Biology subjects

Akalestou, E.

Publications and source records attributed to Akalestou, E..

6 recordsLinked to original sources

bioRxiv2026

Vertical Sleeve Gastrectomy inhibits 11βHSD1 and subsequently reduces IL6 secretion in Mice and Humans: A Shared Anti-Inflammatory Mechanism

BackgroundVertical sleeve gastrectomy (VSG) improves glycaemic control in type 2 diabetes (T2D) through mechanisms that extend beyond weight loss. The interaction between glucocorticoid metabolism and inflammation in this context remains unclear. MethodsWe investigated the role of 11{beta}-hydroxysteroid dehydrogenase type 1 (11{beta}HSD1) in mediating the metabolic effects of VSG in humans and mice. Subcutaneous adipose tissue biopsies were collected before and 6 months after VSG. Parallel studies were conducted in lean and high-fat diet-fed mice undergoing VSG or sham surgery, alongside 11{beta}HSD1 knockout models. Glucose tolerance and expression of 11{beta}HSD1 and interleukin-6 (IL6) were assessed. Mechanistic interactions were examined in IL6-treated human hepatocytes. ResultsVSG reduced 11{beta}HSD1 and IL6 expression in human adipose tissue and improved insulin resistance. In lean mice, VSG improved glucose tolerance and downregulated both markers independently of weight loss. 11{beta}HSD1 knockout mice exhibited improved glucose tolerance despite increased adiposity, partially recapitulating the VSG phenotype. Both interventions reduced circulating and tissue IL6 levels. IL6 stimulation increased HSD11B1 expression in hepatocytes. Conclusions11{beta}HSD1 links glucocorticoid metabolism, inflammation, and glucose homeostasis following VSG. Targeting this pathway may offer a strategy to replicate key metabolic benefits of metabolic bariatric surgery.

physiology↗

bioRxiv2024

Effects of SGLT2 Ablation or Inhibition on Corticosterone Secretion in High-Fat-Fed Mice: Exploring a Nexus with Cytokine Levels

Despite recent therapeutic advances, achieving optimal glycaemic control remains a challenge in managing Type 2 Diabetes (T2D). Sodium-glucose co-transporter type 2 (SGLT2) inhibitors have emerged as effective treatments by promoting urinary glucose excretion. However, the full scope of their mechanisms extends beyond glycaemic control. At present, their immunometabolic effects remain elusive. To investigate the effects of SGLT2 inhibition or deletion, we compared the metabolic and immune phenotype between high fat diet-fed control, chronically dapagliflozin-treated mice and total-body SGLT2/Slc5a2 knockout mice. SGLT2 null mice exhibited superior glucose tolerance and insulin sensitivity compared to control or dapagliflozin-treated mice, independent of glycosuria and body weight. Moreover, SGLT2 null mice demonstrated physiological regulation of corticosterone secretion, with lowered morning levels compared to control mice. Systemic cytokine profiling also unveiled significant alterations in inflammatory mediators, particularly interleukin 6 (IL-6). Furthermore, unbiased proteomic analysis demonstrated downregulation of acute-phase proteins and upregulation of glutathione-related proteins, suggesting a role in the modulation of antioxidant responses. Conversely, IL-6 increased SGLT2 expression in kidney HK2 cells suggesting a role for cytokines in the effects of hyperglycemia. Collectively, our study elucidates a potential interplay between SGLT2 activity, immune modulation, and metabolic homeostasis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/590099v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@140041forg.highwire.dtl.DTLVardef@1ceb1b7org.highwire.dtl.DTLVardef@f575b1org.highwire.dtl.DTLVardef@101d5b4_HPS_FORMAT_FIGEXP M_FIG C_FIG Article HighlightsO_LIThe role of Sodium-glucose co-transporter type 2 (SGLT2) in immunity regulation remains elusive, despite extensive research in SGLT2 inhibitors. C_LIO_LIWe sought to discern the effects of SGLT2 inhibition or deletion on metabolic and immune profiles in high-fat-fed mice, focussing on corticosterone regulation and cytokine alterations. C_LIO_LISGLT2 null mice exhibit enhanced insulin sensitivity, alongside physiologically regulated corticosterone levels and significant alterations in inflammatory cytokines, and we identified changes in protein expression suggestive of antioxidant modulation. C_LIO_LIOur findings emphasize the interplay between immune responses and metabolic regulation mediated by SGLT2 activity. C_LI

