Intragastric botulinum toxin injection directly regulates ghrelin expression via reactive oxygen species and NF-κB signaling.

AIMS: One effective clinical strategy to combat obesity is intragastric botulinum toxin (BTX) injection, which increases gastric emptying time and regulates appetite. However, it remains unknown if and how BTX affects ghrelin levels. MATERIALS AND METHODS: An obese animal model was established by feeding male mice with high-fat diet (HFD). BTX was administered by subserosal injection in the antrum via an upper midline laparotomy. The mice were monitored in terms of body weight and blood biochemical parameters. Glucose utility and insulin sensitivity were measured by intraperitoneal glucose and insulin tolerance tests. Additionally, stomach and liver were histologically examined after BTX treatment. AGS gastric adenocarcinoma cells were used to investigate the molecular mechanism by which BTX affects ghrelin expression. KEY FINDINGS: In HFD-fed mice, BTX injection significantly decreased both food intake and body weight over a 3-week monitoring period. Moreover, HFD-induced hyperglycemia, hyperinsulinemia, dyslipidemia and obesity readouts were improved after BTX injection. Importantly, mice also exhibited decreased plasma and gastric ghrelin levels after BTX injection. In cultured AGS cells, BTX significantly increased reactive oxygen species (ROS) levels and activated nuclear factor-κB (NF-κB), which led to decreased ghrelin expression. Pre-treatment with inhibitors of either ROS or NF-κB reversed the effects of BTX on ghrelin expression in the cultured cells. SIGNIFICANCE: BTX decreases ghrelin expression in HFD-fed animals and in AGS cells through an ROS/NF-κB-dependent pathway. This mechanism may contribute to decreased food intake in obese subjects receiving intragastric BTX injection for weight control.

Transcription repression of estrogen receptor alpha by ghrelin/Gq/11/YAP signaling in granulosa cells promotes polycystic ovary syndrome.

Polycystic ovarian syndrome (PCOS) is a prevalent endocrinological disorder affected by ghrelin. This study aimed to investigate the molecular mechanisms underlying the effects of ghrelin on PCOS manifestations in mice and to assess the therapeutic potential of ghrelin. Female C57BL/6 mice were subcutaneously injected with 6 mg/100 g dehydroepiandrosterone (DHEA) for 20 days to induce PCOS. Alterations in reproductive cycles, ovarian morphology, serum sex hormone levels, and related signaling markers were examined. Furthermore, ghrelin-induced effects on granulosa cells and the role of ghrelin/Gq/11/ Yes-associated protein (YAP) signaling were studied by silencing Gαq/11 or YAP using si-RNAs. Finally, we evaluated the therapeutic potential of anti-ghrelin antibodies in DHEA-induced PCOS mice. DHEA administration led to significant PCOS-associated changes including weight gain, disrupted estrous cycles, ovarian morphological alterations, and hormonal imbalances in mice, with elevated Gαq/11 and acylated ghrelin expression, which was also noted in PCOS patients. However, treatment with anti-ghrelin antibodies effectively managed DHEA-induced damage in PCOS mice. In vitro, ghrelin exposure resulted in granulosa cell injury and modulated estrogen receptors alpha (ERα) and YAP protein levels, whereas silencing YAP and Gαq/11 reversed ghrelin-induced detrimental effects and up-regulated ERα expression. This study revealed that DHEA-induced PCOS traits in mice could be improved by anti-ghrelin antibodies, with the ghrelin/Gq/11/YAP signaling pathway identified as a crucial mediator in granulosa cells, affecting ERα transcription to regulate PCOS. These findings suggest a potential therapeutic strategy for the treatment of PCOS.

In vitro pharmacological characterization of growth hormone secretagogue receptor ligands using the dynamic mass redistribution and calcium mobilization assays.

