Elevated Leptin Levels Research Articles

Mid-late gestation leptin infusion induces placental mitochondrial and endoplasmic reticulum unfolded protein responses in a mouse model of preeclampsia

IntroductionPreeclamptic patients, both lean and obese, present with elevated leptin levels which are associated with the development of maternal endothelial dysfunction and adverse fetal outcomes, such as growth restriction, leading to low birth weight. Recent studies in pregnant mice demonstrate that mid-late gestation leptin infusion induces clinical characteristics of preeclampsia, including elevated maternal blood pressure, maternal endothelial dysfunction and fetal growth restriction. However, whether leptin triggers placental stress responses that contribute to adverse fetal outcomes as in preeclampsia is unknown. MethodsIn the current study we measured the expression of proteins involved in the endoplasmic reticulum (UPRer) and mitochondrial (UPRmt) unfolded protein responses in placentas of wild-type sham normal pregnant and leptin-infused preeclamptic mice. ResultsThe data show that mid-late gestation leptin infusion induced activation of indices of placental UPRer and UPRmt, while reducing placental repair mechanisms to UPRmt in preeclamptic mice. Mid-late gestation infusion with leptin upregulated markers of placental oxidative stress, reduced the placental expression levels of mitochondrial electron transport chain complexes I and II and increased the expression of placental endothelin-1 (ET-1) in preeclamptic mice. The leptin-induced activation of several placental UPRmt markers as well as ET-1 levels correlated with fetal growth restriction and impaired maternal endothelial function in preeclamptic mice. DiscussionCollectively, these data indicate that elevated levels of leptin in mid-late pregnancy in mice promote placental stress responses, akin to those in pregnant women with preeclampsia.

Hippocampal Leptin Resistance and Cognitive Decline: Mechanisms, Therapeutic Strategies and Clinical Implications

Background: Leptin, an adipokine essential for regulating energy balance, exerts important effects on brain function, notably within the hippocampus, a region integral to learning and memory. Leptin resistance, characterized by diminished responsiveness to elevated leptin levels, disrupts hippocampal function and exacerbates both obesity and cognitive impairments. Scope: This review critically examines how leptin resistance impairs hippocampal synaptic plasticity processes, specifically affecting long-term potentiation (LTP) and long-term depression (LTD), which are crucial for cognitive performance. Findings: Recent research highlights that leptin resistance disrupts N-methyl-D-aspartate (NMDA) receptor dynamics and hippocampal structure, leading to deficits in spatial learning and memory. Additionally, high-fat diets (HFDs), which contribute to leptin resistance, further deteriorate hippocampal function. Potential therapeutic strategies, including leptin sensitizers, show promise in mitigating brain disorders associated with leptin resistance. Complementary interventions such as caloric restriction and physical exercise also enhance leptin sensitivity and offer potential benefits to alleviating cognitive impairments. Aims of the review: This review synthesizes recent findings on the molecular pathways underlying leptin resistance and its impact on synaptic transmission and plasticity in the hippocampus. By identifying potential therapeutic targets, this work aims to provide an integrated approach for addressing cognitive deficits in obesity, ultimately improving the quality of life for affected individuals.

Lactobacillus gasseri BNR17 and Limosilactobacillus fermentum ABF21069 Ameliorate High Sucrose-Induced Obesity and Fatty Liver via Exopolysaccharide Production and β-oxidation.

Obesity and metabolic dysfunction-associated fatty liver disease (MAFLD) are prevalent metabolic disorders with substantial global health implications that are often inadequately addressed by current treatments and may have side effects. Probiotics have emerged as promising therapeutic agents owing to their beneficial effects on gut health and metabolism. This study investigated the synergistic effects of a probiotic combination of BNR17 and ABF21069 on obesity and MAFLD in C57BL/6 mice fed a high-sucrose diet. The probiotic combination significantly reduced body weight and fat accumulation compared with the high-sucrose diet. It also alleviated elevated serum leptin levels induced by a high-sucrose diet. Histological analysis revealed a significant reduction in white adipose tissue and fatty liver in the mice treated with the probiotic combination. Furthermore, increased expression of genes related to β-oxidation, thermogenesis, and lipolysis suggested enhanced metabolic activity. The probiotic groups, particularly the BNR17 group, showed an increase in fecal exopolysaccharides, along with a tendency toward a lower expression of intestinal sugar transport genes, indicating reduced sugar absorption. Additionally, inflammatory markers in the liver tissue exhibited lower expression in the ABF21069 group than in the HSD group. Despite each strain in the combination group having distinct characteristics and functions, their combined effect demonstrated synergy in mitigating obesity and MAFLD, likely through the modulation of fecal exopolysaccharides content and improvement in lipid metabolism. These findings underscore the potential of probiotic supplementation as a promising assistant therapy for managing obesity and MAFLD and provide valuable insights into its therapeutic mechanisms in metabolic disorders.