cell biology↗

bioRxiv2020

Bariatric surgery normalizes circulating glucocorticoid levels and lowers glucocorticoid action tissue-selectively in mice

BackgroundGlucocorticoids produced by the adrenal cortex are essential for the maintenance of metabolic homeostasis. Glucocorticoid activation is catalyzed by 11{beta}-hydroxysteroid dehydrogenase 1 (11{beta}-HSD1) and signalling is achieved through the glucocorticoid receptor (GR), a ligand-dependent transcription factor. Excess glucocorticoids are associated with insulin resistance and hyperglycaemia. A small number of studies have investigated the effects of bariatric surgery, a gastrointestinal procedure known to improve insulin sensitivity, on glucocorticoid metabolism, but the hypothesised mechanism is assumed to be via weight loss. AimTo investigate the effect of bariatric surgery on glucocorticoid metabolism in lean and obese mice. MethodsLean mice and HFD mice underwent Vertical Sleeve Gastrectomy (VSG) or sham surgery. Glucose and insulin tolerance tests were performed at four and ten weeks post operatively and circulating corticosterone was measured. Liver and adipose tissues were harvested from fed mice and 11{beta}-HSD1 and GR levels were measured by quantitative RT-PCR or Western (immuno-) blotting, respectively. ResultsVSG did not cause excess weight loss in lean mice when compared to sham operated mice. However, both lean and HFD VSG mice displayed significantly improved glucose clearance and insulin sensitivity. Remarkably, VSG restores physiological corticosterone production in HFD mice and reduces11{beta}-HSD1 levels at four and ten weeks post-surgery. Additionally, lean mice displayed significantly lowered mRNA levels of 11{beta}-HSD1 in subcutaneous adipose tissue and GR in liver. ConclusionsBariatric surgery improves insulin sensitivity and reduces glucocorticoid activation at tissular level, under physiological and pathophysiological (obesity) conditions, irrespective of weight loss. The reduction of glucocorticoid exposure may represent an additional contribution to the health benefits of bariatric surgery. These findings point towards a physiologically relevant gut-adrenal axis.

physiology↗

bioRxiv2020

Intravital imaging of islet Ca2+ dynamics reveals enhanced β cell connectivity after bariatric surgery in mice

Bariatric surgery improves both insulin sensitivity and secretion in type 2 diabetes. However, these changes are difficult to monitor directly and independently. In particular, the degree and the time course over which surgery impacts {beta} cell function, versus mass, have been difficult to establish. In this study, we investigated the effect of bariatric surgery on {beta} cell function in vivo by imaging Ca2+ dynamics prospectively and at the single cell level in islets engrafted into the anterior eye chamber. Islets expressing GCaMP6f selectively in the {beta} cell were transplanted into obese male hyperglycaemic mice that were then subjected to either vertical sleeve gastrectomy (VSG) or sham surgery. Imaged in vivo in the eye, VSG improved coordinated Ca2+ activity, with 90% of islets observed exhibiting enhanced Ca2+ wave activity ten weeks post-surgery, while islet wave activity in sham animals fell to zero discernible coordinated islet Ca2+ activity at the same time point. Correspondingly, VSG mice displayed significantly improved glucose tolerance and insulin secretion. Circulating fasting levels of GLP-1 were also increased after surgery, potentially contributing to improved {beta} cell performance. We thus demonstrate that bariatric surgery leads to time-dependent increases in individual {beta} cell function and intra-islet connectivity, together driving increased insulin secretion and diabetes remission, in a weight-loss independent fashion. Significance StatementUsed widely to treat obesity, bariatric surgery also relieves the symptoms of type 2 diabetes. The mechanisms involved in diabetes remission are still contested, with increased insulin sensitivity and elevated insulin secretion from pancreatic {beta} cells both implicated. Whilst the speed of remission - usually within a few days - argues for improvements in {beta} cell function rather than increases in mass, a direct demonstration of changes at the level of individual {beta} cells or islets has been elusive. Here, we combine vertical sleeve gastrectomy with intravital imaging of islets engrafted into the mouse anterior eye chamber to reveal that surgery causes a time-dependent improvement in glucose-induced Ca2+ dynamics and {beta} cell - {beta} cell connectivity, both of which likely underlie increased insulin release.