Ghrelin modulates several biological functions via selective activation of the growth hormone secretagogue receptor (GHSR). GHSR agonists may be useful for the treatment of anorexia and cachexia, while antagonists and inverse agonists may represent new drugs for the treatment of metabolic and substance use disorders. Thus, the identification and pharmacodynamic characterization of new GHSR ligands is of high interest. In the present work the label-free dynamic mass redistribution (DMR) assay has been used to evaluate the pharmacological activity of a panel of GHSR ligands. This includes the endogenous peptides ghrelin, desacyl-ghrelin and LEAP2(1-14). Among synthetic compounds, the agonists anamorelin and HM01, the antagonists HM04 and YIL-781, and the inverse agonist PF-05190457 have been tested, together with HM03, R011, and H1498 from patent literature. The DMR results have been compared to those obtained in parallel experiments with the calcium mobilization assay. Ghrelin, anamorelin, HM01, and HM03 behaved as potent full GHSR agonists. YIL-781 behaved as a partial GHSR agonist and R011 as antagonist in both the assays. LEAP2(1-14) resulted a GHSR inverse agonist in DMR but not in calcium mobilization assay. PF-05190457, HM04, and H1498 behaved as GHSR inverse agonists in DMR experiments, while they acted as antagonists in calcium mobilization studies. In conclusion, this study provided a systematic pharmacodynamic characterization of several GHSR ligands in two different pharmacological assays. It demonstrated that the DMR assay can be successfully used particularly to discriminate between antagonists and inverse agonists. This study may be useful for the selection of the most appropriate compounds to be used in future studies.

FTO variant is associated with changes in BMI, ghrelin, and brain function following bariatric surgery.

BACKGROUNDA polymorphism in the fat mass and obesity-associated gene (FTO) is linked to enhanced neural sensitivity to food cues and attenuated ghrelin suppression. Risk allele carriers regain more weight than noncarriers after bariatric surgery. It remains unclear how FTO variation affects brain function and ghrelin following surgery.METHODSResting-state functional magnetic resonance imaging and cue-reactivity functional magnetic resonance imaging with high-/low-caloric food cues were performed before surgery and at 1, 6, and 12 months after surgery to examine brain function in 16 carriers with 1 copy of the rs9939609 A allele (AT) and 26 noncarriers (TT). Behavioral assessments up to 5 years after surgery were also conducted.RESULTSThe AT group relative to the TT group had smaller BMI loss at 12-60 months after surgery and lower resting-state activity in posterior cingulate cortex following laparoscopic sleeve gastrectomy (group-by-time interaction effects). Meanwhile, the AT group relative to the TT group showed greater food cue responses in dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC), and insula (group effects). There were negative associations of weight loss with ghrelin and greater activation in DLPFC, DMPFC and insula in the AT but not the TT group.CONCLUSIONThese findings indicate that FTO variation is associated with the evolution of ghrelin signaling and brain function after bariatric surgery, which might hinder weight loss.TRIAL REGISTRATIONChinese Clinical Trial Registry Center, ChiCTR-OOB-15006346.FUNDINGThis work was supported by the National Natural Science Foundation of China (grant nos. 82172023, 82202252, 82302292); National Key R&D Program of China (no. 2022YFC3500603); Natural Science Basic Research Program of Shaanxi (grant nos. 2022JC-44, 2022JQ-622, 2023-JC-QN-0922, 2023-ZDLSF-07); Fundamental Research Funds for the Central Universities (grant nos. ZYTS23188, XJSJ23190, XJS221201, QTZX23093); and the Intramural Research Program of the National Institute on Alcoholism and Alcohol Abuse (grant no. Y1AA3009).

Ghrelin induced by ultraviolet B exposure promotes the restoration of diabetic cutaneous wound healing.

BACKGROUND: Diabetes mellitus (DM) presents impediment to wound healing. While ultraviolet B (UVB) exposure showed therapeutic potential in various skin conditions, its capacity to mediate diabetic wound healing remains unclear. To investigate the efficacy of UVB on wound healing and its underlying basis. MATERIALS AND METHODS: Male C57BL/6 mice were subjected to the high-fat diet followed by streptozotocin administration to establish the diabetic model. Upon confirmation of diabetes, full-thickness wounds were inflicted and the treatment group received UVB radiation at 50 mJ/cm2 for 5 min every alternate day for 2 weeks. Wound healing rate was then assessed, accompanied by evaluations of blood glucose, lipid profiles, CD31 expression, and concentrations of ghrelin and leptin. Concurrently, in vitro studies were executed to evaluate the protective role of ghrelin on human umbilical vein endothelial cells (HUVEC) under high glucose (HG) conditions. RESULTS: Post UVB exposure, there was a marked acceleration in wound healing in DM mice without alterations in hyperglycemia and lipid profiles. Compared to non-UVB-exposed mice, the UVB group showed enhanced angiogenesis manifested by a surge in CD31 expression. This trend appeared to be in harmony with the elevated ghrelin levels. In vitro experiments indicated that ghrelin significantly enhanced the migratory pace and angiogenic properties of HUVEC under HG-induced stress, potentially mediated by an upregulation in vascular endothelial growth factor expression. CONCLUSION: UVB exposure bolstered wound healing in diabetic mice, plausibly mediated through augmented angiogenesis induced by ghrelin secretion. Such findings underscore the vast potential of UVB-induced ghrelin in therapeutic strategies targeting diabetic wound healing.