Impact of BMI on childhood growth, pubertal timing, and bone maturation: A comprehensive review and clinical implications

Introduction: Childhood obesity and undernutrition significantly affect growth patterns, pubertal timing, and bone maturation, leading to long-term health implications. Materials and Methods: A comprehensive literature review was conducted using databases such as PubMed, Google Scholar, and Scopus. Twenty-four studies, including a total of 40,732 patients, were analyzed from two tables examining the impact of BMI, growth patterns, pubertal timing, and bone maturation. Results: Children with high BMI exhibit accelerated linear growth during early childhood, that may be driven by elevated leptin levels, which stimulate growth before puberty. Despite early growth advantages, these children experience reduced height gain during adolescence due to advanced bone maturation and earlier closure of growth plates. High BMI is strongly linked to early puberty, especially in girls, as increased adipose tissue raises leptin levels, triggering early pubertal onset. Boys, however, show variability in pubertal timing, with severe obesity sometimes delaying puberty. In contrast, children with low BMI or undernutrition demonstrate delayed linear growth and delayed puberty. Nutritional deficits lead to reduced growth velocity, delayed pubertal onset, and extended pubertal periods due to a lack of adipose tissue and hormonal deficiencies in leptin and kisspeptin. Nutritional rehabilitation promotes catch-up growth, allowing for extended growth potential by delaying growth plate closure. However, full recovery may not occur in cases of prolonged or severe undernutrition. Advanced bone age in high BMI children shortens the pubertal growth spurt, while delayed bone maturation in undernourished children offers a prolonged period for potential growth, contingent on timely nutritional support. Conclusion: Timely interventions for childhood obesity and undernutrition are critical to improving growth outcomes and preventing long-term developmental delays. Early identification, nutritional rehabilitation, and lifestyle modifications can help optimize growth and pubertal development by addressing both advanced and delayed growth trajectories.

The Role of Adiponectin and Leptin in Fibro-Calcific Aortic Valve Disease: A Systematic Review and Meta-Analysis.

Fibro-calcific aortic valve disease (FCAVD) is a progressive disorder characterized by the thickening and calcification of the aortic valve, eventually leading to aortic stenosis. Adiponectin and leptin, known for their anti-inflammatory and proinflammatory properties, respectively, have been implicated in cardiovascular diseases, but their associations with FCAVD are controversial. This meta-analysis aims to evaluate the relationships between adiponectin and leptin levels and FCAVD, particularly in patients with severe aortic stenosis (AS). A systematic search was conducted across the PubMed, Scopus, and Web of Science databases to identify studies on adiponectin and leptin levels in FCAVD. The methodological quality of each study was assessed using the Newcastle-Ottawa Scale. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) were calculated, and publication bias was evaluated using Egger's test and funnel plots. Out of 191 articles identified, 10 studies involving 2360 patients (989 with FCAVD and 1371 controls) were included. The analysis suggested trends in the associations of lower adiponectin levels (SMD = -0.143, 95% CI: -0.344, 0.057, p = 0.161) and higher leptin levels (SMD = 0.175, 95% CI: -0.045, 0.395, p = 0.119) with FCAVD. The association remained a trend for low adiponectin but showed a significant correlation with high leptin in severe AS patients (SMD = 0.29, 95% CI: 0.036, 0.543, p = 0.025). This meta-analysis indicates a potential association between elevated leptin levels and severe aortic stenosis, while the relationship with adiponectin levels remains inconclusive. These findings highlight the need for further and dedicated research to clarify the roles of these adipokines in the pathogenesis of FCAVD and their potential roles as biomarkers for disease progression.

Cognitive Function during and after Pregnancy and One-Year Postpartum in Type 1 Diabetes: A Longitudinal Study.

This study aims to compare the cognitive function of women with T1DM during and after pregnancy, as well as one year post-delivery. Additionally, it aims to investigate the impacts of leptin and body mass index on cognitive function. A prospective longitudinal cohort study was conducted involving 64 pregnant women with T1DM. Cognitive function was assessed using a cognitive assessment battery during the first trimester, immediately after delivery, and one year postpartum for the final assessment. This program evaluates a wide range of cognitive abilities and provides a comprehensive cognitive well-being score (high-moderate-low), identifying strengths and weaknesses in reasoning, memory, attention, coordination, and perception. The average age of the participants was 30.9 years, with a mean diabetes duration of 14.9 years. Pregnant women with a BMI of 30 kg/m2 or higher faced an increased risk of reduced cognitive function, memory, and reasoning. Additionally, mothers with lower overall cognitive function and memory levels had significantly higher concentrations of leptin in their blood. Cognitive functions-particularly reasoning and attention-are adversely affected in women with T1DM during pregnancy and shortly after delivery. Elevated BMI and leptin levels can be linked to worse cognitive outcomes in this population.