cell biology↗

bioRxiv2019

Vertical sleeve gastrectomy lowers kidney SGLT2 expression in the mouse

BackgroundBariatric surgery has been established to improve insulin sensitivity and glucose clearance, but also increases insulin and glucagon secretion. Each of the above effects have also been observed following treatment with sodium glucose co-transporter 2 (SGLT2) inhibitors.\n\nAimTo determine whether there is an effect of bariatric surgery (Vertical Sleeve Gastrectomy; VSG) on renal SGLT2 expression in mice.\n\nMethodsEighteen lean mice underwent VSG (n=8) or sham (n=9) surgery. Glucose tolerance tests with or without treatment with the SGLT2 inhibitor dapagliflozin were performed four weeks post operatively, in order to assess if pharmacological SGLT2 inhibition has the same euglycemic effects after bariatric surgery. Kidneys were harvested from fed mice and SGLT2 expression was analysed using Quantitative reverse-transcription PCR and immunofluorescence.\n\nResultsVSG mice displayed significantly improved glucose tolerance (AUC=103{+/-}6.8; AUC=66.6{+/-}2.9 in control and VSG mice, respectively; p<0.001), despite an absence of significant weight loss when compared to sham operated mice (p=0.37, Mann-Whitney test). Treatment of sham-operated mice with dapagliflozin (10 mg/kg) improved glucose tolerance. In contrast, dapagliflozin did not further improve glucose tolerance in VSG-operated mice. Moreover, qRT-PCR and immunofluorescence analysis on mouse kidneys demonstrated a significant lowering of SGLT2 expression at both the mRNA (n=7, p<0.0001) and protein (n=5, p=0.0007) levels four weeks after VSG.\n\nConclusionsVertical sleeve gastrectomy in lean animals causes a significant inhibition of SGLT2 expression in the kidney cortex. These findings are in line with our previous results on the effects of Duodenal Jejunal Bypass in lean rats, and point towards a physiologically-relevant gut-kidney axis. SGLT2 inhibition may thus be an important mechanism through which bariatric surgery improves glucose tolerance in man.

physiology↗

bioRxiv2019

Interpreting, forecasting, and controlling feeding behaviour using high-resolution data

Better understanding of feeding behaviour will be vital in reducing obesity and metabolic syndrome, but we lack a standard model that captures the complexity of feeding behaviour. We construct an accurate stochastic model of rodent feeding at the bout level in order to perform quantitative behavioural analysis. Analysing the different effects on feeding behaviour of PYY3-36, lithium chloride, GLP-1 and leptin shows the precise behavioural changes caused by each anorectic agent. Our analysis demonstrates that the changes in feeding behaviour evoked by the anorectic agents investigated not mimic satiety. In the ad libitum fed state during the light period, meal initiation is governed by complete stomach emptying, whereas in all other conditions there is a graduated response. We show how robust homeostatic control of feeding thwarts attempts to reduce food intake, and how this might be overcome. In silico experiments suggest that introducing a minimum intermeal interval or modulating gastric emptying can be as effective as anorectic drug administration.

animal behavior and cognition↗