PPHG than No PPHG group (p = 0.03). After surgery, BMI and fasting glucose and insulin levels decreased similarly in the two groups; insulin secretion during the first hour of the OGTT increased more in the PPHG than No PPHG group (p = 0.04). Beta-cell glucose sensitivity increased more in individuals with PPHG than those without (p = 0.002). Over the same time interval, the glucagon-like peptide 1 (GLP-1) response was lower in individuals with PPHG before surgery (p = 0.05), and increased more after surgery. At 2 h after glucose ingestion in the OGTT, postsurgery plasma glucagon level was significantly lower in the PPHG than No PPHG group. CONCLUSIONS/INTERPRETATION: In morbidly obese individuals with type 2 diabetes, spontaneous PPHG may occur after bariatric surgery independently of a remission of diabetes. Before surgery, individuals had a shorter duration and were more insulin sensitive. Two years after surgery, these individuals developed greater beta-cell glucose sensitivity, and showed greater insulin and GLP-1 release early in the OGTT.

Association between blood pressure variability, cardiovascular disease and mortality in type 2 diabetes: A systematic review and meta-analysis.

AIM: To investigate the associations of blood pressure variability (BPV), expressed as long-term (visit-to-visit) and short-term (ambulatory blood pressure monitoring [ABPM] and home blood pressure monitoring [HBPM]) and all-cause mortality, major adverse cardiovascular events (MACEs), extended MACEs, microvascular complications (MiCs) and hypertension-mediated organ damage (HMOD) in adult patients with type 2 diabetes. MATERIALS AND METHODS: PubMed, Medline, Embase, Cinahl, Web of Science, ClinicalTrials.gov and grey literature databases were searched for studies including patients with type 2 diabetes, at least one variable of BPV (visit-to-visit, HBPM, ABPM) and evaluation of the incidence of at least one of the following outcomes: all-cause mortality, MACEs, extended MACEs and/or MiCs and/or HMOD. The extracted information was analyzed using random effects meta-analysis and meta-regression. RESULTS: Data from a total of 377 305 patients were analyzed. Systolic blood pressure (SBP) variability was associated with a significantly increased risk of all-cause mortality (HR 1.12, 95% CI 1.04-1.21), MACEs (HR 1.01, 95% CI 1.04-1.17), extended MACEs (HR 1.07, 95% CI 1.03-1.11) and MiCs (HR 1. 12, 95% CI 1.01-1.24), while diastolic blood pressure was not. Associations were mainly driven from studies on long-term SBP variability. Qualitative analysis showed that BPV was associated with the presence of HMOD expressed as carotid intima-media thickness, pulse wave velocity and left ventricular hypertrophy. Results were independent of mean blood pressure, glycaemic control and serum creatinine levels. CONCLUSIONS: Our results suggest that BPV might provide additional information rather than mean blood pressure on the risk of cardiovascular disease in patients with type 2 diabetes.

Aging Modulates the Influence of Arginase on Endothelial Dysfunction in Obesity.

Objective- Arginase can reduce NO availability. In this study, we explored arginase as a determinant of endothelial dysfunction in small arteries from obese patients and its relationship with aging and microvascular remodeling. Approach and Results- Small arteries were dissected after subcutaneous fat biopsies and evaluated on a pressurized micromyograph. Endothelium-dependent vasodilation was assessed by acetylcholine, repeated under L-NAME ( N G-nitro-L-arginine-methyl ester), N(ω)-hydroxy-nor-l-arginine (arginase inhibitor) and gp91ds-tat (NADPH [nicotinamide adenine dinucleotide phosphate oxidase] oxidase inhibitor) in vessels from young (age <30 years) control and obese and old (>30 years) control and obese subjects. Media-lumen ratio and amount of vascular wall fibrosis were used as markers of vascular remodeling. Amount of vascular superoxide anions and NO production were determined with immunofluorescence, whereas arginase expression was quantified using Western blot and quantitative polymerase chain reaction. Obese and older age groups had lower vascular NO, as well as higher media-lumen ratio, wall fibrosis, intravascular superoxide, and blunted inhibitory effect of L-NAME on acetylcholine versus controls and younger age groups. N(ω)-hydroxy-nor-l-arginine restored the acetylcholine-induced vasodilation in young and, to a lesser extent, in old obese subjects. This effect was abolished by addition of L-NAME. Gp91ds-tat increased the vasodilatory response to N(ω)-hydroxy-nor-l-arginine in old obese. Superoxide anions and arginase I/II levels were higher in the vascular wall of obese versus controls. Conclusions- Arginase contributes to microvascular endothelial dysfunction in obesity. Its impact is reduced by aging because of higher levels of vascular oxidative stress. Obesity is accompanied by accelerated microvascular remodeling, the extent of which is related to the amount of arginase in the vascular wall.