Abstract Mo135: Correlation of Leptin Resistance With Attenuation of Cardiac Vagal Activation in Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) is one of the most prominent diseases impacting individuals worldwide. A leading cause of death for T2DM patients is MI-related ventricular arrhythmia, which is associated with cardiac vagal nerve dysfunction. As T2DM patients exhibit leptin resistance, and leptin signaling has been implicated in heart rate regulation, we set out to characterize changes in cardiac vagal ganglionic neuron activity during development of T2DM and determine leptin signaling’s role in cardiac vagal dysfunction. In this study, T2DM was induced in Sprague-Dawley rats by feeding a high fat diet (HFD) plus a low dose streptozotocin injection. To characterize cardiac dysfunction, we measured arterial baroreflex sensitivity and found that 12 wks post-T2DM induction, rats experienced a diminished baroreflex response (gain max 0.62 ± 0.04 bpm/mm Hg T2DM vs. 2.21 ± 0.14 bpm/mm Hg sham). To determine if the change in baroreflex sensitivity is due to altered cardiac vagal nerve activity, we measured nAChR currents and cell excitability in intracardiac ganglion (ICG) neurons and found that T2DM rat cardiac vagal neurons exhibited reduced nAChR current density (213.9 ± 25.6 pA/pF T2DM vs. 375.5 ± 44.3 pA/pF sham) and action potential frequency (9.1 ± 0.5 spikes/s T2DM vs. 19.9 ± 1.4 spikes/s sham). Furthermore, acetylcholine release from cardiac vagal nerve terminals was attenuated in T2DM rats (0.4 ± 0.16 nM T2DM vs. 1.07 ± 0.12 nM sham). To determine the role of leptin signaling in the decrease of cardiac vagal nerve activity, we examined leptin and leptin receptor levels in ICG at 4, 8, and 12 wks post-T2DM induction. Western blots revealed elevated ICG leptin levels at 4, 8, and 12 wks post-T2DM induction (8.9 ± 0.7, 9.1 ± 1.3, and 11.7 ± 2.1 times sham level, respectively). qRT-PCR revealed reduced levels of leptin receptor transcript at 12 wks post-T2DM induction (48 ± 12% of sham). A reduction of leptin receptor protein in ICG neurons at 12 wks post-T2DM induction was observed using IF microscopy. These data demonstrate that T2DM reduces cardiac vagal nerve activity resulting in diminished control of cardiac functions such as the baroreflex. Furthermore, leptin resistance may play a role in this diminished cardiac function through reductions in leptin receptor levels.

Tanycytic transcytosis inhibition disrupts energy balance, glucose homeostasis and cognitive function in male mice

ObjectivesIn Western society, high-caloric diets rich in fats and sugars have fueled the obesity epidemic and its related disorders. Disruption of the body-brain communication, crucial for maintaining glucose and energy homeostasis, arises from both obesogenic and genetic factors, leading to metabolic disorders. Here, we investigate the role of hypothalamic tanycyte shuttles between the pituitary portal blood and the third ventricle cerebrospinal fluid in regulating energy balance. MethodsWe inhibited vesicle-associated membrane proteins (VAMP1-3)-mediated release in tanycytes by expressing the botulinum neurotoxin type B light chain (BoNT/B) in a Cre-dependent manner in tanycytes. This was achieved by injecting either TAT-Cre in the third ventricle or an AAV1/2 expressing Cre under the control of the tanycyte-specific promoter iodothyronine deiodinase 2 into the lateral ventricle of adult male mice. ResultsIn male mice fed a standard diet, targeted expression of BoNT/B in adult tanycytes blocks leptin transport into the mediobasal hypothalamus and results in normal-weight central obesity, including increased food intake, abdominal fat deposition, and elevated leptin levels but no marked change in body weight. Furthermore, BoNT/B expression in adult tanycytes promotes fatty acid storage, leading to glucose intolerance and insulin resistance. Notably, these metabolic disturbances occur despite a compensatory increase in insulin secretion, observed both in response to exogenous glucose boluses in vivo and in isolated pancreatic islets. Intriguingly, these metabolic alterations are associated with impaired spatial memory in BoNT/B-expressing mice. ConclusionsThese findings underscore the central role of tanycytes in brain-periphery communication and highlight their potential implication in the age-related development of type 2 diabetes and cognitive decline. Our tanycytic BoNT/B mouse model provides a robust platform for studying how these conditions progress over time, from prediabetic states to full-blown metabolic and cognitive disorders, and the mechanistic contribution of tanycytes to their development. The recognition of the impact of tanycytic transcytosis on hormone transport opens new avenues for developing targeted therapies that could address both metabolic disorders and their associated cognitive comorbidities, which often emerge or worsen with advancing age.