Impact of different hormones on the regulation of nitric oxide in diabetes.

Polymetabolic syndrome achieved pandemic proportions and dramatically influenced public health systems functioning worldwide. Chronic vascular complications are the major contributors to increased morbidity, disability, and mortality rates in diabetes patients. Nitric oxide (NO) is among the most important vascular bed function regulators. However, NO homeostasis is significantly deranged in pathological conditions. Additionally, different hormones directly or indirectly affect NO production and activity and subsequently act on vascular physiology. In this paper, we summarize the recent literature data related to the effects of insulin, estradiol, insulin-like growth factor-1, ghrelin, angiotensin II and irisin on the NO regulation in physiological and diabetes circumstances.

Calorie restriction activates a gastric Notch-FOXO1 pathway to expand ghrelin cells.

Calorie restriction increases lifespan. Among the tissue-specific protective effects of calorie restriction, the impact on the gastrointestinal tract remains unclear. We report increased numbers of chromogranin A-positive (+), including orexigenic ghrelin+ cells, in the stomach of calorie-restricted mice. This effect was accompanied by increased Notch target Hes1 and Notch ligand Jag1 and was reversed by blocking Notch with DAPT, a gamma-secretase inhibitor. Primary cultures and genetically modified reporter mice show that increased endocrine cell abundance is due to altered Lgr5+ stem and Neurog3+ endocrine progenitor cell proliferation. Different from the intestine, calorie restriction decreased gastric Lgr5+ stem cells, while increasing a FOXO1/Neurog3+ subpopulation of endocrine progenitors in a Notch-dependent manner. Further, activation of FOXO1 was sufficient to promote endocrine cell differentiation independent of Notch. The Notch inhibitor PF-03084014 or ghrelin receptor antagonist GHRP-6 reversed the phenotypic effects of calorie restriction in mice. Tirzepatide additionally expanded ghrelin+ cells in mice. In summary, calorie restriction promotes Notch-dependent, FOXO1-regulated gastric endocrine cell differentiation.

Ghrelin Improves Glucolipotoxicity-Induced Pancreatic ß-Cellular Dysfunction and Apoptosis by Inhibiting Endoplasmic Reticulum Stress-Induced IRE1/JNK Pathway.

BACKGROUND: Glucose and fatty acid overload-induced glucolipid toxicity of pancreatic ß-cells is associated with the development of diabetes. Endoplasmic reticulum stress (ERS) plays an essential role in this process. Ghrelin, a peptide secreted by the pancreas, negatively correlates with oxidative stress. The study aimed to investigate ghrelin's role in glycolipid-induced ß-cell dysfunction and its possible mechanism. METHODS: Mouse insulinoma ß-cell, NIT-1 cells, were stimulated with high fat and high glucose to induce glucolipid toxicity. High fat and high glucose-induced NIT-1 cells were treated with acylated ghrelin (AG) or [d-Lys3]-growth hormone releasing peptide (GHRP)-6. Flow cytometry and Cell Counting Kit-8 (CCK-8) assay were performed to assess apoptosis and cell viability. The protein expression related to apoptosis, inositol-requiring kinase 1 (IRE1)/c-Jun N-terminal kinase (JNK) signaling, and ERS were investigated using western blot. Enzyme-linked immunosorbent assay (ELISA) was adopted to examine insulin's synthesis and secretion levels. RESULTS: Ghrelin treatment improved cell viability while inhibiting cell glucolipotoxicity-induced NIT-1 cell apoptosis. Ghrelin can promote the synthesis and secretion of insulin in NIT-1 cells. Mechanistically, ghrelin attenuates ERS and inhibits the IRE1/JNK signaling pathway in NIT-1 cells induced by glucolipotoxicity. CONCLUSION: Ghrelin improves ß-cellular dysfunction induced by glucolipotoxicity by inhibiting the IRE1/JNK pathway induced by ERS. It could be an effective treatment for ß-cellular dysfunction.