Insulin resistance and normal thyroid hormone levels: prospective study and metabolomic analysis.

While hyperthyroidism and hypothyroidism cause dysglycemia, the relationship between thyroid hormone levels within the normal range and insulin resistance (IR) is unclear. In 940 participants with strictly normal serum concentrations of free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH) followed up for 3 yr, we measured insulin sensitivity (by the insulin clamp technique) and 35 circulating metabolites. At baseline, across quartiles of increasing fT3 levels (or fT3/fT4 ratio) most features of IR emerged [i.e., male sex, greater body mass index (BMI), waist circumference, heart rate, blood pressure, fatty liver index, free fatty acids, and triglycerides; reduced insulin-mediated glucose disposal; and ß-cell glucose sensitivity). In multiadjusted analyses, fT3 was reciprocally related to insulin sensitivity and, in a subset of 303 subjects, directly related to endogenous glucose production. In multiple regression models adjusting for sex, age, BMI, and baseline value of insulin sensitivity, higher baseline fT3 levels were significant predictors of decreases in insulin sensitivity. Moreover, baseline fT3 predicted follow-up increases in glycemia independently of sex, age, BMI, insulin sensitivity, ß-cell glucose sensitivity, and baseline glycemia. Serum tyrosine levels were higher with IR and were directly associated with fT3; higher α-hydroxybutyrate levels signaled enhanced oxidative stress, thereby impairing tyrosine degradation. In 25 patients with morbid obesity, surgery-induced weight loss improved IR and consensually lowered fT3 levels. High-normal fT3 levels are associated with IR both cross-sectionally and longitudinally, and predict deterioration of glucose tolerance. This association is supported by a metabolite pattern that points at increased oxidative stress as part of the IR syndrome.

Long-Term effects of physical activity on weight loss, metabolic parameters and blood pressure in subjects undergoing bariatric surgery: A 5-year follow-up study.

BACKGROUND: bariatric surgery stands as an effective intervention for weight loss and improved metabolic control in obesity, although over time there is a proportion of weight regain and type-2-diabetes (T2D) relapse. AIMS: to explore the role of physical activity (PA) after surgery and its impact on metabolic parameters during a 5-year follow-up. METHODS: 148 individuals who underwent bariatric surgery completed scheduled examinations over 5-years. Physical assessments and laboratory tests were conducted pre-surgery and annually thereafter. PA levels were evaluated using the International Physical Activity Questionnaire. RESULTS: participants were split into the PA group, who engaged in regular physical activity, and No-PA group, who remained sedentary throughout. In T2D individuals before surgery, PA group showed significant reductions in blood pressure and a lower T2D recurrence (6.7 â€‹% vs 36 â€‹%) compared to No-PA group. In normoglycemic individuals, the PA group led to sustained BMI reduction and improved blood pressure control (p â€‹< â€‹0.001) compared to No-PA group, for the entire duration of follow-up. CONCLUSIONS: regular PA demonstrated cardio-metabolic benefits post-bariatric surgery. Integrating PA into post-bariatric care could enhance long-term outcomes.

Decreased Weight Loss Following Bariatric Surgery in Patients with Type 2 Diabetes.