The interplay between white adipose tissue, adipokines, and structural gray matter changes

AbstractThe growing global obesity issue emphasizes the importance of understanding its health implications. Previous research has identified consistent alterations in gray matter (GM) volume in connection with obesity. Given the various implications of distinct fat compartments and the potential role of adipose tissue‐derived adipokines in brain health, a more detailed investigation of adiposity is required. This study investigates a sample of 65 males with varying body mass indices to explore the relationship between various fat compartments, adipokine levels, and volumetric GM variations, aiming to provide a deeper understanding of the interplay between adiposity, brain structure, and metabolic signals. Whole‐body magnetic resonance imaging (MRI) was used to assess total, visceral, and subcutaneous adipose tissue, while MR spectroscopy was performed to capture liver fat content. For the assessment of adipokine levels leptin and adiponectin concentrations were measured, and structural brain images underwent cortical and subcortical segmentation for GM volume and thickness. A predictive modeling approach with leave‐one‐out cross‐validation was used to predict body composition metrics and adipokine levels based on structural GM data. Our investigation revealed diminished GM volume and thickness correlated with elevated leptin levels in areas crucial for appetite regulation, decision‐making, and cognitive control, including the anterior insula, orbitofrontal cortex, and anterior cingulate cortex. These findings suggest a potential adverse impact of heightened leptin concentrations on brain health and eating habits. Contrary to expectations, our investigation found no significant relationship between GM volume and any of the measured fat compartments. This result prompts the need for further research to elucidate the relationship between obesity, adipokines, and brain structure.

The effects of leptin on human cytotrophoblast invasion are gestational age and dose-dependent.

Leptin and its receptors are expressed by the human placenta throughout gestation, yet the role of leptin in early human placental development is not well characterized. Leptin is overexpressed in the placentas from preeclamptic (PE) pregnancies. PE can result from the impaired invasion of fetal placental cells, cytotrophoblasts (CTBs), into the maternal decidua. We hypothesized that elevated leptin levels would impair human CTB invasion. The effects of leptin on the invasion of human CTBs were evaluated in three cell models, HTR-8/SVneo cells, primary CTBs, and placental villous explants using invasion assays. Further, leptin receptor expression was characterized in all three cell models using RT-PCR. Further phosphokinase assays were performed in HTR-8/SVneo cells to determine signaling pathways involved in CTB invasion in response to differential leptin doses. We found that, prior to 8 weeks gestation, leptin promoted CTB invasion in the explant model. After 11 weeks gestation in explants, primary CTBs and in HTR-8/SVneo cells, leptin promoted invasion at moderate but not at high concentrations. Further, leptin receptor characterization revealed that leptin receptor expression did not vary over gestation, however, STAT, PI3K and MAPK pathways showed different signaling in response to varied leptin doses. These data suggest that the excess placental leptin observed in PE may cause impaired CTB invasion as a second-trimester defect. Leptin's differential effect on trophoblast invasion may explain the role of hyperleptinemia in preeclampsia pathogenesis.

Body fat and circulating leptin levels in the captive short-beaked echidna (Tachyglossus aculeatus)

It is possible that the reproductive strategy of the short-beaked echidna is related to seasonal changes in fat deposition and energy availability, regulated by seasonal changes in endocrine function. We predicted that circulating leptin levels would be directly proportional to adiposity during most of the year, but that a change in this relationship would occur during the pre-breeding season to allow increased fat deposition. To test this hypothesis, we made use of a captive colony of echidnas to describe and quantify changes in fat distribution and the adipostatic hormone leptin. First we assessed seasonal changes in circulating leptin levels, body mass and adiposity for three male and three female adult echidnas maintained on a standard diet. Second, we explored the relationship between circulating leptin levels and increased caloric intake for an additional five adult female echidnas that were provided with supplemented nutrition. Third we visualised fat distribution in male and female adult echidnas using magnetic resonance imaging (MRI) before and after the breeding season, to determine where fat is deposited in this species. For echidnas maintained on the standard diet, there were no seasonal changes in body mass, body fat or plasma leptin levels. However, female echidnas provided with supplemented nutrition had significantly elevated plasma leptin levels during the breeding season, compared to the pre-and post- breeding periods. MRI showed substantial subcutaneous fat depots extending dorso-laterally from the base of the skull to the base of the tail, in both sexes. Pre-breeding season, both sexes had considerable fat deposition in the pelvic/rump region, whilst the female echidna accumulated most fat in the abdominal region. This study shows that male and female echidnas accumulate body fat in the pelvic/rump and the abdominal regions, respectively and that circulating leptin may promote fattening in female echidnas during the breeding season by means of leptin resistance. However, further research is required to evaluate the precise relationship between seasonal changes in leptin and adiposity.