Chronic Social Defeat Stress Increases Brain Permeability to Ghrelin in Male Mice.

Ghrelin is a stomach-derived hormone that increases feeding and is elevated in response to chronic psychosocial stressors. The effects of ghrelin on feeding are mediated by the binding of ghrelin to the growth hormone secretagogue receptor (GHSR), a receptor located in hypothalamic and extrahypothalamic regions important for regulating food intake and metabolic rate. The ability of ghrelin to enter the brain, however, seems to be restricted to circumventricular organs like the median eminence and the brainstem area postrema, whereas ghrelin does not readily enter other GHSR-expressing regions like the ventral tegmental area (VTA). Interestingly, social stressors result in increased blood-brain barrier permeability, and this could therefore facilitate the entry of ghrelin into the brain. To investigate this, we exposed mice to social defeat stress for 21 d and then peripherally injected a Cy5-labelled biologically active ghrelin analog. The results demonstrate that chronically stressed mice exhibit higher Cy5-ghrelin fluorescence in several hypothalamic regions in addition to the ARC, including the hippocampus and midbrain. Furthermore, Cy5-ghrelin injections resulted in increased FOS expression in regions associated with the reward system in chronically stressed mice. Further histologic analyses identified a reduction in the branching of hypothalamic astrocytes in the ARC-median eminence junction, suggesting increased blood-brain barrier permeability. These data support the hypothesis that during metabolically challenging conditions like chronic stress, ghrelin may be more able to cross the blood-brain barrier and diffuse throughout the brain to target GHSR-expressing brain regions away from circumventricular organs.

GHSR in a Subset of GABA Neurons Controls Food Deprivation-Induced Hyperphagia in Male Mice.

The growth hormone secretagogue receptor (GHSR), primarily known as the receptor for the hunger hormone ghrelin, potently controls food intake, yet the specific Ghsr-expressing cells mediating the orexigenic effects of this receptor remain incompletely characterized. Since Ghsr is expressed in gamma-aminobutyric acid (GABA)-producing neurons, we sought to investigate whether the selective expression of Ghsr in a subset of GABA neurons is sufficient to mediate GHSR's effects on feeding. First, we crossed mice that express a tamoxifen-dependent Cre recombinase in the subset of GABA neurons that express glutamic acid decarboxylase 2 (Gad2) enzyme (Gad2-CreER mice) with reporter mice, and found that ghrelin mainly targets a subset of Gad2-expressing neurons located in the hypothalamic arcuate nucleus (ARH) and that is predominantly segregated from Agouti-related protein (AgRP)-expressing neurons. Analysis of various single-cell RNA-sequencing datasets further corroborated that the primary subset of cells coexpressing Gad2 and Ghsr in the mouse brain are non-AgRP ARH neurons. Next, we crossed Gad2-CreER mice with reactivable GHSR-deficient mice to generate mice expressing Ghsr only in Gad2-expressing neurons (Gad2-GHSR mice). We found that ghrelin treatment induced the expression of the marker of transcriptional activation c-Fos in the ARH of Gad2-GHSR mice, yet failed to induce food intake. In contrast, food deprivation-induced refeeding was higher in Gad2-GHSR mice than in GHSR-deficient mice and similar to wild-type mice, suggesting that ghrelin-independent roles of GHSR in a subset of GABA neurons is sufficient for eliciting full compensatory hyperphagia in mice.

Ghrelin alleviates intestinal ischemia-reperfusion injury by activating the GHSR-1α/Sirt1/FOXO1 pathway.