BACKGROUND: Bariatric surgery represents the most effective treatment for achieving significant and sustained weight loss. We aimed to assess whether presence of type 2 diabetes (T2D) at baseline, and T2D remission following bariatric surgery affect the weight loss outcome. METHODS: Data of 312 consecutive morbidly obese subjects who underwent bariatric surgery were analysed. Patients underwent either RYGB (77%), or sleeve gastrectomy (23%), and their body weight was followed-up for 1, 2, 3, 4, and 5 years at regular ambulatory visits (N = 269, 312, 210, 151, 105, at each year, respectively). T2D remission was assessed according to the ADA criteria. RESULTS: In the whole dataset, 92 patients were affected by T2D. Patients with T2D were older than patients without T2D (52 ± 9 vs 45 ± 11 years, p < 0.0001), but there were no differences in baseline BMI, sex, and type of intervention received. We found that presence of T2D at baseline was associated with smaller weight loss at 1, 2, 3, 4, and 5 years following bariatric surgery (δ BMI at 2 years: - 13.7 [7.7] vs - 16.4 [7.3] kg/m2; at 5 years - 12.9 [8.8] vs - 16.3 [8.7] kg/m2 in patients with T2D vs patients without T2D respectively, all p < 0.05). When dividing the patients with T2D in remitters and non-remitters, non-remitters had significantly smaller weight loss compared to remitters (δ BMI at 2 years: - 11.8 [6.3] vs - 15.4 [7.8] kg/m2; at 5 years: - 8.0 [7.1] vs - 15.0 [7.2] kg/m2, non-remitters vs remitters respectively, all p < 0.05). CONCLUSIONS: T2D is independently associated to smaller weight loss following bariatric surgery, especially in subjects not achieving diabetes remission. • Patients with T2D achieve smaller weight loss following bariatric surgery • When dividing the T2D patients in remitters and non-remitters, non-remitters achieve significantly smaller weight loss compared to remitters.

Non-albumin proteinuria marks tubular involvement and is associated with arterial stiffness in subjects affected by severe obesity.

INTRODUCTION: Obesity is a well-established risk factor for kidney disease, and tubular damage can play a pivotal role in the development of obesity-related kidney damage. This study aimed to investigate the pathophysiological pathways involved in the development of non-albumin proteinuria (NAP), a marker of tubular involvement, in a cohort of subjects with severe obesity and preserved kidney function. METHODS: A total of 106 subjects with BMI ≥ 35 kg/m2 in waiting list for bariatric surgery underwent blood chemistry analysis including metabolic and lipid profile, vascular tests for cardiovascular risk stratification and a comprehensive assessment of kidney function, including renal resistive index (RRI) and NAP measurement. RESULTS: Nineteen patients with ACR ≥ 30 mg/g regardless of NAP values (ALB+), nineteen with NAP≥ 150 mg/g and albuminuria < 30 mg/g (iNAP) and sixty-eight without proteinuria (No-P) were found. Both ALB+ and iNAP groups exhibited a higher prevalence of hypertension and anti-hypertensive treatment compared to No-P, while the prevalence of diabetes was similar between groups. Concerning lipid profile, no differences in total, HDL and LDL cholesterol were found, while ALB+ patients had higher serum triglyceride levels than the other two groups. RRI and carotid-femoral pulse wave velocity (cf-PWV) was significantly higher in ALB+ and iNAP groups compared to No-P. Remarkably, cf-PWV remained still significant after adjustment for age, sex and MBP (p = 0.0004). In overall population, a multiple regression analysis showed that cf-PWV was an independent determinant of NAP in a model including age, sex, glycated hemoglobin, systolic and mean blood pressure (R2 =0.17, p = 0.031). CONCLUSION: iNAP subjects showed increased arterial stiffness comparable to that observed in ALB+ group, suggesting that they may represent a subgroup at higher cardiovascular risk, often unrecognized in clinical practice.

The renal resistive index is associated with microvascular remodeling in patients with severe obesity.

BACKGROUND: Renal hemodynamics is impaired since the early stage of cardiometabolic disease. However, in obesity, its noninvasive ultrasound assessment still fails to provide pathophysiologic and clinical meaningfulness. We aimed to explore the relationship between peripheral microcirculation and renal hemodynamics in severe obesity. METHODS: We enrolled fifty severely obese patients with an indication for bariatric referring to our outpatient clinic. Patients underwent an extensive reno-metabolic examination, paired with Doppler ultrasound and measurement of the renal resistive index (RRI). On the day of the surgery, visceral fat biopsies were collected to perform an ex-vivo complete microcirculatory assessment. Media-to-lumen ratio (M/L) and vascular response to acetylcholine (ACh), alone or co-incubated with N G -nitro arginine methyl ester (L-NAME), were measured. RESULTS: Patients were stratified according to their normotensive (NT) or hypertensive (HT) status. HT had lower estimated glomerular filtration rate and higher RRI compared to NT, while the presence and extent of albuminuria were similar between the two groups. Concerning microcirculatory assessment, there were no differences between groups as regards the microvascular structure, while the vasorelaxation to ACh was lower in HT ( P = 0.042). Multivariable analysis showed a relationship between M/L and RRI ( P  = 0.016, St. ß 0.37) and between albuminuria and the inhibitory response of L-NAME to Ach vasodilation ( P   =  0.036, St. ß = -0.34). Notably, all these correlations were consistent also after adjustment for confounding factors. CONCLUSIONS: The RRI and albuminuria relationship with microvascular remodeling in patients affected by severe obesity supports the clinical implementation of RRI to improve risk stratification in obesity and suggests a tight pathophysiologic connection between renal haemodynamics and microcirculatory disruption.