Reoxygenation Mitigates Intermittent Hypoxia-Induced Systemic Inflammation and Gut Microbiota Dysbiosis in High-Fat Diet-Induced Obese Rats.

Obstructive sleep apnea (OSA) is a prevalent sleep breathing disorder characterized by intermittent hypoxia (IH), with continuous positive airway pressure (CPAP) as its standard treatment. However, the effects of intermittent hypoxia/reoxygenation (IH/R) on weight regulation in obesity and its underlying mechanism remain unclear. Gut microbiota has gained attention for its strong association with various diseases. This study aims to explore the combined influence of IH and obesity on gut microbiota and to investigate the impact of reoxygenation on IH-induced alterations. Diet-induced obese (DIO) rats were created by 8-week high-fat diet (HFD) feeding and randomly assigned into three groups (n=15 per group): normoxia (NM), IH (6% O2, 30 cycles/h, 8 h/day, 4 weeks), or hypoxia/reoxygenation (HR, 2-week IH followed by 2-week reoxygenation) management. After modeling and exposure, body weight and biochemical indicators were measured, and fecal samples were collected for 16S rRNA sequencing. DIO rats in the IH group showed increased weight gain (p=0.0016) and elevated systemic inflammation, including IL-6 (p=0.0070) and leptin (p=0.0004). Moreover, IH rats exhibited greater microbial diversity (p<0.0167), and significant alterations in the microbial structure (p=0.014), notably the order Clostridiales, accompanied by an upregulation of bile acid metabolism predicted pathway (p=0.0043). Reoxygenation not only improved IH-exacerbated obesity, systemic inflammation, leptin resistance, and sympathetic activation, but also showed the potential to restore IH-induced microbial alterations. Elevated leptin levels were associated with Ruminococcaceae (p=0.0008) and Clostridiales (p=0.0019), while body weight was linked to Blautia producta (p=0.0377). Additionally, the abundance of Lactobacillus was negatively correlated with leptin levels (p=0.0006) and weight (p=0.0339). IH leads to gut dysbiosis and metabolic disorders, while reoxygenation therapy demonstrates a potentially protective effect by restoring gut homeostasis and mitigating inflammation. It highlights the potential benefits of CPAP in reducing metabolic risk among obese patients with OSA.

Alterations in food preference and stress reactivity in mice with a knockout of MeCP2 in POMC neurons

Methyl-CpG binding protein 2 (MeCP2) is an epigenetic factor associated with the neurodevelopmental disorders Rett Syndrome and MECP2 duplication syndrome. Previous studies have demonstrated that knocking out MeCP2 globally in the central nervous system leads to an overweight phenotype and hyperphagia, however it is not clear if the hyperphagia is the result of an increased motivation to obtain food reward or enhancements in food preference. Here, we show that mice deficient in MeCP2 specifically in pro-opiomelanocortin (POMC) neurons have an increased preference for high fat diet but do not have a greater motivation to obtain food reward, relative to wildtype (WT) littermate controls. We also demonstrate that POMC-Cre MeCP2 knockout (KO) mice have increased body weight after long-term high fat diet exposure as well as elevated plasma leptin and corticosterone (CORT) levels compared to wildtype mice. Given that our POMC-Cre MeCP2 KO mice have elevated CORT, we wanted to determine if our KO mice also respond differentially to early life stress such as maternal separation stress compared to WT controls. Collectively, our data suggest that POMC-specific loss-of-function Mecp2 mutations leads to dissociable effects on the rewarding/motivational properties of food as well as changes to hormones associated with body weight homeostasis and stress and could underlie differential behavioral responses to early life stress. NIGMS 1SC1GM144190-01 (ESN), Texas Woman's University internal funds. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract 2184: A high-fat diet accelerates early-stage murine pancreatic carcinogenesis by influencing, in part, mesenteric adipose tissue metabolism