Ischemia-reperfusion (IR) injury is primarily characterized by the restoration of blood flow perfusion and oxygen supply to ischemic tissue and organs, but it paradoxically leads to tissue injury aggravation. IR injury is a challenging pathophysiological process that is difficult to avoid clinically and frequently occurs during organ transplantation, surgery, shock resuscitation, and other processes. The major causes of IR injury include increased levels of free radicals, calcium overload, oxidative stress, and excessive inflammatory response. Ghrelin is a newly discovered brain-intestinal peptide with anti-inflammatory and antiapoptotic effects that improve blood supply. The role and mechanism of ghrelin in intestinal ischemia-reperfusion (IIR) injury remain unclear. We hypothesized that ghrelin could attenuate IIR-induced oxidative stress and apoptosis. To investigate this, we established IIR by using a non-invasive arterial clip to clamp the root of the superior mesenteric artery (SMA) in mice. Ghrelin was injected intraperitoneally at a dose of 50 µg/kg 20 min before IIR surgery, and [D-Lys3]-GHRP-6 was injected intraperitoneally at a dose of 12 nmol/kg 20 min before ghrelin injection. We mimicked the IIR process with hypoxia-reoxygenation (HR) in Caco-2 cells, which are similar to intestinal epithelial cells in structure and biochemistry. Our results showed that ghrelin inhibited IIR/HR-induced oxidative stress and apoptosis by activating GHSR-1α. Moreover, it was found that ghrelin activated the GHSR-1α/Sirt1/FOXO1 signaling pathway. We further inhibited Sirt1 and found that Sirt1 was critical for ghrelin-mediated mitigation of IIR/HR injury. Overall, our data suggest that pretreatment with ghrelin reduces oxidative stress and apoptosis to attenuate IIR/HR injury by binding with GHSR-1α to further activate Sirt1.

Beyond Restrictive: Sleeve Gastrectomy to Single Anastomosis Duodeno-Ileal Bypass with Sleeve Gastrectomy as a Spectrum of One Single Procedure.

INTRODUCTION: Single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) is a restrictive/hypoabsorptive procedure recommended for patients with obesity class 3. For safety reasons, SADI-S can be split into a two-step procedure by performing a sleeve gastrectomy (SG) first. This stepwise approach also provides an unprecedented opportunity to disentangle the weight loss mechanisms triggered by each component. The objective was to compare weight trajectories and post-prandial endocrine and metabolic responses of patients with obesity class 3 submitted to SADI-S or SG as the first step of SADI-S. METHODS: Subjects submitted to SADI-S (n = 7) or SG (n = 7) at a tertiary referral public academic hospital underwent anthropometric evaluation and a liquid mixed meal tolerance test (MMTT) pre-operatively and at 3, 6, and 12 months post-operatively. RESULTS: Anthropometric parameters, as well as metabolic and micronutrient profiles, were not significantly different between groups, neither before nor after surgery. There were no significant differences in fasting or post-prandial glucose, insulin, C-peptide, ghrelin, insulin secretion rate, and insulin clearance during the MMTT between subjects submitted to SADI-S and SG. There was no lost to follow-up. CONCLUSIONS: The restrictive component seems to be the main driver for weight loss and metabolic adaptations observed during the first 12 months after SADI-S, given that the weight trajectories and metabolic profiles do not differ from SG. These data provide support for surgeons' choice of a two-step SADI-S without jeopardizing the weight loss outcomes.

Central neural mechanisms of cancer cachexia.

PURPOSE OF REVIEW: Cachexia is a devasting syndrome which impacts a large number of patients with cancer. This review aims to provide a comprehensive overview of the central mechanisms of cancer cachexia. In particular, it focuses on the role of the central nervous system (CNS), the melanocortin system, circulating hormones and molecules which are produced by and act on the CNS and the psychological symptoms of cancer cachexia. RECENT FINDINGS: A growing body of evidence suggests that a central mechanism of action underpins this multi-system disorder. Recent research has focused on the role of neuroinflammation that drives the sickness behaviour seen in cancer cachexia, with emphasis on the role of the hypothalamus. Melanocortin receptor antagonists are showing promise in preclinical studies. There are also new pharmacological developments to overcome the short half-life of ghrelin. GDF-15 has been identified as a core target and trials of compounds that interfere with its signalling or its central receptor are underway. SUMMARY: Understanding the central mechanisms of cancer cachexia is pivotal for enhancing treatment outcomes in patients. While emerging pharmacological interventions targeting these pathways have shown promise, further research is essential.