The Beneficial Effects of Bariatric-Surgery-Induced Weight Loss on Renal Function.

Obesity represents an independent risk factor for the development of chronic kidney disease (CKD), leading to specific histopathological alterations, known as obesity-related glomerulopathy. Bariatric surgery is the most effective means of inducing and maintaining sustained weight loss. Furthermore, in the context of bariatric-surgery-induced weight loss, a reduction in the proinflammatory state and an improvement in the adipokine profile occur, which may also contribute to the improvement of renal function following bariatric surgery. However, the assessment of renal function in the context of obesity and following marked weight loss is difficult, since the formulas adopted to estimate glomerular function use biomarkers whose production is dependent on muscle mass (creatinine) or adipose tissue mass and inflammation (cystatin-c). Thus, following bariatric surgery, the extent to which reductions in plasma concentrations reflect the actual improvement in renal function is not clear. Despite this limitation, the available literature suggests that in patients with hyperfiltration at baseline, GFR is reduced following bariatric surgery, whereas GFR is increased in patients with decreased GFR at baseline. These findings are also confirmed in the few studies that have used measured rather than estimated GFR. Albuminuria is also decreased following bariatric surgery. Moreover, bariatric surgery seems superior in achieving the remission of albuminuria and early CKD than the best medical treatment. In this article, we discuss the pathophysiology of renal complications in obesity, review the mechanisms through which weight loss induces improvements in renal function, and provide an overview of the renal outcomes following bariatric surgery.

Progressive Additive Benefits of Prehabilitation and Subsequent Bariatric Surgery on Cardiac Autonomic Regulation as Assessed by Means of a Simple Unitary Composite Index: Preliminary Data from an Observational Study.

Obesity is associated with an increased risk of several chronic comorbidities, which may also be determined by dysfunctional autonomic nervous system (ANS). The influence of bariatric surgery (BS) on ANS balance was explored in previous studies, but with high heterogeneity in both the assessment timing and methods employed. In the present observational study, we applied a clinical protocol which considers two subsequent phases. Twenty-nine non-diabetic obese subjects were studied at baseline (T0), after one month of lifestyle modification (prehabilitation) (phase 1-T1), and after eight months following BS (phase 2-T2). ANS regulation was assessed across the three study epochs by means of ANSI, a single composite percent-ranked proxy of autonomic balance, being free of gender and age bias, economical and simple to apply in a clinical setting. The aim of the present study was to investigate the effects of the clinical protocol based on prehabilitation and subsequent BS on the ANS regulation by means of ANSI. Potential intertwined correlations with metabolic parameters were also investigated. Notably, we observed a progressive improvement in ANS control, even by employing ANSI. Moreover, the reduction in the markers of sympathetic overactivity was found to significantly correlate with the amelioration in some metabolic parameters (fasting glucose, insulin levels, and waist circumference), as well as in stress and tiredness perception. In conclusion, this study provides convincing evidence that a unitary proxy of cardiac autonomic regulation (CAR) may reflect the progressive improvement in autonomic regulation following behavioral and surgical interventions in obese patients. Intriguingly, this might contribute to reducing cardiovascular and metabolic risk.

Early long-term L-T3 replacement rescues mitochondria and prevents ischemic cardiac remodelling in rats.