Abstract Increased adiposity represents a modifiable risk factor of pancreatic cancer. Multiple preclinical studies have shown that a high-fat and high-sugar diets on the acceleration of pancreatic carcinogenesis, in the context of obesity. However, the impact of diets resembling the omega-6 to omega-3 fatty acid (FA) ratio in a Western-style diet, remains unclear. Furthermore, the role of the mesenteric adipose tissue (MAT) in pancreatic carcinogenesis is poorly characterized. Thus, we aimed to determine the impact of a high-fat diet with a ratio of 9 parts omega-6 FA to each omega-3 FA, on early stages of pancreatic carcinogenesis in a genetically engineered LSL- KrasLSL-G12D; Ptf1aCre/+ (KC) model of pancreatic cancer, with an emphasis on evaluating the contribution of the MAT within the pancreatic microenvironment. For this purpose, cohorts of male and female KC mice (6-8 males and females per diet group) were randomly assigned to either a control diet (CD) group (9:1 of omega-6 FAs to omega-3 FAs) or a high-fat diet (HFD) group (9:1 of omega-6 FAs to omega-3 FAs) and fed their respective diets until three months of age. After eight weeks on their diets, HFD-fed mice had significantly increased body weight, fat mass, and elevated serum leptin levels. Furthermore, HFD-fed mice had increased acinar-to-ductal metaplasia, associated with increased PCNA expression, ERK and STAT3 phosphorylation and elevated pro-tumorigenic immune cell expression compared to CD-fed mice. Although no significant differences in MAT weight or adipocyte size were observed after 8 weeks between the groups, metabolomics analysis of the MAT revealed that HFD-fed mice had significant upregulation of many key metabolites linked to proliferative and inflammatory pathways. For instance, HFD-fed female KC mice had significant differences in α-linolenic acid metabolism and the biosynthesis of unsaturated fatty acids, while male mice had significant differences in arginine biosynthesis, amino acid metabolism, linoleic acid metabolism, and α-linolenic acid metabolism. HFD-fed female mice had a significant increase in α-linolenic acid and linoleic acid in MAT, concurrent with a reduction in inosine 5-monophosphate and α-tocopherol compared to female CD-fed mice. HFD-fed male mice displayed a more pronounced difference in metabolites, including an increase in α-linolenic acid, linoleic acid, malic acid, glutamine, isoleucine, and several other amino acids, with a concurrent reduction in lauric acid and palmitoleic acid compared to male CD-fed mice. In summary, a HFD accelerates pancreatic carcinogenesis through multifaceted mechanisms, including effects on the tumor and surrounding adipose depots. A HFD increases affects MAT metabolism in a sex-dependent manner, that might ultimately promote early-stage progression of pancreatic carcinogenesis. Citation Format: Aya Ead, Joanna Wirkus, Gerardo G. Mackenzie. A high-fat diet accelerates early-stage murine pancreatic carcinogenesis by influencing, in part, mesenteric adipose tissue metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2184.

The Level of Leptin in the Blood of Patients with Chronic Obstructive Pulmonary Disease and its Correlations with the Levels of Clinical, Functional and Anamnestic Indicators

Leptin, a hormone produced by white adipose tissue and recognised as an inflammatory biomarker, has an undefined role in the progression of chronic obstructive pulmonary disease (COPD). Objective — to evaluate the leptin level and its correlations with the levels of clinical, functional and anamnestic indicators in COPD patients. Materials and methods. This study employed a case-control design involving 42 patients experiencing acute exacerbation of COPD and 20 control subjects. The patients were examined according to the standard protocol. Additionally, the examination included ultrasonic scanning of the abdominal cavity, evaluation of the serum leptin level, scoring of the anxiety and depression and quality of life. Results and discussion. It was revealed that hyperleptinemia in the patients with acute exacerbation of COPD occurred significantly more frequently than in the healthy persons ((73.8 ± 6.8) vs (40.0 ± 11.0) %; р &lt; 0.05). Besides, the COPD patients manifested increased leptin levels much more frequently than normal levels ((73.8 ± 6.8) vs (26.2 ± 6.8) %; р &lt; 0.01). Hyperleptinemia was found to co-occur with severe COPD cases belonging to E clinical group ((51.6 ± 9.0) vs (18.2 ± 11.6) % in group with normal leptin level; р &lt; 0.05). Kendall correlation analysis established that elevated circulating leptin levels were associated with an increased body mass index (τ = 0.3; р = 0.02), female gender (τ = 0.3; р = 0.01), non-smoking history (τ = – 0.2; р = 0.03), stronger manifestation of such symptoms as shortness of breath (τ = 0.3; р=0.01), disturbed home (τ = 0.3; р = 0.002) and out-of-home activities (τ = 0.3; р = 0.02) and lack of energy (τ = 0.3; р = 0.01). It also correlated with increased severity of pulmonary insufficiency (τ = 0.3; р = 0.003) and decreased forced vital capacity (τ = – 0.2; р = 0.04), elevated systolic blood pressure (τ = 0.2; р = 0.02), elevated cholesterol (τ = 0.3; р = 0.01) and β-lipoproteins levels (τ = 0.2; р = 0.04), pronounced depression (τ = 0.3; р = 0.002) and lowered quality of life (τ = 0.3; р = 0.01). Сonclusions. COPD patients with elevated leptin levels manifest not only with an increased body weight, but also with arterial hypertension, disturbed lipid metabolism, more pronounced pulmonary insufficiency, depressive disorders and lowered life quality with more severe subjective respiratory symptoms.