Exploring the Role of Metabolic Hormones in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive loss of motor neurons. Emerging evidence suggests a potential link between metabolic dysregulation and ALS pathogenesis. This study aimed to investigate the relationship between metabolic hormones and disease progression in ALS patients. A cross-sectional study was conducted involving 44 ALS patients recruited from a tertiary care center. Serum levels of insulin, total amylin, C-peptide, active ghrelin, GIP (gastric inhibitory peptide), GLP-1 active (glucagon-like peptide-1), glucagon, PYY (peptide YY), PP (pancreatic polypeptide), leptin, interleukin-6, MCP-1 (monocyte chemoattractant protein-1), and TNFα (tumor necrosis factor alpha) were measured, and correlations with ALSFRS-R, evolution scores, and biomarkers were analyzed using Spearman correlation coefficients. Subgroup analyses based on ALS subtypes, progression pattern of disease, and disease progression rate patterns were performed. Significant correlations were observed between metabolic hormones and ALS evolution scores. Insulin and amylin exhibited strong correlations with disease progression and clinical functional outcomes, with insulin showing particularly robust associations. Other hormones such as C-peptide, leptin, and GLP-1 also showed correlations with ALS progression and functional status. Subgroup analyses revealed differences in hormone levels based on sex and disease evolution patterns, with male patients showing higher amylin and glucagon levels. ALS patients with slower disease progression exhibited elevated levels of amylin and insulin. Our findings suggest a potential role for metabolic hormones in modulating ALS progression and functional outcomes. Further research is needed to elucidate the underlying mechanisms and explore the therapeutic implications of targeting metabolic pathways in ALS management.

Human milk-specific fat components enhance the secretion of ghrelin by MGN3-1 cells.

Triacylglycerols (TAGs) are a major fat component in human milk. Since gastric lipase produces 1,2-diacylglycerol from TAGs, we focused on the bioactivity of human milk-derived diacylglycerols in stomach cells. Ghrelin is produced in the stomach and acts as an important regulator of growth hormone secretion and energy homeostasis. In this study, we showed that 1-oleoyl-2-palmitoylglycerol (OP) increased ghrelin secretion, whereas 1,3-dioleoyl-2-palmitoylglycerol (OPO), a major component of human milk TAGs, did not increase ghrelin secretion in the ghrelin-secreting cell line, MGN3-1. Therefore, diacylglycerol OP may directly contribute to the regulation of ghrelin secretion. We also found that 2-palmitoylglycerol and 1- and 2-oleoylglycerol increased ghrelin secretion. Finally, we demonstrated that intracellular cAMP levels and preproghrelin and ghrelin O-acyl transferase expression levels were enhanced by OP treatment in MGN3-1 cells. This may represent an example of a novel mother-infant interaction mediated by fat components derived from human breast milk.

Gut hormones and appetite regulation.

PURPOSE OF REVIEW: Various gut hormones interact with the brain through delicate communication, thereby influencing appetite and subsequent changes in body weight. This review summarizes the effects of gut hormones on appetite, with a focus on recent research. RECENT FINDINGS: Ghrelin is known as an orexigenic hormone, whereas glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), postprandial peptide YY (PYY), and oxyntomodulin (OXM) are known as anorexigenic hormones. Recent human studies have revealed that gut hormones act differently in various systems, including adipose tissue, beyond appetite and energy intake, and even involve in high-order thinking. Environmental factors including meal schedule, food contents and quality, type of exercise, and sleep deprivation also play a role in the influence of gut hormone on appetite, weight change, and obesity. Recently published studies have shown that retatrutide, a triple-agonist of GLP-1, GIP, and glucagon receptor, and orforglipron, a GLP-1 receptor partial agonist, are effective in weight loss and improving various metabolic parameters associated with obesity. SUMMARY: Various gut hormones influence appetite, and several drugs targeting these receptors have been reported to exert positive effects on weight loss in humans. Given that diverse dietary and environmental factors affect the actions of gut hormones and appetite, there is a need for integrated and largescale long-term studies in this field.

Gut motility and hormone changes after bariatric procedures.

PURPOSE OF REVIEW: Metabolic and bariatric surgery (MBS) and endoscopic bariatric therapies (EBT) are being increasingly utilized for the management of obesity. They work through multiple mechanisms, including restriction, malabsorption, and changes in the gastrointestinal hormonal and motility. RECENT FINDINGS: Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (LSG) cause decrease in leptin, increase in GLP-1 and PYY, and variable changes in ghrelin (generally thought to decrease). RYGB and LSG lead to rapid gastric emptying, increase in small bowel motility, and possible decrease in colonic motility. Endoscopic sleeve gastroplasty (ESG) causes decrease in leptin and increase in GLP-1, ghrelin, and PYY; and delayed gastric motility. SUMMARY: Understanding mechanisms of action for MBS and EBT is critical for optimal care of patients and will help in further refinement of these interventions.