3,5,3'-Levo-triiodothyronine (L-T3) is essential for DNA transcription, mitochondrial biogenesis and respiration, but its circulating levels rapidly decrease after myocardial infarction (MI). The main aim of our study was to test whether an early and sustained normalization of L-T3 serum levels after MI exerts myocardial protective effects through a mitochondrial preservation. Seventy-two hours after MI induced by anterior interventricular artery ligation, rats were infused with synthetic L-T3 (1.2 µg/kg/day) or saline over 4 weeks. Compared to saline, L-T3 infusion restored FT3 serum levels at euthyroid state (3.0 ± 0.2 versus 4.2 ± 0.3 pg/ml), improved left ventricular (LV) ejection fraction (39.5 ± 2.5 versus 65.5 ± 6.9%), preserved LV end-systolic wall thickening in the peri-infarct zone (6.34 ± 3.1 versus 33.7 ± 6.21%) and reduced LV infarct-scar size by approximately 50% (all P < 0.05). Moreover, L-T3 significantly increased angiogenesis and cell survival and enhanced the expression of nuclear-encoded transcription factors involved in these processes. Finally, L-T3 significantly increased the expression of factors involved in mitochondrial DNA transcription and biogenesis, such as hypoxic inducible factor-1α, mitochondrial transcription factor A and peroxisome proliferator activated receptor γ coactivator-1α, in the LV peri-infarct zone. To further explore mechanisms of L-T3 protective effects, we exposed isolated neonatal cardiomyocytes to H(2)O(2) and found that L-T3 rescued mitochondrial biogenesis and function and protected against cell death via a mitoKATP dependent pathway. Early and sustained physiological restoration of circulating L-T3 levels after MI halves infarct scar size and prevents the progression towards heart failure. This beneficial effect is likely due to enhanced capillary formation and mitochondrial protection.

Reply to Landry et al. Findings from Diet Comparison Difficult to Interpret in the Absence of Adherence Assessment. Comment on "Tricò et al. Effects of Low-Carbohydrate versus Mediterranean Diets on Weight Loss, Glucose Metabolism, Insulin Kinetics and ß-Cell Function in Morbidly Obese Individuals. Nutrients 2021, 13, 1345".

We thank Dr. Landry and colleagues [...].

Effects of Low-Carbohydrate versus Mediterranean Diets on Weight Loss, Glucose Metabolism, Insulin Kinetics and ß-Cell Function in Morbidly Obese Individuals.

Low-calorie Mediterranean-style or low-carbohydrate dietary regimens are widely used nutritional strategies against obesity and associated metabolic diseases, including type 2 diabetes. The aim of this study was to compare the effectiveness of a balanced Mediterranean diet with a low-carbohydrate diet on weight loss and glucose homeostasis in morbidly obese individuals at high risk to develop diabetes. Insulin secretion, insulin clearance, and different ß-cell function components were estimated by modeling plasma glucose, insulin and C-peptide profiles during 75-g oral glucose tolerance tests (OGTTs) performed at baseline and after 4 weeks of each dietary intervention. The average weight loss was 5%, being 58% greater in the low-carbohydrate-group than Mediterranean-group. Fasting plasma glucose and glucose tolerance were not affected by the diets. The two dietary regimens proved similarly effective in improving insulin resistance and fasting hyperinsulinemia, while enhancing endogenous insulin clearance and ß-cell glucose sensitivity. In summary, we demonstrated that a low-carbohydrate diet is a successful short-term approach for weight loss in morbidly obese patients and a feasible alternative to the Mediterranean diet for its glucometabolic benefits, including improvements in insulin resistance, insulin clearance and ß-cell function. Further studies are needed to compare the long-term efficacy and safety of the two diets.

NLRP3 at the crossroads between immune/inflammatory responses and enteric neuroplastic remodelling in a mouse model of diet-induced obesity.

BACKGROUND AND PURPOSE: Enteric neurogenic/inflammation contributes to bowel dysmotility in obesity. We examined the role of NLRP3 in colonic neuromuscular dysfunctions in mice with high-fat diet (HFD)-induced obesity. EXPERIMENTAL APPROACH: Wild-type C57BL/6J and NLRP3-KO (Nlrp3-/- ) mice were fed with HFD or standard diet for 8 weeks. The activation of inflammasome pathways in colonic tissues from obese mice was assessed. The role of NLRP3 in in vivo colonic transit and in vitro tachykininergic contractions and substance P distribution was evaluated. The effect of substance P on NLRP3 signalling was tested in cultured cells. KEY RESULTS: HFD mice displayed increased body and epididymal fat weight, cholesterol levels, plasma resistin levels and plasma and colonic IL-1ß levels, colonic inflammasome adaptor protein apoptosis-associated speck-like protein containing caspase-recruitment domain (ASC) and caspase-1 mRNA expression and ASC immunopositivity in macrophages. Colonic tachykininergic contractions were enhanced in HFD mice. HFD NLRP3-/- mice developed lower increase in body and epididymal fat weight, cholesterol levels, systemic and bowel inflammation. In HFD Nlrp3-/- mice, the functional alterations of tachykinergic pathways and faecal output were normalized. In THP-1 cells, substance P promoted IL-1ß release. This effect was inhibited upon incubation with caspase-1 inhibitor or NK1 antagonist and not observed in ASC-/- cells. CONCLUSION AND IMPLICATIONS: In obesity, NLRP3 regulates an interplay between the shaping of enteric immune/inflammatory responses and the activation of substance P/NK1 pathways underlying the onset of colonic dysmotility. Identifying NLRP3 as a therapeutic target for the treatment of bowel symptoms related to obesity.