The Prevalence, Risk Factors and Cardiometabolic Complications of Obesity in Childhood Survivors of Acute Lymphoblastic Leukemia.

Prevalence, risk factors and metabolic complications of overweight/obesity (OW/OB) are not well described in the childhood survivors of acute lymphoblastic leukemia (ALL). Longitudinal changes in body mass index-z score (BMIz) from diagnosis to the last follow-up visit after the end of treatment were evaluated in 73 children at first complete remission. Of them, 40 were tested for adipokine profiles at visit. The mean BMIz increased gradually from diagnosis (0.07 ± 1.68) to the end of dexamethasone containing reinduction therapy (0.70 ± 1.48, P:0.007), followed by a fall at the end of treatment (0.15 ± 1.24) and a rise again at visit (0.40 ± 1.23, P:0.007). OW/OB percentage of 15% at diagnosis, increased to 35% at visit (p < 0.05). Post-treatment OW/OB in survivors was related with being OW/OB at diagnosis (OR 5.4, 95% CI [0.94-31.7]; P = 0.02) and after dexamethasone containing reinduction therapy (OR 5.1, 95% CI [1.1-21.4]; P = 0.05), but not with age at diagnosis, gender, treatment intensity and cranial irradiation. Metabolic syndrome (MetS) was more prevalent in survivors (13%) than in Turkish children (2%). As compared with controls, survivors had higher leptin level (8.1 ± 8.6 vs 3.2 ± 2.2ng/ml, P = 0.01) and leptin/adiponectin ratio (2.1 ± 3.5 vs 0.6 ± 0.5, P = 0.03). Leptin/adiponectin ratio was correlated with HOMA-IR (r: 0.57, P = 0.001). The prevalence of OW/OB and MetS are elevated in the childhood survivors of ALL. Post-treatment OW/OB in survivors is related with OW/OB at diagnosis and dexamethasone containing therapy. Elevated leptin level and leptin: adiponectin ratio may serve as an early sign of metabolic derangement increasing the risk for early cardiovascular disease.

POMC-specific knockdown of MeCP2 leads to adverse phenotypes in mice chronically exposed to high fat diet

Methyl-CpG binding protein 2 (MeCP2) is an epigenetic factor associated with the neurodevelopmental disorders Rett Syndrome and MECP2 duplication syndrome. Previous studies have demonstrated that knocking out MeCP2 globally in the central nervous system leads to an obese phenotype and hyperphagia, however it is not clear if the hyperphagia is the result of an increased preference for food reward or due to an increase in motivation to obtain food reward. We show that mice deficient in MeCP2 specifically in pro-opiomelanocortin (POMC) neurons have an increased preference for high fat diet as measured by conditioned place preference but do not have a greater motivation to obtain food reward using a progressive ratio task, relative to wildtype littermate controls. We also demonstrate that POMC-Cre MeCP2 knockout (KO) mice have increased body weight after long-term high fat diet exposure as well as elevated plasma leptin and corticosterone levels compared to wildtype mice. Taken together, these results are the first to show that POMC-specific loss-of-function Mecp2 mutations leads to dissociable effects on the rewarding/motivational properties of food as well as changes to hormones associated with body weight homeostasis and stress.

Subclinical Hypothyroidism in Patients with Obesity and Metabolic Syndrome: A Narrative Review.

The literature on the connection between obesity, metabolic syndrome, and subclinical hypothyroidism is critically analyzed in this narrative review. These conditions are frequently observed among adult populations and various studies and meta-analyses have assessed their association. The prevalence of subclinical hypothyroidism in obese individuals is higher than in non-obese subjects and this trend is more pronounced in unhealthy obesity phenotypes. However, the diagnosis and treatment of subclinical hypothyroidism can be difficult in obese patients. Exaggerated body fat is linked to thyroid hypoechogenicity as evident through ultrasonography and euthyroid obese people have greater TSH, FT3, and FT3/FT4 ratios than non-obese individuals in a euthyroid condition. Moreover, a reduced expression of the TSH receptor and altered function of deiodinases has been found in the adipose tissue of obese patients. Current data do not support the necessity of a pharmacological correction of the isolated hyperthyrotropinemia in euthyroid obese patients because treatment with thyroid hormone does not significantly improve weight loss and the increase in serum TSH can be reversible after hypocaloric diet or bariatric surgery. On the other hand, obesity is linked to elevated leptin levels. Inflammation can raise the risk of Hashimoto thyroiditis, which increases the likelihood that obese patients will experience overt or subclinical hypothyroidism. Both metabolic syndrome and subclinical hypothyroidism are associated with atherosclerosis, liver and kidney disease. Hence, the association of these two illnesses may potentiate the adverse effects noted in each of them. Subclinical hypothyroidism should be identified in patients with obesity and treated with appropriate doses of L-thyroxine according to the lean body mass and body weight. Randomized controlled trials are necessary to verify whether treatment of thyroid deficiency could counteract the expected risks.