New Lessons from the gut: Studies of the role of gut peptides in weight loss and diabetes resolution after gastric bypass and sleeve gastrectomy.

It has been known since 2005 that the secretion of several gut hormones changes radically after gastric bypass operations and, although more moderately, after sleeve gastrectomy but not after gastric banding. It has therefore been speculated that increased secretion of particularly GLP-1 and Peptide YY (PYY), which both inhibit appetite and food intake, may be involved in the weight loss effects of surgery and for improvements in glucose tolerance. Experiments involving inhibition of hormone secretion with somatostatin, blockade of their actions with antagonists, or blockade of hormone formation/activation support this notion. However, differences between results of bypass and sleeve operations indicate that distinct mechanisms may also be involved. Although the reductions in ghrelin secretion after sleeve gastrectomy would seem to provide an obvious explanation, experiments with restoration of ghrelin levels pointed towards effects on insulin secretion and glucose tolerance rather than on food intake. It seems clear that changes in GLP-1 secretion are important for insulin secretion after bypass and appear to be responsible for postbariatric hypoglycemia in glucose-tolerant individuals; however, with time the improvements in insulin sensitivity, which in turn are secondary to the weight loss, may be more important. Changes in bile acid metabolism do not seem to be of particular importance in humans.

Effects of 3.5-GHz radiofrequency radiation on energy-regulatory hormone levels in the blood and adipose tissue.

In recent years exposure of living beings to radiofrequency radiation (RFR) emitted from wireless equipment has increased. In this study, we investigated the effects of 3.5-GHz RFR on hormones that regulate energy metabolism in the body. Twenty-eight rats were divided into four groups: healthy sham (n = 7), healthy RFR (n = 7), diabetic sham (n = 7), and diabetic RFR (n = 7). Over a month, each group spent 2 h/day in a Plexiglas carousel. The rats in the experimental group were exposed to RFR, but the sham groups were not. At the end of the experiment, blood and adipose tissues were collected from euthanized rats. Total antioxidant, total oxidant, hydrogen peroxide, ghrelin, nesfatin-1, and irisin were determined. Insulin expression in pancreatic tissues was examined by immunohistochemical analysis. Whole body specific absorption rate was 37 mW/kg. For the parameters analyzed in blood and fat, the estimated effect size varied within the ranges of 0.215-0.929 and 0.503-0.839, respectively. The blood and adipose nesfatin-1 (p = 0.002), blood and pancreatic insulin are decreased, (p = 0.001), gherelin (p = 0.020), irisin (p = 0.020), and blood glucose (p = 0.040) are increased in healthy and diabetic rats exposed to RFR. While nesfatin-1 are negatively correlated with oxidative stress, hyperglycemia and insulin, ghrelin and irisin are positively correlated with oxidative stress and hyperglycemia. Thus, RFR may have deleterious effects on energy metabolism, particularly in the presence of diabetes.

Leptin and energy balance: exploring Leptin's role in the regulation of energy intake and energy expenditure.

Leptin is a tonic appetite-regulating hormone, which is integral for the long-term regulation of energy balance. The current evidence suggests that the typical orexigenic or anorexigenic response of many of these appetite-regulating hormones, most notably ghrelin and cholecystokinin (CCK), require leptin to function whereas glucagon-like peptide-1 (GLP-1) is required for leptin to function, and these responses are altered when leptin injection or gene therapy is administered in combination with these same hormones or respective agonists. The appetite-regulatory pathway is complex, thus peptide tyrosine tyrosine (PYY), brain-derived neurotrophic factor (BDNF), orexin-A (OXA), and amylin also maintain ties to leptin, however these are less well understood. While reviews to date have focused on the existing relationships between leptin and the various neuropeptide modulators of appetite within the central nervous system (CNS) or it's role in thermogenesis, no review paper has synthesised the information regarding the interactions between appetite-regulating hormones and how leptin as a chronic regulator of energy balance can influence the acute appetite-regulatory response. Current evidence suggests that potential relationships exist between leptin and the circulating peripheral appetite hormones ghrelin, GLP-1, CCK, OXA and amylin to exhibit either synergistic or opposing effects on appetite inhibition. Though more research is warranted, leptin appears to be integral in both energy intake and energy expenditure. More specifically, functional leptin receptors appear to play an essential role in these processes.