Impact of Postprandial Hypoglycemia on Weight Loss After Bariatric Surgery.

INTRODUCTION: Postprandial hypoglycemia (PPHG) is a well-known complication after bariatric surgery (BS). However, it is not known whether PPHG affects weight loss after BS. AIMS: To assess the impact of PPHG on weight loss after BS in subjects without and with type 2 diabetes mellitus (T2D). METHODS: Data from 338 subjects who had undergone gastric bypass (RYGB) or sleeve gastrectomy (LSG) and were followed up for at least 2 years were analyzed. At each follow-up visit, the patient's anthropometric and biochemical characteristics were recorded and the Edinburgh Questionnaire was performed to evaluate the presence of PPHG symptoms. RESULTS: Before surgery: younger age and lower BMI predicted PPHG after BS (p = 0.02 and p = 0.0008, respectively). Also, the baseline OGTT indicated that subjects who developed PPHG had an earlier glucose peak and more often had low glucose levels at 2 h compared with the no-PPHG group (p = 0.03 and p = 0.004, respectively). After surgery: Mild-to-moderate PPHG occurred equally after RYGB and LSG (38% vs 25%, p = ns when accounting for confounders), and in T2D who achieved remission and those who did not (29.5% vs 28.6%, ns). At the 2-year follow-up, occurrence of PPHG was independently associated with smaller weight loss (p = 0.0006). CONCLUSIONS: Mild-to-moderate PPHG is a frequent complication after bariatric surgery and results in smaller weight loss after 2 years. Age, baseline BMI, and an earlier glucose peak during OGTT predict PPHG after bariatric surgery.

Obesity prolongs the hospital stay in patients affected by COVID-19, and may impact on SARS-COV-2 shedding.

INTRODUCTION: On the last three months the new SARS-COV-2 coronavirus has created a pandemic, rapidly spreading all around the world. The aim of the study is to investigate whether obesity impacts on COVID-19 morbidity. METHODS: One hundred consecutive patients with COVID-19 pneumonia admitted in our Medical Unit were evaluated. Anthropometric parameters and past medical history were registered. Nasopharyngeal swab samples and biochemical analysis were obtained at admission and during hospital stay. RESULTS: Patients with (OB, 29) and without obesity (N-OB, 71) were similar in age, gender and comorbidities, with the exception of hypertension that was more frequent in OB group. At admission, inflammatory markers were higher in OB than N-OB group. OB group showed a worse pulmonary clinical picture, with lower PaO2 (57 ± 15 vs. 68 ± 14 mmHg, p = 0.042), and SaO2 (88 ± 6 vs. 92 ± 5%, p = 0.049) at admission consequently requiring higher volumes of oxygen (Fi02: 38 ± 15 vs. 29 ± 19%, p = 0.047) and a longer period to achieve oxygen weaning (10 ± 6 vs. 15 ± 7 days, p = 0.03). OB group also had positive swabs for longer time (19 ± 8 vs. 13 ± 7, days, p = 0.002), and required longer hospital stay (21 ± 8 vs. 13 ± 8, days, p = 0.0008). Partial least square regression analysis showed that BMI, age and CRP at admission were related to longer length of hospital stay, and time for negative swab. On the contrary, in this cohort, obesity did not predict higher mortality. CONCLUSIONS: Subjects with obesity affected by COVID-19 require longer hospitalization, more intensive and longer oxygen treatment, and they may have longer SARS-COV-2 shedding.