Does leptin cause proximal gastric cancer in the obese? The role of serum leptin in the etiology of proximal gastric cancer.

The aim of the present study was to determine the correlation between obesity, serum levels of leptin and proximal gastric cancer. Sixty-four gastric cancer patients operated on with curative intent were included in the study. We determined the correlation between the preoperative serum levels of leptin and the tumor's location. Serum leptin levels were correlated significantly with the proximal third location (p=0.04), gastric outlet obstructing tumors (p<0.0001), CRP levels (p=0.03) and BMI (p<0.0001). Patients with high serum levels of leptin had significantly more intestinal types of gastric cancer (p=0.033) and better differentiation (p=0.009). The linear regression model determined the proximal tumor location (beta: 0.467; p=0.045), BMI (beta: 0.657; p=0.001), high preoperative serum albumin (beta: 0.563; p=0.016) and the presence of pyloric stenosis (beta: 0.525; p=0.006) as related significantly to serum leptin levels. The Cox proportional hazard model identified age (HR: 0.003; 95 % CI: 0-0.794; p=0.041), preoperative serum levels of leptin (HR: 0.125; 95 % CI: 0.018-0.887; p=0.037) and the number of extracted LNs (HR: 0.001; 95 % CI: 0-0.677; p=0.038) as independent prognostic factors. Serum levels of leptin were significantly elevated in patients with proximal gastric cancer, suggesting that the leptin's effect might be due to its systemic secretion. This might explain the higher incidence of proximal gastric cancer in obese patients. Elevated serum leptin levels were an independent prognostic factor.

Leptin-Mediated Induction of IL-6 Expression in Hofbauer Cells Contributes to Preeclampsia Pathogenesis.

Leptin plays a crucial role in regulating energy homoeostasis, neuroendocrine function, metabolism, and immune and inflammatory responses. The adipose tissue is a main source of leptin, but during pregnancy, leptin is also secreted primarily by the placenta. Circulating leptin levels peak during the second trimester of human pregnancy and fall after labor. Several studies indicated a strong association between elevated placental leptin levels and preeclampsia (PE) pathogenesis and elevated serum interleukin-6 (IL-6) levels in PE patients. Therefore, we hypothesized that a local increase in placental leptin production induces IL-6 production in Hofbauer cells (HBCs) to contribute to PE-associated inflammation. We first investigated HBCs-specific IL-6 and leptin receptor (LEPR) expression and compared their immunoreactivity in PE vs. gestational age-matched control placentas. Subsequently, we examined the in vitro regulation of IL-6 as well as the phosphorylation levels of intracellular signaling proteins STAT3, STAT5, NF-κB, and ERK1/2 by increasing recombinant human leptin concentrations (10 to 1000 ng/mL) in primary cultured HBCs. Lastly, HBC cultures were incubated with leptin ± specific inhibitors of STAT3 or STAT5, or p65 NF-κB or ERK1/2 MAPK signaling cascades to determine relevant cascade(s) involved in leptin-mediated IL-6 regulation. Immunohistochemistry revealed ~three- and ~five-fold increases in IL-6 and LEPR expression, respectively, in HBCs from PE placentas. In vitro analysis indicated that leptin treatment in HBCs stimulate IL-6 in a concentration-dependent manner both at the transcriptional and secretory levels (p < 0.05). Moreover, leptin-treated HBC cultures displayed significantly increased phosphorylation levels of STAT5, p65 NF-κB, and ERK1/2 MAPK and pre-incubation of HBCs with a specific ERK1/2 MAPK inhibitor blocked leptin-induced IL-6 expression. Our in situ results show that HBCs contribute to the pathogenesis of PE by elevating IL-6 expression, and in vitro results indicate that induction of IL-6 expression in HBCs is primarily leptin-mediated. While HBCs display an anti-inflammatory phenotype in normal placentas, elevated levels of leptin may transform HBCs into a pro-inflammatory phenotype by activating ERK1/2 MAPK to augment IL-6 expression.